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CHEMBL5051832 | nan | 38 | Patent Bioactivity Data | Inhibitors of eya3-protein tyrosine phosphatase in dna damage repair signaling of pulmonary arterial hypertension | nan | nan | US-20210130312-A1 | nan | 2021 | nan | nan | nan | nan | PATENT | nan | nan | nan | nan | CHEMBL_32 | 2023-01-26 |
CHEMBL4303081 | nan | 52 | SARS-CoV-2 Screening Data 2020-21 | nan | nan | nan | nan | nan | nan | nan | nan | nan | nan | DATASET | nan | nan | nan | nan | CHEMBL_27 | 2020-05-18 |
CHEMBL2331186 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Five new phenolic glycosides from Hedyotis scandens. | 23333151 | 10.1016/j.bmcl.2012.12.077 | nan | Wang GC, Li T, Deng FY, Li YL, Ye WC. | 2013 | 23 | 5 | 1379 | 1382 | PUBLICATION | Five new phenolic glycosides, hedyotosides A-E (1-5), including a new cyanogenic glycoside (1), along with 10 known compounds (6-15) were isolated from the whole plants of Hedyotis scandens. The structures of compounds 1-5 were established by extensive spectroscopic analyses and acid hydrolysis. All the isolated compounds were evaluated for their in vitro antiviral activity against respiratory syncytial virus (RSV) with cytopathic effect (CPE) reduction assay. Compounds 6 and 15 showed anti-RSV effects with IC(50) values of 20 and 25 μg/mL, respectively. | 15 | 1 | 15 | CHEMBL_17 | 2013-08-29 |
CHEMBL2375307 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and identification of β-aryloxyquinoline based diversely fluorine substituted N-aryl quinolone derivatives as a new class of antimicrobial, antituberculosis and antioxidant agents. | 23567957 | 10.1016/j.ejmech.2013.03.017 | nan | Kathrotiya HG, Patel MP. | 2013 | 63 | nan | 675 | 684 | PUBLICATION | A new class of β-aryloxyquinoline based diversely fluorine substituted N-aryl quinolone derivatives 8a-x have been synthesized via a one-pot multicomponent reaction. In vitro antimicrobial activity of the synthesized compounds was investigated against a representative panel of pathogenic strains. Compounds 8g, 8h, 8m, 8q and 8v exhibited excellent antimicrobial activity compared with first line drugs. In vitro antituberculosis activity was evaluated against Mycobacterium tuberculosis H37Rv and compounds 8h and 8q emerged as the promising antimicrobial member with better antituberculosis activity. The brine shrimp bioassay was carried out to study the in vitro cytotoxic properties of the synthesized compounds. In vitro antioxidant activity was evaluated by ferric-reducing antioxidant power method. Compounds 8e, 8k, 8l, 8s, 8u and 8w showed highest antioxidant potency. | 36 | 11 | 372 | CHEMBL_18 | 2014-03-12 |
CHEMBL1125643 | Journal of medicinal chemistry. | 1 | Scientific Literature | N-(5-fluorobenzothiazol-2-yl)-2-guanidinothiazole-4-carboxamide. A novel, systemically active antitumor agent effective against 3LL Lewis lung carcinoma. | 2002471 | 10.1021/jm00107a007 | nan | Schnur RC, Fliri AF, Kajiji S, Pollack VA. | 1991 | 34 | 3 | 914 | 918 | PUBLICATION | N-(5-Fluorobenzothiazol-2-yl)-2-guanidinothiazole-4-carboxam ide (1) is a member of a series of amides found to substantially increase lifespan in mice bearing established micrometastatic 3LL Lewis lung carcinoma. Amide 1 is effective after either oral or intraperitoneal dosing in acute, subacute, or chronic regimens. 1 is well tolerated in this model with an excellent therapeutic index relative to the cytotoxic anticancer drug adriamycin. | 6 | 1 | 65 | CHEMBL_1 | 2009-09-03 |
CHEMBL1145982 | Journal of medicinal chemistry. | 1 | Scientific Literature | Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening. | 12773035 | 10.1021/jm020495y | nan | Wyss PC, Gerber P, Hartman PG, Hubschwerlen C, Locher H, Marty HP, Stahl M. | 2003 | 46 | 12 | 2304 | 2312 | PUBLICATION | Novel 2,4-diaminopyrimidines bearing N,N-disubstituted aminomethyl residues at the 5-position were designed as dihydrofolate reductase (DHFR) inhibitors. These compounds were obtained by treatment of 1-[(2,4-diamino-5-pyrimidinyl)methyl]pyridinium bromide with secondary amines in a polar solvent and in the presence of triethylamine at room temperature. The procedure was found to be very efficient and suitable for application in high-throughput synthesis. In addition, we found that high-throughput screening for enzymatic and in vitro antibacterial activity could be performed on crude reaction mixtures, thus avoiding any purification step. Over 1200 proprietary secondary amines were selected for high-throughput synthesis, based on structural and diversity-related criteria, and the resulting products were submitted to high-throughput screening. A greater number of hits, and significantly more active compounds, were obtained through structure-based library design than through diversity-based library design. Different classes of inhibitors of DHFR were identified in this way, including compounds derived from di-, tri-, and tetracyclic amines. In general, these products showed high activity against the enzymes derived from both TMP-sensitive and TMP-resistant Streptococcus pneumoniae. Some compounds possessed appreciable selectivity for the bacterial over the human enzyme, whereas other compounds were not at all selective. In most cases, active enzyme inhibitors also displayed antibacterial activity. | 13 | 3 | 101 | CHEMBL_1 | 2009-09-03 |
CHEMBL1135515 | Journal of medicinal chemistry. | 1 | Scientific Literature | Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI). | 12109908 | 10.1021/jm020050+ | nan | Miller WH, Seefeld MA, Newlander KA, Uzinskas IN, Burgess WJ, Heerding DA, Yuan CC, Head MS, Payne DJ, Rittenhouse SF, Moore TD, Pearson SC, Berry V, DeWolf WE, Keller PM, Polizzi BJ, Qiu X, Janson CA, Huffman WF. | 2002 | 45 | 15 | 3246 | 3256 | PUBLICATION | Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections. | 15 | 9 | 106 | CHEMBL_1 | 2009-09-03 |
CHEMBL1641603 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Inhibition of β-carbonic anhydrases with ureido-substituted benzenesulfonamides. | 21145236 | 10.1016/j.bmcl.2010.11.064 | nan | Pacchiano F, Carta F, Vullo D, Scozzafava A, Supuran CT. | 2011 | 21 | 1 | 102 | 105 | PUBLICATION | A series of sulfonamides was prepared by reaction of sulfanilamide with aryl/alkyl isocyanates. The ureido-substituted benzenesulfonamides showed a very interesting profile for the inhibition of several carbonic anhydrases (CAs, EC 4.2.1.1) such as the human hCA II and three β-CAs from pathogenic fungal or bacterial species. The Candida albicans enzyme was inhibited with potencies in the range of 3.4-3970 nM, whereas the Mycobacterium tuberculosis enzymes Rv1284 and Rv3273 were inhibited with K(i)s in the range of 4.8-6500 nM and of 6.4-6850 nM, respectively. The structure-activity relationship for this class of inhibitors is rather complex, but the main features associated with effective inhibition of both α- and β-CAs investigated here have been delineated. The nature of the moiety substituting the second ureido nitrogen is the determining factor in controlling the inhibitory power, probably due to the flexibility of the ureido linker and the possibility of this moiety to orientate in different subpockets of the active site cavities of these enzymes. | 29 | 4 | 125 | CHEMBL_11 | 2011-08-01 |
CHEMBL1155901 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Sialyl alpha(2-->3) lactose clusters using carbosilane dendrimer core scaffolds as influenza hemagglutinin blockers. | 18639456 | 10.1016/j.bmcl.2008.06.101 | nan | Oka H, Onaga T, Koyama T, Guo CT, Suzuki Y, Esumi Y, Hatano K, Terunuma D, Matsuoka K. | 2008 | 18 | 15 | 4405 | 4408 | PUBLICATION | An efficient synthesis of a series of carbosilane dendrimers uniformly functionalized with sialyl alpha(2-->3) lactose (Neu5Acalpha(2-->3)Galbeta(1-->4)Glcbeta1-->) moieties was accomplished. The results of a preliminary study on biological responses against influenza virus hemagglutinin, using the sialyl lactose clusters showed unique biological activities on the basis of the structure-activity relationship according to the carbosilane scaffolds. | 7 | 2 | 15 | CHEMBL_2 | 2009-11-30 |
CHEMBL1629509 | European journal of medicinal chemistry. | 1 | Scientific Literature | Design, synthesis and inhibitory activity against Mycobacterium tuberculosis thymidine monophosphate kinase of acyclic nucleoside analogues with a distal imidazoquinolinone. | 20951473 | 10.1016/j.ejmech.2010.09.056 | nan | Familiar O, Munier-Lehmann H, Aínsa JA, Camarasa MJ, Pérez-Pérez MJ. | 2010 | 45 | 12 | 5910 | 5918 | PUBLICATION | Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt) has been proposed as an attractive target in the search of new agents to fight against tuberculosis. We recently reported that thymine derivatives carrying a naphtholactam or naphthosultam moiety at position 4 of a (Z)-butenyl chain inhibit TMPKmt in the subμM range. Here we describe the replacement of the planar naphtholactam and naphthosultam rings in our identified hits by 5,6-dihydro-1H-imidazo[4,5,1-ij]quinolinones and a 5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3,2-ij]quinoline-2,2-dioxide where the planarity has been broken. Interestingly, these non-planar compounds were similarly potent against the target enzyme than their aromatic analogues, suggesting a bioisosteric behavior that may also be applied to other biologically active compounds. The synthesis of the different targeted imidazoquinolinones has been successfully performed via a hypervalent iodide mediated oxidative cyclization of N-methoxyureas catalized by bis(trifluoroacetoxy)iodobenzene (PIFA) expanding the reported use of this reagent for the synthesis of differently substituted imidazoquinolinones. | 10 | 4 | 25 | CHEMBL_11 | 2011-08-01 |
CHEMBL1145675 | Journal of natural products. | 1 | Scientific Literature | Antibacterial activity studies of flavonoids from Salvia palaestina. | 6677714 | 10.1021/np50030a007 | nan | Miski M, Ulubelen A, Johansson C, Mabry TJ. | 1983 | 46 | 6 | 874 | 875 | PUBLICATION | Ten aglycones and six glycosides of luteolin and apigenin were identified from the leaves of Salvia palaestina Bentham (Labiatae). Among them cirsimaritin showed a high activity against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa, while the others have little or no activity against the same bacterial strains. | 4 | 6 | 35 | CHEMBL_2 | 2009-11-30 |
CHEMBL1142505 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Synthesis and antitubercular activity of ferrocenyl diaminoalcohols and diamines. | 18835177 | 10.1016/j.bmc.2008.09.030 | nan | Andrianina Ralambomanana D, Razafimahefa-Ramilison D, Rakotohova AC, Maugein J, Pélinski L. | 2008 | 16 | 21 | 9546 | 9553 | PUBLICATION | A total of 21 ferrocenyl and benzyl diaminoalcohols and diamines were synthesized and evaluated against Mycobacterium tuberculosis H37Rv. Interestingly, ferrocenyl diamines exhibit better activities than ferrocenyl diaminoalcohols. | 4 | 1 | 4 | CHEMBL_2 | 2009-11-30 |
CHEMBL1132470 | Journal of medicinal chemistry. | 1 | Scientific Literature | Structure-activity relationships of novel 2-substituted quinazoline antibacterial agents. | 10579832 | 10.1021/jm9903500 | nan | Kung PP, Casper MD, Cook KL, Wilson-Lingardo L, Risen LM, Vickers TA, Ranken R, Blyn LB, Wyatt JR, Cook PD, Ecker DJ. | 1999 | 42 | 22 | 4705 | 4713 | PUBLICATION | High-throughput screening of in-house compound libraries led to the discovery of a novel antibacterial agent, compound 1 (MIC: 12-25 microM against S. pyogenes). In an effort to improve the activity of this active compound, a series of 2-substituted quinazolines was synthesized and evaluated in several antibacterial assays. One such compound (22) displayed improved broad-spectrum antibacterial activity against a variety of bacterial strains. This molecule also inhibited transcription/translation of bacterial RNA, suggesting a mechanism for its antibiotic effects. Structure-activity relationship studies of 22 led to the synthesis of another 24 compounds. Although some of these molecules were found to be active in bacterial growth assays, none were as potent as 22. Compound 22 was tested for its ability to cure a systemic K. pneumonia infection in the mouse and displayed moderate effects compared with a control antibiotic, gentamycin. | 39 | 5 | 93 | CHEMBL_1 | 2009-09-03 |
CHEMBL1140333 | Journal of medicinal chemistry. | 1 | Scientific Literature | Structure-based design, synthesis, and biological evaluation of inhibitors of Mycobacterium tuberculosis type II dehydroquinase. | 16033267 | 10.1021/jm0501836 | nan | Sánchez-Sixto C, Prazeres VF, Castedo L, Lamb H, Hawkins AR, González-Bello C. | 2005 | 48 | 15 | 4871 | 4881 | PUBLICATION | The syntheses by Suzuki cross-coupling of 12 5-aryl analogues of the known inhibitor (1R,3R,4R)-1,3,4-trihydroxycyclohex-5-en-1-carboxylic acid are reported. These compounds were found to be reversible competitive inhibitors against Mycobacterium tuberculosis type II dehydroquinase, the third enzyme of the shikimic acid pathway. The most potent inhibitor, the 3-nitrophenyl derivative, has a K(i) of 54 nM, over 180 times more potent than the reported inhibitor (1R,3R,4R)-5-fluoro-1,3,4-trihydroxycyclohex-5-en-1-carboxylic acid and more than 700 times lower than the K(M) of the substrate, making it the most potent known inhibitor against any type II dehydroquinase. Docking studies using GOLD (version 2.2) indicated a key electrostatic binding interaction between the aromatic rings and Arg19, a residue that has been identified as essential for enzyme activity. | 15 | 1 | 15 | CHEMBL_1 | 2009-09-03 |
CHEMBL1127361 | Journal of medicinal chemistry. | 1 | Scientific Literature | Polyacrylamides bearing pendant alpha-sialoside groups strongly inhibit agglutination of erythrocytes by influenza A virus: multivalency and steric stabilization of particulate biological systems. | 7932570 | 10.1021/jm00046a027 | nan | Lees WJ, Spaltenstein A, Kingery-Wood JE, Whitesides GM. | 1994 | 37 | 20 | 3419 | 3433 | PUBLICATION | An alpha-sialoside linked to acrylamide by a short connector (5-acetamido-2-O-(N-acryloyl-8-amino-5-oxaoctyl)-2,6-anhydro-3,5-d ideoxy-D-galacto-alpha-nonulopyranosonoic acid, 1) was prepared. Compound 1 formed high molecular weight copolymers with acrylamide, derivatives of acrylamide, and/or vinylpyrrolidone upon photochemically-initiated free radical polymerization. Those copolymers for which the substituents on the acrylamido nitrogen were small inhibited the agglutination of chicken erythrocytes induced by influenza virus (X-31 (H3N2); a recombinant strain of A/Aichi/2/68 (H3N2) and A/Puerto Rico/8/34 grown in chicken eggs). The inhibitory power of the polymers depended strongly on the conditions of polymerization and the sialic acid content of the polymer. The strongest inhibitors were copolymers (poly(1-co-acrylamide)) formed from mixtures of monomer containing [1]/([1] + [acrylamide]) approximately 0.2-0.7; these copolymers inhibited hemagglutination 10(4)-10(5) times more strongly than did similar concentrations of alpha-methyl sialoside (calculated on the basis of the total concentration of individual sialic acid groups in the solution, whether attached to polymer or present as monomers). Samples polymerized in the presence of low concentrations of cross-linking reagents (bis(acrylamido)methane, BIS, and 2,2'-bis(acrylamido)ethyl disulfide, BAC) also showed increased inhibition (10-10(3)-fold relative to monomers), but their use was limited by their poor solubility. Sterically demanding substituents on any position of the acrylamide component (substituents attached to the vinyl group or N-alkyl groups that are larger than hydroxyethyl) reduced the inhibitory power of the polymer. A 1H NMR assay and a fluorescence depolarization assay showed that poly(1-co-acrylamide) bound to a solubilized trimeric form of the viral receptor for sialic acid (bromelain cleaved hemagglutinin, BHA), less tightly than 1, on a per sialic acid basis. A similar result was also obtained with a model system comprising lactic dehydrogenase (a tetramer) and polymeric derivatives of oxamic acid: that is, poly((28, 29, 30, or 31)-co-acrylamide) had a higher inhibition constant for tetrameric lactic dehydrogenase than did the corresponding monomers (28, 29, 30, or 31) on a per oxamate basis. Poly(1-co-acrylamide) is, in principle, capable of inhibiting the agglutination of erythrocytes by several mechanisms: (1) entropically enhanced binding of the polymer (acting as a polyvalent inhibitor) to the surface of the virus; (2) steric interference of the approach of the virus to the surface of the erythrocyte by a water-swollen layer of the polymer on the surface of the virus; (3) aggregation of the virus induced by the polymer.(ABSTRACT TRUNCATED AT 400 WORDS) | 9 | 1 | 9 | CHEMBL_1 | 2009-09-03 |
CHEMBL1811849 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Development of a plate-based scintillation proximity assay for the mycobacterial AftB enzyme involved in cell wall arabinan biosynthesis. | 20800502 | 10.1016/j.bmc.2010.07.040 | nan | Zhang J, Amin AG, Hölemann A, Seeberger PH, Chatterjee D. | 2010 | 18 | 19 | 7121 | 7131 | PUBLICATION | A number of mycobacterial arabinosyltransferases, such as the Emb proteins, AftA, AftB, AftC, and AftD have been characterized and implicated to be involved in the cell wall arabinan assembly. These arabinosyltransferases are essential for the viability of the organism and are logically valid targets for developing new anti-tuberculosis agents. For instance, Ethambutol, a first line anti-tuberculosis drug, targets the Emb proteins involved in the formation of the arabinan of cell wall arabinogalactan. Among these arabinosyltransferases, the terminal β-(1→2) arabinosyltransferase activity has been associated with AftB. The predicted topology of AftB in Mycobacterium tuberculosis has 10 N terminal transmembrane domains and a C terminal hydrophilic domain similar to the Emb proteins. It has a conserved GT-C motif and is difficult to express. In a cell free assay, synthetic disaccharide, α-D-Araf-(1→5)-α-D-Araf-octyl, has been used as a substrate to explore the function of AftB. In our work, the disaccharide was synthesized in its pentenylated and biotinylated form, and the enzymatic product formed was identified as the β-(1→2) arabinofuranose adduct. When synthetic tri- and tetra-saccharides were used as substrates, a mixture of products containing both β-(1→2) and α-(1→5) linkages were formed. Therefore, the biotinylated disaccharide was selected to develop a scintillation proximity assay. | 4 | 1 | 4 | CHEMBL_13 | 2012-02-21 |
CHEMBL1145344 | Journal of medicinal chemistry. | 1 | Scientific Literature | Brunsvicamides A-C: sponge-related cyanobacterial peptides with Mycobacterium tuberculosis protein tyrosine phosphatase inhibitory activity. | 16884299 | 10.1021/jm060327w | nan | Müller D, Krick A, Kehraus S, Mehner C, Hart M, Küpper FC, Saxena K, Prinz H, Schwalbe H, Janning P, Waldmann H, König GM. | 2006 | 49 | 16 | 4871 | 4878 | PUBLICATION | The cyanobacterium Tychonema sp. produces the new cyclic hexapeptides brunsvicamide A-C (1-3). Brunsvicamide B (2) and C (3) selectively inhibit the Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB), a potential drug target for tuberculosis therapy for which no inhibitors are known to date. Brunsvicamide C contains an N-methylated N'-formylkynurenine moiety, a unique structural motif in cyclic peptides. The new peptides are related to the sponge-derived mozamides, supporting the suggestion that secondary metabolites of certain marine invertebrates are produced by associated microorganisms. Thus, microorganisms phylogenetically related to symbionts of marine invertebrates can be judged as a means to supply 'marine-like' compounds for drug development. | 3 | 6 | 18 | CHEMBL_1 | 2009-09-03 |
CHEMBL1143611 | Journal of medicinal chemistry. | 1 | Scientific Literature | Additivity of molecular fields: CoMFA study on dual activators of PPARalpha and PPARgamma. | 15828840 | 10.1021/jm049383s | nan | Khanna S, Sobhia ME, Bharatam PV. | 2005 | 48 | 8 | 3015 | 3025 | PUBLICATION | Recent trends in drug discovery include methods to identify dual and triple activating drugs. This approach is being successfully employed in malaria, cancer, asthma, insulin resistance, etc. Molecular field analysis has been employed in correlating pharmacological data and field parameters. In this paper we introduce the concept of additivity of molecular fields to correlate molecular fields of dual activators and their pIC(50) values. PPARalpha and PPARgamma dual activators, which affect hypertriglyceridemia and hyperglycemia, have been chosen to validate the molecular field additivity concept. Three CoMFA models namely alpha-model, gamma-model and dual-model have been developed. The validity of this concept has been ascertained by (a) comparing contour maps, (b) by comparing CoMFA results with FlexX docking results and (c) by analyzing newly designed molecules. | 34 | 2 | 102 | CHEMBL_1 | 2009-09-03 |
CHEMBL1146905 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and evaluation of phenoxy acetic acid derivatives as [corrected] anti-mycobacterial agents. | 16784842 | 10.1016/j.bmcl.2006.06.021 | nan | Shaharyar M, Siddiqui AA, Ali MA. | 2006 | 16 | 17 | 4571 | 4574 | PUBLICATION | In present investigation, 2-(4-formyl-2-methoxyphenoxy) acetic acid on condensation with various ketones in methanolic KOH solution yielded the corresponding chalcones (1-3). These corresponding chalcones were reacted with appropriate acid hydrazide in glacial acetic acid led to the formation of phenoxy acetic acid derivatives. All newly synthesized compounds were evaluated for their anti-mycobacterial activities against Mycobacterium tuberculosis H(37)Rv. | 19 | 1 | 76 | CHEMBL_1 | 2009-09-03 |
CHEMBL1144358 | Journal of medicinal chemistry. | 1 | Scientific Literature | LEA3D: a computer-aided ligand design for structure-based drug design. | 15801836 | 10.1021/jm0492296 | nan | Douguet D, Munier-Lehmann H, Labesse G, Pochet S. | 2005 | 48 | 7 | 2457 | 2468 | PUBLICATION | We present an improved version of the program LEA developed to design organic molecules. Rational drug design involves finding solutions to large combinatorial problems for which an exhaustive search is impractical. Genetic algorithms provide a tool for the investigation of such problems. New software, called LEA3D, is now able to conceive organic molecules by combining 3D fragments. Fragments were extracted from both biological compounds and known drugs. A fitness function guides the search process in optimizing the molecules toward an optimal value of the properties. The fitness function is build up by combining several independent property evaluations, including the score provided by the FlexX docking program. One application in de novo drug design is described. The example makes use of the structure of Mycobacterium tuberculosis thymidine monophosphate kinase to generate analogues of one of its natural substrates. Among 22 tested compounds, 17 show inhibitory activity in the micromolar range. | 24 | 1 | 24 | CHEMBL_1 | 2009-09-03 |
CHEMBL1144355 | Journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antibacterial activity of the 4-quinolone-3-carboxylic acid derivatives having a trifluoromethyl group as a novel N-1 substituent. | 15857152 | 10.1021/jm040204g | nan | Asahina Y, Araya I, Iwase K, Iinuma F, Hosaka M, Ishizaki T. | 2005 | 48 | 9 | 3443 | 3446 | PUBLICATION | Novel 1-trifluoromethyl-4-quinolone derivatives (8a,b) were synthesized, and the antibacterial activity of each was evaluated. An oxidative desulfurization-fluorination reaction was employed to introduce a trifluoromethyl group at the N-1 position as a key step. Among the derivatives, 8a was found to exhibit antibacterial activity comparable to that of norfloxacin (1) against Staphylococcus aureus Smith, Streptococcus pneumoniae IID1210, and Escherichia coli NIHJ JC-2. | 9 | 4 | 36 | CHEMBL_1 | 2009-09-03 |
CHEMBL1144381 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antimycobacterial activity of ferrocenyl ethambutol analogues and ferrocenyl diamines. | 15837313 | 10.1016/j.bmcl.2005.03.004 | nan | Razafimahefa D, Ralambomanana DA, Hammouche L, Pélinski L, Lauvagie S, Bebear C, Brocard J, Maugein J. | 2005 | 15 | 9 | 2301 | 2303 | PUBLICATION | A new series of ferrocenyl diamino alcohols and diamines were synthesized and their inhibitory potencies were probed with Mycobacterium tuberculosis. Interestingly, ferrocenyl diamines 6a and b display significant activities against M. tuberculosis H37Rv. | 9 | 1 | 9 | CHEMBL_1 | 2009-09-03 |
CHEMBL1914302 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | The structure-antituberculosis activity relationships study in a series of 5-aryl-2-thio-1,3,4-oxadiazole derivatives. | 22001325 | 10.1016/j.bmc.2011.09.038 | nan | Macaev F, Ribkovskaia Z, Pogrebnoi S, Boldescu V, Rusu G, Shvets N, Dimoglo A, Geronikaki A, Reynolds R. | 2011 | 19 | 22 | 6792 | 6807 | PUBLICATION | A series of 82 5-aryl-2-thio-1,3,4-oxadiazole derivatives were screened for their anti-mycobacterial activities against Mycobacterium tuberculosis H37Rv. The synthesized compounds 30-37 appeared to be the most active derivatives exhibiting more than 90% inhibition of mycobacterial growth at 12.5 μg/mL. Structure-activity relationships study was performed for the given series by using the electronic-topological method combined with neural networks (ETM-NN). A system for the anti-mycobacterial activity prediction was developed as the result of training associative neural network (ASNN) with weights calculated from projections of a compound and each pharmacophoric fragment found on the elements of the Kohonen's self-organizing maps (SOMs). From the detailed analysis of all compounds under study, the necessary requirements for a compound to possess antituberculosis activity have been formulated. The analysis has shown that any requirement's violation for a molecule implies a considerable decrease or even complete loss of its activity. Molecular docking studies of the compounds allowed shedding light on the binding mode of these novel anti-mycobacterial inhibitors. | 82 | 1 | 82 | CHEMBL_14 | 2012-06-27 |
CHEMBL1156671 | European journal of medicinal chemistry. | 1 | Scientific Literature | QSAR studies on benzoylaminobenzoic acid derivatives as inhibitors of beta-ketoacyl-acyl carrier protein synthase III. | 17707951 | 10.1016/j.ejmech.2007.06.018 | nan | Singh S, Soni LK, Gupta MK, Prabhakar YS, Kaskhedikar SG. | 2008 | 43 | 5 | 1071 | 1080 | PUBLICATION | Fatty acid biosynthesis is essential for most of the bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a attractive target since it is central to the initiation of fatty acid biosynthesis. Quantitative structure-activity relationship (QSAR) studies have been carried out on a series of benzoylaminobenzoic acid derivatives as potent inhibitors of FabH and antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Neisseria meningitidis and Escherichia coli, which demonstrate FabH inhibitory activity in cell free and whole cell system. The QSAR studies revealed that inhibitory activity increases with increase in hydrophobicity, molar refractivity, aromaticity, and presence of OH group (on x position of the nucleus). On the other side presence of hetero-atoms like N, O, or S at R(1) position of the nucleus decreases the inhibitory activity. The comparison of QSAR between the FabH inhibitory activity and antibacterial activity against S. aureus, S. pneumoniae, S. pyogenes, E. faecalis, N. meningitidis also demonstrates that the hydrophobicity, aromaticity and presence of OH group (on x position of the nucleus) are conducive for the inhibitory activity. | 43 | 5 | 83 | CHEMBL_2 | 2009-11-30 |
CHEMBL1138166 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antimycobacterial activity of some alkyl [5-(nitroaryl)-1,3,4-thiadiazol-2-ylthio]propionates. | 16359863 | 10.1016/j.bmcl.2005.11.087 | nan | Foroumadi A, Kargar Z, Sakhteman A, Sharifzadeh Z, Feyzmohammadi R, Kazemi M, Shafiee A. | 2006 | 16 | 5 | 1164 | 1167 | PUBLICATION | Two series of 2- and 3-[5-(nitroaryl)-1,3,4-thiadiazol-2-ylthio, sulfinyl and sulfonyl] propionic acid alkyl esters were synthesized and screened for antituberculosis activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system. The MIC values for the compounds showing more than 90% inhibition were determined. The result of comparison between two groups of data exhibited that among the synthesized derivatives, the compound propyl 3-[5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-ylthio]propionate was the most active one (MIC=1.56 microgml(-1)). | 20 | 1 | 58 | CHEMBL_1 | 2009-09-03 |
CHEMBL1142174 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Pyrazinoic acid and its n-propyl ester inhibit fatty acid synthase type I in replicating tubercle bacilli. | 17101678 | 10.1128/aac.01369-06 | nan | Zimhony O, Vilchèze C, Arai M, Welch JT, Jacobs WR. | 2007 | 51 | 2 | 752 | 754 | PUBLICATION | The activity of different analogs of pyrazinamide on Mycobacterium tuberculosis fatty acid synthase type I (FASI) in replicating bacilli was studied. Palmitic acid biosynthesis was diminished by 96% in bacilli treated with n-propyl pyrazinoate, 94% in bacilli treated with 5-chloro-pyrazinamide, and 97% in bacilli treated with pyrazinoic acid, the pharmacologically active agent of pyrazinamide. We conclude that the minimal structure of pyrazine ring with an acyl group is sufficient for FASI inhibition and antimycobacterial activity. | 4 | 2 | 11 | CHEMBL_1 | 2009-09-03 |
CHEMBL3244240 | Journal of medicinal chemistry. | 1 | Scientific Literature | Antitubercular 2,8-bis(alkylaminomethyl)phenazines. | 650670 | 10.1021/jm00202a020 | nan | Murdock KC, Lin Y, Thomas JP, Lang SA. | 1978 | 21 | 4 | 403 | 405 | PUBLICATION | The preparation and antitubercular properties of a series of 2,8-bis(alkylaminomethyl)phenazines are described. These compounds all inhibited the growth of Mycobacterium smegmatis ATCC 607 in vitro. 2,8-Bis(dibutylaminomethyl)phenazine (5c) was also active against a lethal Mycobacterium tuberculosis H37Rv infection in mice. | 13 | 2 | 18 | CHEMBL_20 | 2015-01-14 |
CHEMBL3217504 | nan | 1 | Scientific Literature | Potent growth inhibitory activity of ()-platencin towards multi-drug-resistant and extensively drug-resistant Mycobacterium tuberculosis | nan | 10.1039/C3MD00016H | nan | Moustafa GAI, Nojima S, Yamano Y, Aono A, Arai M, Mitarai S, Tanaka T, Yoshimitsu T | 2013 | 4 | 4 | 720 | 723 | PUBLICATION | nan | 2 | 2 | 18 | CHEMBL_20 | 2015-01-14 |
CHEMBL1142089 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | High-level telithromycin resistance in a clinical isolate of Streptococcus pneumoniae. | 17210764 | 10.1128/aac.01153-06 | nan | Wolter N, Smith AM, Low DE, Klugman KP. | 2007 | 51 | 3 | 1092 | 1095 | PUBLICATION | A rare clinical isolate of Streptococcus pneumoniae, highly resistant to telithromycin, contained erm(B) with a truncated leader peptide and a mutant ribosomal protein L4. By transformation of susceptible strains, this study shows that high-level telithromycin resistance is conferred by erm(B), wild type or mutant, in combination with a (69)GTG(71)-to-TPS mutation in ribosomal protein L4. | 7 | 1 | 56 | CHEMBL_1 | 2009-09-03 |
CHEMBL1141481 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Probing the structural and topological requirements for CCR2 antagonism: holographic QSAR for indolopiperidine derivatives. | 18226895 | 10.1016/j.bmcl.2007.12.072 | nan | Srikanth K, Nair PC, Sobhia ME. | 2008 | 18 | 4 | 1450 | 1456 | PUBLICATION | CCR2 is the major family of chemokine receptors which involve in the pathophysiology of the acute or chronic inflammatory conditions such as rheumatoid arthritis, atherosclerosis, asthma, obesity, and type-2 diabetes. Herein, we report the results of HQSAR model, developed for CCR2 antagonistic activity of indolopiperidine derivatives. The best HQSAR model with r(2)=0.916, q(2)=0.562 with atom count=4-7 was used to predict the activity of the test set molecules. The predicted values are in good agreement with experimental results and show the potential of the model for untested compounds. Analysis of molecular fragments throws light on essential structural and topological features of indolopiperidine derivatives for antagonist activity. The analysis shows that the presence of tertiary hydrogen bond acceptor groups is important for CCR2 antagonism. Fragments containing benzene ring substituted with one or more chlorine atoms show the positive effect of electron withdrawing group for favorable activity. | 29 | 1 | 58 | CHEMBL_1 | 2009-09-03 |
CHEMBL1129519 | Journal of medicinal chemistry. | 1 | Scientific Literature | Optimal recognition of neutral endopeptidase and angiotensin-converting enzyme active sites by mercaptoacyldipeptides as a means to design potent dual inhibitors. | 8632427 | 10.1021/jm950590p | nan | Coric P, Turcaud S, Meudal H, Roques BP, Fournie-Zaluski MC. | 1996 | 39 | 6 | 1210 | 1219 | PUBLICATION | An interesting approach for the treatment of congestive heart failure and chronic hypertension could be to avoid the formation of angiotensin II by inhibiting angiotensin converting enzyme (ACE) and to protect atrial natriuretic factor by blocking neutral endopeptidase 24.11 (NEP). This is supported by recent results obtained with potent dual inhibitors of the two zinc metallopeptidases, such as RB 105, HSCH2CH(CH3)PhCONHCH(CH3)COOH (Fournié-Zaluski et al. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4072-4076), which reduces blood pressure in experimental models of hypertension, independently of the salt and renin angiotensin system status. In order to develop new dual inhibitors with improved affinities, long duration of action, and/or better bioavailabilities, various series of mercaptoacyldipeptides corresponding to the general formula HSCH(R1)CONHCH(R1')CON(R)CH(R2')COOH have been synthesized. The introduction of well-selected beta-branched chains in positions R1 and R1', associated with a tyrosine or a cyclic amino acid in the C-terminal position, led to potent dual inhibitors of NEP and ACE such as 21 [N-[(2S)-2-mercapto-3-methylbutanoyl]-Ile-Tyr] and 22 [N-[(2S)-2-mercapto-3-phenylpropanoyl]Ala-Pro] which have IC50 values in the nanomolar range for NEP and subnanomolar range for ACE. These compounds could have different modes of binding to the two peptidases. In NEP, the dual inhibitors seem to interact only with the S1' and S2' subsites, whereas additional interactions with the S1 binding subsite of ACE probably account for their subnanomolar inhibitory potencies for this enzyme. The localization of the Pro residue of 22 outside the NEP active site is supported by biochemical data using (Arg102,Glu)NEP and molecular modeling studies with thermolysin used as model of NEP. One hour after oral administration in mice of a single dose (2.7 x 10(-5) mol/kg), 21 inhibited 80% and 36% of kidney NEP and lung ACE, respectively, while 22 inhibited 40% of kidney NEP and 56% of lung ACE. | 40 | 2 | 80 | CHEMBL_1 | 2009-09-03 |
CHEMBL1130686 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | A new series of C3-aza carbocyclic influenza neuraminidase inhibitors: synthesis and inhibitory activity. | 9873727 | 10.1016/s0960-894x(98)00587-3 | nan | Lew W, Wu H, Mendel DB, Escarpe PA, Chen X, Laver WG, Graves BJ, Kim CU. | 1998 | 8 | 23 | 3321 | 3324 | PUBLICATION | The synthesis and influenza neuraminidase inhibitory activity of a new series of C3-aza carbocyclic neuraminidase inhibitors are described. Analogues 3c and 3j, bearing a 3-pentyl group, exhibit influenza A inhibitory activities comparable to that of 1. | 14 | 2 | 28 | CHEMBL_1 | 2009-09-03 |
CHEMBL1909569 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and structure-activity relationships of novel substituted 8-amino, 8-thio, and 1,8-pyrazole congeners of antitubercular rifamycin S and rifampin. | 21903392 | 10.1016/j.bmcl.2011.08.054 | nan | Jin Y, Gill SK, Kirchhoff PD, Wan B, Franzblau SG, Garcia GA, Showalter HD. | 2011 | 21 | 20 | 6094 | 6099 | PUBLICATION | A series of rifamycin S and rifampin analogues incorporating substituted 8-amino, 8-thio, and 1,8-pyrazole substituents has been synthesized. The compounds were made by activation of the C-8 phenol as a sulfonate ester, followed by displacement with selected nitrogen and sulfur nucleophiles. The analogues were screened in assays to quantify their antitubercular activity under both aerobic and anaerobic conditions, and for inhibition of wild-type Mycobacterium tuberculosis (MTB) RNAP and rifamycin-resistant MTB RNAP (S450L) via an in vitro rolling circle transcription assay. Additionally, the MIC(90) values were determined for these analogues against Escherichia coli strains. Although none of the analogues displayed superior enzymatic or microbiological activity to their parent scaffolds, the results are consistent with the Rif C-8 hydroxyl acting as a hydrogen bond acceptor with S450 and that Rif resistance in the S450L mutant is due to loss of this hydrogen bond. Representative analogues were also evaluated in the human pregnane X receptor (PXR) activation assay. | 33 | 5 | 150 | CHEMBL_14 | 2012-06-27 |
CHEMBL3217677 | nan | 1 | Scientific Literature | Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]pyridine-based Mycobacterium tuberculosis glutamine synthetase inhibitors | nan | 10.1039/C2MD00310D | nan | Nordqvist A, Nilsson MT, Lagerlund O, Muthas D, Gising J, Yahiaoui S, Odell LR, Srinivasa BR, Larhed M, Mowbray SL, Karlen A | 2012 | 3 | 5 | 620 | 626 | PUBLICATION | nan | 32 | 1 | 32 | CHEMBL_20 | 2015-01-14 |
CHEMBL1909588 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and in vitro antitubercular evaluation of novel sansanmycin derivatives. | 21982497 | 10.1016/j.bmcl.2011.09.031 | nan | Li YB, Xie YY, Du NN, Lu Y, Xu HZ, Wang B, Yu Y, Liu YX, Song DQ, Chen RX. | 2011 | 21 | 22 | 6804 | 6807 | PUBLICATION | Tuberculosis (TB) is a major health problem worldwide. A series of novel sansanmycin derivatives were designed, semi-synthesized and evaluated for their activity against drug-susceptible Mycobacterium tuberculosis strain H(37)Rv with sansanmycin A (SSA) as the lead. Among these analogs tested, compound 1d possessing an isopropyl group at the amino terminal afforded an increased antimycobacterial activity with a MIC value of 8 μg/mL in comparison with SSA. Importantly, it was active for rifampicin- and isoniazid-resistant M. tuberculosis strain isolated from patients in China. These promising results offer an opportunity for further exploration of this novel class of analogs as antitubercular agents. | 20 | 1 | 24 | CHEMBL_14 | 2012-06-27 |
CHEMBL1124579 | Journal of medicinal chemistry. | 1 | Scientific Literature | 7-Heteroaryl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin -2(1H)-one derivatives with cardiac stimulant activity. | 2769678 | 10.1021/jm00129a005 | nan | Bell AS, Campbell SF, Roberts DA, Ruddock KS. | 1989 | 32 | 9 | 2042 | 2049 | PUBLICATION | A series of 7-heteroaryl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin++ +-2 (1H)-ones was synthesized and evaluated in dogs for cardiac stimulant activity. Compounds were obtained by a palladium-catalyzed cross-coupling reaction between a heteroarylzinc chloride and a 7-iodo-1,2,3,5-tetrahydroimidazo [2,1-b]quinazolin-2(1H)-one or by cyclization of an N-[(2-aminophenyl)methyl]glycinate with cyanogen bromide. Compared to the parent ring system (3), introduction of a 2,6-dimethylpyridin-3-yl (6), 2,4-dimethylimidazol-1-yl (7), or 1,2,4-triazol-1-yl (8) moiety at the 7-position led to a 13-17-fold increase in positive inotropic activity (percentage increase in dP/dtmax) in anesthetized dogs. Potency could be further enhanced with a 9-methyl substituent (10-12). The most potent member of the series, 7-(2,4-dimethylimidazol-1-yl)-9-methyl-1,2,3,5-tetrahydroimidaz o [2,1-b]quinazolin-2(1H)-one (11) (23% increase in dP/dtmax, 2 micrograms/kg), was 80 times more active than 3 and displayed a 5-fold advantage over milrinone. In conscious dogs, 6 elicited marked and sustained positive inotropic activity (decrease in QA interval) after oral administration (1 mg/kg), whereas 10-12 were 10 times more potent. 11 produced an obvious increase in cardiac contractility (20% increase in dP/dtmax) at low dose levels (25 micrograms/kg) while, after 100 micrograms/kg, the marked response (50% increase in dP/dtmax) was maintained for the whole 7-h test period. In these experiments, 11 had no effect on heart rate, and the compound also displayed exceptional selectivity for increasing the force rather than the rate of cardiac contraction (greater than 150% increase in dP/dtmax) in the Starling heart-lung preparation. These studies demonstrate that the tetrahydroimidazoquinazolinone nucleus is an effective bioisostere for the 2(1H)-quinolinone system and that 11 displays improved cardiac stimulant activity and duration of action when compared to milrinone. | 15 | 2 | 48 | CHEMBL_1 | 2009-09-03 |
CHEMBL1139752 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | New rifabutin analogs: synthesis and biological activity against Mycobacterium tuberculosis. | 16987658 | 10.1016/j.bmcl.2006.08.090 | nan | Barluenga J, Aznar F, García AB, Cabal MP, Palacios JJ, Menéndez MA. | 2006 | 16 | 22 | 5717 | 5722 | PUBLICATION | The synthesis, structure, and biological evaluation of a series of novel rifamycin derivatives, Rifastures (RFA) with potent anti-tuberculosis activity are presented. Some of these derivatives showed higher in vitro activity than rifabutin and rifampicin against not only Mycobacterium tuberculosis strains but also against MAC and Mycobacterium kansasii. | 9 | 3 | 81 | CHEMBL_1 | 2009-09-03 |
CHEMBL3352529 | Journal of medicinal chemistry. | 1 | Scientific Literature | Discovery of N-substituted oseltamivir derivatives as potent and selective inhibitors of H5N1 influenza neuraminidase. | 25255388 | 10.1021/jm500892k | nan | Xie Y, Xu D, Huang B, Ma X, Qi W, Shi F, Liu X, Zhang Y, Xu W. | 2014 | 57 | 20 | 8445 | 8458 | PUBLICATION | To discover group-1-specific neuraminidase (NA) inhibitors that are especially involved in combating the H5N1 virus, two series of oseltamivir derivatives were designed and synthesized by targeting the 150-cavity. Among these, compound 20l was the most potent N1-selective inhibitor, with IC50 values of 0.0019, 0.0038, and 0.0067 μM against NAs from three H5N1 viruses. These values are better than those of oseltamivir carboxylate. Compound 32 was another potent N1-selective inhibitor that exhibited a 12-fold increase in activity against the H274Y mutant relative to oseltamivir carboxylate. Molecular docking studies revealed that the 150-cavity was an auxiliary binding site that may contribute to the high selectivity of these compounds. The present work is a significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors, which may be further investigated for the treatment of infection by the H5N1 virus. | 37 | 4 | 189 | CHEMBL_21 | 2016-02-01 |
CHEMBL3351260 | European journal of medicinal chemistry. | 1 | Scientific Literature | A new efficient route to 7-aryl-6-fluoro-8-nitroquinolones as potent antibacterial agents. | 25180924 | 10.1016/j.ejmech.2014.08.065 | nan | Al-Trawneh SA, El-Abadelah MM, Al-Abadleh MM, Zani F, Incerti M, Vicini P. | 2014 | 86 | nan | 364 | 367 | PUBLICATION | A series of 7-aryl-6-fluoro-8-nitroquinolones (6a-e) were synthesized through a novel, simple and clean synthetic procedure, through a Suzuki-Miyaura reaction. The target compounds were evaluated in vitro for their antimicrobial properties against bacterial and fungal strains. All of them showed antibacterial activity higher than the activity of ciprofloxacin, both towards Gram positive Bacillus subtilis and Staphylococcus aureus, and Gram negative Haemophilus influenzae strains. Compound 6d, containing the trisubstituted 7-aryl moiety, emerged as the most active quinolone derivative with MIC values ranging from 0.00007 μg/mL to 0.015 μg/mL. | 6 | 7 | 41 | CHEMBL_21 | 2016-02-01 |
CHEMBL3351272 | European journal of medicinal chemistry. | 1 | Scientific Literature | Sequential synthesis of amino-1,4-naphthoquinone-appended triazoles and triazole-chromene hybrids and their antimycobacterial evaluation. | 25129868 | 10.1016/j.ejmech.2014.08.009 | nan | Devi Bala B, Muthusaravanan S, Choon TS, Ashraf Ali M, Perumal S. | 2014 | 85 | nan | 737 | 746 | PUBLICATION | A general method for the synthesis of a library of hitherto unreported amino-1,4-naphthoquinone-appended triazoles was accomplished via a sequential three-component reaction of substituted N-propargylaminonaphthoquinones with variously substituted alkyl bromides/2-bromonaphthalene-1,4-dione and sodium azide in the presence of Et3N/CuI in water. Aminonaphthoquinone-appended iminochromene-triazole hybrid heterocycles were also synthesized from the amino-1,4-naphthoquinone-appended-1,2,3-triazolylacetonitriles. All the triazole hybrids were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB). Among the triazoles, 2-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)(4-(trifluoromethyl)phenyl)amino)naphthalene-1,4-dione (7d) emerged as the most active one with IC50 = 1.87 μM, being more potent than the anti-TB drugs, cycloserine (6 times), pyrimethamine (20 times) and equipotent as the drug ethambutol (IC50 < 1.56 μM). | 43 | 1 | 131 | CHEMBL_21 | 2016-02-01 |
CHEMBL2417356 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Identification of 2,3-disubstituted pyridines as potent, orally active PDE4 inhibitors. | 23910988 | 10.1016/j.bmc.2013.07.007 | nan | Kato Y, Kawasaki M, Nigo T, Nakamura S, Fusano A, Teranishi Y, Ito MN, Sumiyoshi T. | 2013 | 21 | 18 | 5851 | 5854 | PUBLICATION | A series of 2,3-disubstituted pyridines were synthesized and evaluated for their PDE4 inhibitory activity. We successfully modified undesirable cyano group of initial lead compound 2 to 4-pyridyl group with improvement of in vitro efficacy and optimized the position of nitrogen atoms in pyridine moiety and alkylene linker. The most potent compound showed significant efficacy in animal models of asthma and inflammation. | 10 | 3 | 16 | CHEMBL_18 | 2014-03-12 |
CHEMBL2412962 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Human acidic mammalian chitinase as a novel target for anti-asthma drug design using in silico screening. | 23623259 | 10.1016/j.bmc.2013.03.047 | nan | Wakasugi M, Gouda H, Hirose T, Sugawara A, Yamamoto T, Shiomi K, Sunazuka T, Ōmura S, Hirono S. | 2013 | 21 | 11 | 3214 | 3220 | PUBLICATION | Human acidic mammalian chitinase (hAMCase) was recently shown to be involved in the development of asthma, suggesting a possible application for hAMCase inhibitors as novel therapeutic agents for asthma. We therefore initiated drug discovery research into hAMCase using a combination of in silico methodologies and a hAMCase assay system. We first selected 23 candidate hAMCase inhibitors from a database of four million compounds using a multistep screening system combining Tripos Topomer Search technology, a docking calculation and two-dimensional molecular similarity analysis. We then measured hAMCase inhibitory activity of the selected compounds and identified seven compounds with IC50 values ≤100 μM. A model describing the binding modes of these hit compounds to hAMCase was constructed, and we discuss the structure-activity relationships of the compounds we identified, suggested by the model and the actual inhibitory activities of the compounds. | 7 | 1 | 7 | CHEMBL_18 | 2014-03-12 |
CHEMBL2429724 | Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents. | 1 | Scientific Literature | Computational POM evaluation of experimental in vitro Trypanosoma cruzi and Mycobacterium tuberculosis inhibition of heterocyclic-2-carboxylic acid (3-cyano-1,4-di-noxidequinoxalin-2-yl)amide derivatives | nan | 10.1007/s00044-013-0781-3 | nan | Hadda TB, Bendaha H, Sheikh J, Ahmad M, Warad I | 2013 | nan | nan | 1 | 10 | PUBLICATION | nan | 42 | 2 | 85 | CHEMBL_18 | 2014-03-12 |
CHEMBL2073805 | The Journal of pharmacology and experimental therapeutics. | 18 | TP-search Transporter Database | Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A). | 15331656 | 10.1124/jpet.104.073395 | nan | Heffeter P, Pongratz M, Steiner E, Chiba P, Jakupec MA, Elbling L, Marian B, Körner W, Sevelda F, Micksche M, Keppler BK, Berger W. | 2005 | 312 | 1 | 281 | 289 | PUBLICATION | KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A) is a metal complex with promising anticancer activity. Since chemoresistance is a major obstacle in chemotherapy, this study investigated the influence of several drug resistance mechanisms on the anticancer activity of KP1019. Here we demonstrate that the cytotoxic effects of KP1019 are neither substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1, breast cancer resistance protein, and lung resistance protein nor the transferrin receptor and only marginally by the cellular p53 status. In contrast, P-glycoprotein overexpression weakly but significantly (up to 2-fold) reduced KP1019 activity. P-glycoprotein-related resistance was based on reduced intracellular KP1019 accumulation and reversible by known P-glycoprotein modulators. KP1019 dose dependently inhibited ATPase activity of P-glycoprotein with a K(i) of approximately 31 microM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC(50), approximately 8 microM), however, with reduced activity at increased serum concentrations (EC(50) at 10% serum, approximately 35 microM). Moreover, P-glycoprotein-mediated daunomycin resistance could only be marginally restored by KP1019 in serum-containing medium, also indicating an influence of serum proteins on the interaction between KP1019 and P-glycoprotein. Acquired KP1019 resistance was investigated by selecting KB-3-1 cells against KP1019 for more than 1 year. Only an approximately 2-fold KP1019 resistance could be induced, which unexpectedly was not due to overexpression of P-glycoprotein or other efflux pumps. Accordingly, KP1019-resistant cells did not display reduced drug accumulation. Their unique cross-resistance pattern confirmed an ABC transporter-independent resistance phenotype. In summary, the likeliness of acquiring insensitivity to KP1019 during therapy is expected to be low, and resistance should not be based on overexpression of drug efflux transporters. | 1 | 1 | 10 | CHEMBL_15 | 2013-01-23 |
CHEMBL1151284 | Journal of natural products. | 1 | Scientific Literature | Antimycobacterial scalarane-based sesterterpenes from the Red Sea sponge Hyrtios erecta. | 16378375 | 10.1021/np0502645 | nan | Youssef DT, Shaala LA, Emara S. | 2005 | 68 | 12 | 1782 | 1784 | PUBLICATION | A new scalarane-type pentacyclic sesterterpene, sesterstatin 7 (1), was isolated from the Red Sea sponge Hyrtios erecta, together with 16-epi-scalarolbutenolide (2), 25-dehydroxy-12-epi-deacetylscalarin (3), 3-acetylsesterstatin 1 (4), and 21-acetoxydeoxyscalarin. The structure of 1 was elucidated by spectroscopic data interpretation. Sesterstatin 7 (1) showed 63% inhibition of Mycobacterium tuberculosis (H(37)Rv) at a concentration of 6.25 microg/mL. Compound 2 displayed moderate inhibitory activity, while 3 and 4 were weakly active against the same biological target. | 4 | 1 | 4 | CHEMBL_2 | 2009-11-30 |
CHEMBL1138665 | Journal of medicinal chemistry. | 1 | Scientific Literature | Probing the activity differences of simple and complex brominated aryl compounds against 15-soybean, 15-human, and 12-human lipoxygenase. | 15267244 | 10.1021/jm049872s | nan | Segraves EN, Shah RR, Segraves NL, Johnson TA, Whitman S, Sui JK, Kenyon VA, Cichewicz RH, Crews P, Holman TR. | 2004 | 47 | 16 | 4060 | 4065 | PUBLICATION | Lipoxygenases (LO) have been implicated in asthma, immune disorders, and various cancers. As a consequence of these broad biological implications, there is great interest in understanding the effects of naturally occurring and environmental contaminants against its activity. On the basis of our earlier studies indicating that polybrominated diphenol ethers are potent inhibitors to mammalian 15-LO, we expanded our structure-activity study to include marine-derived brominated phenol ethers (including a newly discovered tribrominated diphenyl ether), dioxins, and bastadins, as well as the synthetic brominated fire retardants, brominated bisphenol A (BBPA), and polybrominated diphenyl ethers (PBDEs). We report herein the effects of 21 simple and complex organobromine compounds against human platelet 12-LO, human reticulocyte 15-LO, and soybean 15-LO-1. | 20 | 4 | 80 | CHEMBL_1 | 2009-09-03 |
CHEMBL2407013 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Novel 3,4-disubstituted-Neu5Ac2en derivatives as probes to investigate flexibility of the influenza virus sialidase 150-loop. | 23800724 | 10.1016/j.bmc.2013.05.054 | nan | Rudrawar S, Dyason JC, Maggioni A, Thomson RJ, von Itzstein M. | 2013 | 21 | 16 | 4820 | 4830 | PUBLICATION | Novel 3,4-disubstituted-Neu5Ac2en derivatives have been synthesised to probe the open 150-loop conformation of influenza virus sialidases. Both equatorially and axially (epi) substituted C4 amino and guanidino 3-(p-tolyl)allyl-Neu5Ac2en derivatives were prepared, via the 4-epi-hydroxy derivative. The equatorially-substituted 4-amino derivative showed low micromolar inhibition of both group-1 (pdm09 H1N1) and group-2 (pdm57 H2N2) sialidases, and provides the first in vitro evidence that a group-2 sialidase may exhibit 150-loop flexibility. | 7 | 1 | 14 | CHEMBL_18 | 2014-03-12 |
CHEMBL2396653 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antimycobacterial evaluation of N-substituted 5-chloropyrazine-2-carboxamides. | 23659859 | 10.1016/j.bmcl.2013.04.021 | nan | Servusová B, Vobicková J, Paterová P, Kubíček V, Kuneš J, Doležal M, Doležal M, Zitko J. | 2013 | 23 | 12 | 3589 | 3591 | PUBLICATION | To develop new potential antimycobacterial drugs, a series of pyrazinamide derivatives was designed, synthesized and tested for their ability to inhibit the growth of selected mycobacterial strains (Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two strains of Mycobacterium avium). This Letter is focused on binuclear pyrazinamide analogues containing the -CONH-CH2- bridge, namely on N-benzyl-5-chloropyrazine-2-carboxamides with various substituents on the phenyl ring and their comparison with some analogously substituted 5-chloro-N-phenylpyrazine-2-carboxamides. Compounds from the N-benzyl series exerted lower antimycobacterial activity against M. tuberculosis H37Rv then corresponding anilides, however comparable with pyrazinamide (12.5-25 μg/mL). Remarkably, 5-chloro-N-(4-methylbenzyl)pyrazine-2-carboxamide (8, MIC=3.13 μg/mL) and 5-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (1, MIC=6.25 μg/mL) were active against M. kansasii, which is naturally unsusceptible to PZA. Basic structure-activity relationships are presented. | 20 | 20 | 379 | CHEMBL_18 | 2014-03-12 |
CHEMBL1147480 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis, absolute stereochemistry and molecular design of the new antifungal and antibacterial antibiotic produced by Streptomyces sp.201. | 15177476 | 10.1016/j.bmcl.2004.04.025 | nan | Boruwa J, Kalita B, Barua NC, Borah JC, Mazumder S, Thakur D, Gogoi DK, Bora TC. | 2004 | 14 | 13 | 3571 | 3574 | PUBLICATION | The absolute stereochemistry of the new antifungal and antibacterial antibiotic produced by Streptomyces sp.201 has been established by achieving the total synthesis of the product. A series of analogues have also been synthesized by changing the side chain and their bioactivity assessed against different microbial strains. Among them, 1e (R = C8H17) was found to be the most potent with MIC of 8 microg/mL against Mycobacterium tuberculosis, 12 microg/mL against Escherichia coli and 16 microg/mL against Bacillus subtilis 6 microg/mL against Proteus vulgaris. This was followed by 1b (R = C5H11) with MIC of 10-20 microg/mL range and 1d (R = C7H15) with MIC of 14-24 g/mL, whereas 1a (R = C4H9) and 1f (R = C18H35) were found to be completely inactive. Besides, 1c (R = C6H13) showed certain extent of antibacterial activity in the range of 24-50 microg/mL. Mycobacterium tuberculosis was very sensitive to 1e (R = C8H17) with MIC of 8 microg/mL. Antifungal activity of analogues 1d (R = C7H15) and 1e, (R = C8H17) against Fusarium oxysporum and Rhizoctonia solani were found promising with MFCs in the 15-18 microg/mL range. | 8 | 6 | 48 | CHEMBL_1 | 2009-09-03 |
CHEMBL1126623 | Journal of medicinal chemistry. | 1 | Scientific Literature | Neuraminidase-resistant hemagglutination inhibitors: acrylamide copolymers containing a C-glycoside of N-acetylneuraminic acid. | 8459405 | 10.1021/jm00058a016 | nan | Sparks MA, Williams KW, Whitesides GM. | 1993 | 36 | 6 | 778 | 783 | PUBLICATION | Copolymers consisting of a polyacrylamide backbone with side chains terminated in C-glycosidic analogs of N-acetylneuraminic acid were synthesized by free radical copolymerization of alpha-2-C-[3-[[2-(N-acryloylamino)ethyl]thio]propyl]-N- acetylneuraminic acid (5) with acrylamide. Unlike natural and synthetic polyvalent materials that contain N-acetylneuraminic acid in O-glycosidic form, these C-glycosidic copolymers resist neuraminidase-catalyzed cleavage of the neuraminic acid residue from the copolymer backbone. Examination of these C-glycosidic copolymers in a hemagglutination inhibition assay indicated that they are as effective in vitro as polyvalent O-glycosidic copolymers in inhibiting agglutination of erythrocytes by influenza virus. The minimum value of the inhibition constant, calculated on the basis of the concentration of Neu5Ac groups in solution, is Ki(HAI) approximately 10(-7) M for both copolymers. The inhibitory potency of the C-glycoside-based copolymers becomes more significant at lower concentrations of Neu5Ac moieties in solution than does the inhibitory potency of the O-glycoside-based copolymer. | 2 | 1 | 2 | CHEMBL_1 | 2009-09-03 |
CHEMBL2331351 | Journal of medicinal chemistry. | 1 | Scientific Literature | 5-Oxo-ETE receptor antagonists. | 23581530 | 10.1021/jm400480j | nan | Gore V, Patel P, Chang CT, Sivendran S, Kang N, Ouedraogo YP, Gravel S, Powell WS, Rokach J. | 2013 | 56 | 9 | 3725 | 3732 | PUBLICATION | 5-Oxo-ETE is the most powerful eosinophil chemoattractant among lipid mediators. Eosinophil infiltration into the lungs of asthmatics may be responsible for the late phase of inflammatory asthma. We have designed and synthesized a 5-oxo-ETE receptor antagonist, the purpose of which is to prevent eosinophil migration to the lung during an asthma attack and thereby reduce asthma symptoms. | 11 | 1 | 19 | CHEMBL_17 | 2013-08-29 |
CHEMBL1140917 | Journal of medicinal chemistry. | 1 | Scientific Literature | Structure-activity relationships of antitubercular nitroimidazoles. 1. Structural features associated with aerobic and anaerobic activities of 4- and 5-nitroimidazoles. | 19209889 | 10.1021/jm801246z | nan | Kim P, Zhang L, Manjunatha UH, Singh R, Patel S, Jiricek J, Keller TH, Boshoff HI, Barry CE, Dowd CS. | 2009 | 52 | 5 | 1317 | 1328 | PUBLICATION | The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4- and 5-nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-nitroimidazoles, neither the corresponding bicyclic analogue nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase (Ddn) retained anaerobic sensitivity to some compounds. Aerobic activity appears to be correlated with efficiency as a substrate for Ddn, suggesting a means of structure-based optimization of improved nitroimidazoles. | 16 | 2 | 89 | CHEMBL_2 | 2009-11-30 |
CHEMBL2417467 | Journal of natural products. | 1 | Scientific Literature | Antiproliferative cardiac glycosides from the latex of Antiaris toxicaria. | 24033101 | 10.1021/np4005147 | nan | Liu Q, Tang JS, Hu MJ, Liu J, Chen HF, Gao H, Wang GH, Li SL, Hao XJ, Zhang XK, Yao XS. | 2013 | 76 | 9 | 1771 | 1780 | PUBLICATION | Phytochemical investigation of the latex of Antiaris toxicaria resulted in the isolation of 15 new [antiarosides J-X (1-15)] and 17 known cardiac glycosides. The effects of the cardiac glycosides on apoptosis and the expression of orphan nuclear receptor Nur77 were examined in human NIH-H460 lung cancer cells. Several of the cardiac glycosides induced apoptosis in lung cancer cells, which was accompanied by induction of Nur77 protein expression. Treatment of cancer cells with the cardiac glycosides resulted in translocation of the Nur77 protein from the nucleus to the cytoplasm and subsequent targeting to mitochondria. The results show that the cardiac glycosides exert their apoptotic effect through the Nur77-dependent apoptotic pathway. | 31 | 2 | 59 | CHEMBL_18 | 2014-03-12 |
CHEMBL1124911 | Journal of medicinal chemistry. | 1 | Scientific Literature | Inhibition of human leukocyte elastase. 2. Inhibition by substituted cephalosporin esters and amides. | 2391692 | 10.1021/jm00171a029 | nan | Finke PE, Ashe BM, Knight WB, Maycock AL, Navia MA, Shah SK, Thompson KR, Underwood DJ, Weston H, Zimmerman M. | 1990 | 33 | 9 | 2522 | 2528 | PUBLICATION | A variety of 7 alpha-methoxycephalosporin ester and amide sulfones were prepared and tested to determine the structure-activity relations for inhibition of human leukocyte elastase (HLE), a serine protease which has been implicated in several degenerative lung and tissue diseases. The most potent IC50 values were obtained with neutral, lipophilic derivatives, with the esters being more active than the amides. However, the best time-dependent inhibition in this series was observed with the p- and m-carboxybenzyl esters 7b and 7c. These results are discussed in terms of the proposed mechanism of inhibition as well as a molecular modeling study using the recently solved X-ray crystal structure of HLE. | 33 | 1 | 51 | CHEMBL_1 | 2009-09-03 |
CHEMBL1153924 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antibacterial activity of 4'',11-di-O-arylalkylcarbamoyl azithromycin derivatives. | 19232491 | 10.1016/j.bmcl.2009.01.092 | nan | Ma S, Jiao B, Liu Z, Wang H, Xian R, Zheng M, Lou H. | 2009 | 19 | 6 | 1698 | 1701 | PUBLICATION | A series of new 4'',11-di-O-arylalkylcarbamoyl azithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. Some derivatives exhibited greatly improved activity against erythromycin-resistant bacteria. Among them, compounds 5f and 5k were found to have potent activity against erythromycin-resistant Streptococcus pneumoniae whose resistance was encoded by the erm or mef gene. | 17 | 1 | 68 | CHEMBL_2 | 2009-11-30 |
CHEMBL3244401 | Journal of medicinal chemistry. | 1 | Scientific Literature | Prostaglandins and congeners. 15. Synthesis and bronchodilator activity of dl-11-deoxy-15- or 16-alkylprostaglandins. | 592319 | 10.1021/jm00222a003 | nan | Skotnicki JS, Schaub RE, Bernady KF, Siuta GJ, Poletto JF, Weiss MJ. | 1977 | 20 | 12 | 1551 | 1557 | PUBLICATION | The synthesis of dl-11-doxy-15- or 16-alkylprostaglandins by the conjugate addition of appropriately substituted lithium alanate or lithium cuprate reagents to several cyclopentenones is described as is the preparation of the requisite intermediate (E)-1-iodo-1-alkenyl compounds 4, 22, 23, and 31. The bronchodilator activity of these prostaglandin congeners is presented. | 32 | 1 | 96 | CHEMBL_20 | 2015-01-14 |
CHEMBL2150987 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and evaluation of novel 1,3,4-oxadiazole derivatives of marine bromopyrrole alkaloids as antimicrobial agent. | 22967765 | 10.1016/j.bmcl.2012.08.061 | nan | Rane RA, Gutte SD, Sahu NU. | 2012 | 22 | 20 | 6429 | 6432 | PUBLICATION | In an attempt to identify new potential lead as antimicrobial agent, twenty hybrids of marine bromopyrrole alkaloids with 1,3,4-oxadiazole were designed based on molecular hybridization technique and synthesized. Synthesized molecules were evaluated for their antibacterial, antifungal and antitubercular activities. Hybrids 5d, 5i, 5j and 5k exhibited equivalent antibacterial activity (MIC of 1.56 μg/mL) compared with standard drug ciprofloxacin against Staphylococcus aureus and Escherichia coli. Equal antifungal activity (MIC of 1.56 μg/mL) was shown by of hybrids 5j, 5k and 7d compared with standard Amphotericin-B. The inhibition of Mycobacterium tuberculosis at concentrations as low as 1.6 and 1.5 μg/mL by compounds 5f and 7d respectively indicates that these compounds can act as leads for development of newer anti-TB compounds. | 23 | 6 | 126 | CHEMBL_16 | 2013-05-07 |
CHEMBL3352020 | Journal of medicinal chemistry. | 1 | Scientific Literature | Targeting matrix metalloproteinases: exploring the dynamics of the s1' pocket in the design of selective, small molecule inhibitors. | 25265401 | 10.1021/jm500505f | nan | Fabre B, Ramos A, de Pascual-Teresa B. | 2014 | 57 | 24 | 10205 | 10219 | PUBLICATION | Matrix metalloproteinases (MMPs) are important targets for pathological conditions such as arthritis, chronic obstructive pulmonary disease, and cancer. The failure of the first broad-spectrum MMP inhibitors in clinical trials has led researchers to address the selectivity as one of their main objectives. The S1' pocket has been widely used to modulate the selectivity of these enzymes because it displays the highest variability in length and shape among MMPs. In this review, we encourage medicinal chemists to also consider the dynamics of this pocket as an important parameter to achieve the desired selectivity. To support this proposal, we collect examples from the literature where the flexibility of the S1' pocket was highlighted as a relevant and significant issue affecting selectivity. We also review the experimental studies on the dynamics of this pocket. | 11 | 10 | 38 | CHEMBL_21 | 2016-02-01 |
CHEMBL3352563 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Design, synthesis and molecular docking of substituted 3-hydrazinyl-3-oxo-propanamides as anti-tubercular agents. | 25442308 | 10.1016/j.bmcl.2014.09.080 | nan | Naqvi A, Malasoni R, Srivastava A, Pandey RR, Dwivedi AK. | 2014 | 24 | 22 | 5181 | 5184 | PUBLICATION | Based on the anti-mycobacterial activity of various acid hydrazides, a series of substituted 3-hydrazinyl-3-oxo-propanamides has been designed. The target compounds have been synthesized from diethylmalonate using substituted amines and hydrazine hydrate in ethanol. Computational studies and anti-tubercular activity screenings were undertaken to test their inhibitory effect on protein kinase PknB from Mycobacterium tuberculosis. Binding poses of the compounds were energetically favorable and showed good interactions with active site residues. Designed molecules obey the Lipinski's rule of 5 and gave moderate to good drug likeness score. Among the sixteen compounds (1-16) taken for in silico and in vitro studies, 3 compounds (11, 12 and 15) have shown good binding energies along with exhibiting good anti-tubercular activity and thus may be considered as a good inhibitors of PknB. | 18 | 2 | 34 | CHEMBL_21 | 2016-02-01 |
CHEMBL1143597 | Journal of medicinal chemistry. | 1 | Scientific Literature | Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities. | 15828822 | 10.1021/jm0401560 | nan | Haviv F, Bradley MF, Kalvin DM, Schneider AJ, Davidson DJ, Majest SM, McKay LM, Haskell CJ, Bell RL, Nguyen B, Marsh KC, Surber BW, Uchic JT, Ferrero J, Wang YC, Leal J, Record RD, Hodde J, Badylak SF, Lesniewski RR, Henkin J. | 2005 | 48 | 8 | 2838 | 2846 | PUBLICATION | The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 microM, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies. | 12 | 2 | 20 | CHEMBL_1 | 2009-09-03 |
CHEMBL1148665 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and evaluation of 4-substituted benzylamine derivatives as beta-tryptase inhibitors. | 16540315 | 10.1016/j.bmcl.2006.02.064 | nan | Miyazaki Y, Kato Y, Manabe T, Shimada H, Mizuno M, Egusa T, Ohkouchi M, Shiromizu I, Matsusue T, Yamamoto I. | 2006 | 16 | 11 | 2986 | 2990 | PUBLICATION | Since beta-tryptase is considered a critical mediator of asthma, potent tryptase inhibitors may be useful as new agents for the treatment of asthma. We investigated 4-substituted benzylamine derivatives and obtained M58539 (15h) as a potent inhibitor of beta-tryptase (IC50 = 5.0 nM) with high selectivity against other serine proteases, low molecular weight, clog P value less than 5, lack of amidino and guanidino groups, and independence of Zn2+ ion. | 17 | 6 | 37 | CHEMBL_1 | 2009-09-03 |
CHEMBL1149766 | European journal of medicinal chemistry. | 1 | Scientific Literature | Quantitative structure activity relationship studies on thiourea analogues as influenza virus neuraminidase inhibitors. | 17513019 | 10.1016/j.ejmech.2007.03.020 | nan | Nair PC, Sobhia ME. | 2008 | 43 | 2 | 293 | 299 | PUBLICATION | Influenza virus is a major global threat that impacts the world in one form or another as flu infections. Neuraminidase, one of the targets for these viruses, has recently been exploited in the treatment of these infections. Quantitative structure activity relationship studies were performed on thiourea analogues using spatial, topological, electronic, thermodynamic and E-state indices. Genetic algorithm based genetic function approximation method of variable selection was used to generate the model. Highly statistically significant model was obtained when number of descriptors in the equation was set to 5. The atom type log P and shadow indices descriptors showed enormous contributions to neuraminidase inhibition. The validation of the model was done by cross validation, randomization and external test set prediction. The model gives insight on structural requirements for designing more potent analogues against influenza virus neuraminidase. | 40 | 1 | 70 | CHEMBL_2 | 2009-11-30 |
CHEMBL1144018 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | SAR studies of capsazepinoid bronchodilators. Part 2: Chlorination and catechol replacement in the A-ring. | 18065228 | 10.1016/j.bmc.2007.11.061 | nan | Berglund M, Dalence-Guzmán MF, Skogvall S, Sterner O. | 2008 | 16 | 5 | 2513 | 2528 | PUBLICATION | Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This paper concerns the chlorination of the A-ring as well as the replacement of the catechol with bioisosteric groups. It is revealed that chlorination of the A-ring has a profound effect on activity. Moreover, di-chlorination of the 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline structure results in a 10-fold increase in potency compared to capsazepine. | 31 | 1 | 31 | CHEMBL_1 | 2009-09-03 |
CHEMBL1156648 | Journal of natural products. | 1 | Scientific Literature | Tetrahdroxysqualene from Rhus taitensis shows antimycobacterial activity against Mycobacterium tuberculosis. | 18710283 | 10.1021/np800082e | nan | Noro JC, Barrows LR, Gideon OG, Ireland CM, Koch M, Matainaho T, Piskaut P, Pond CD, Bugni TS. | 2008 | 71 | 9 | 1623 | 1624 | PUBLICATION | Tuberculosis has become a major health problem, in particular with the emergence of extremely drug resistant tuberculosis (XDRTB). In our search for new therapeutic leads against TB, we isolated a new triterpene (1) from the plant Rhus taitensis collected in Papua New Guinea. Tetrahydroxysqualene (1) was isolated using bioassay-guided fractionation of the methanolic extract of R. taitensis leaves and twigs. The structure of tetrahydroxysqualene (1) was elucidated on the basis of HRESIMS and 1D and 2D NMR spectra. Tetrahydroxysqualene (1) exhibited antituberculosis activity with an MIC of 10.0 microg/mL, while showing only modest cytotoxicity. | 4 | 2 | 8 | CHEMBL_2 | 2009-11-30 |
CHEMBL3217686 | nan | 1 | Scientific Literature | A new route to indoles via in situ desilylationSonogashira strategy: identification of novel small molecules as potential anti-tuberculosis agents | nan | 10.1039/C1MD00148E | nan | Nakhi A, Prasad B, Reddy U, Rao RM, Sandra S, Kapavarapu R, Rambabu D, Rama Krishna G, Reddy CM, Ravada K, Misra P, Iqbal J, Pal M | 2011 | 2 | 10 | 1006 | 1010 | PUBLICATION | nan | 15 | 1 | 17 | CHEMBL_20 | 2015-01-14 |
CHEMBL1132673 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Preparation and immunosuppressive activity of 32-(O)-acylated and 32-(O)-thioacylated analogues of ascomycin. | 10021934 | 10.1016/s0960-894x(98)00702-1 | nan | Hersperger R, Schuler W, Zenke G. | 1999 | 9 | 2 | 227 | 232 | PUBLICATION | A series of 32-(O)-acylated and 32-(O)-thioacylated derivatives of the antibiotic ascomycin (1) have been synthesized. These readily accessible analogues exhibit potent immunosuppressive activity in vitro, as measured by an interleukin-2 reporter gene assay and the mixed lymphocyte reaction. Such molecules are expected to have a therapeutic potential in chronic inflammatory diseases of the airways such as asthma. | 11 | 3 | 33 | CHEMBL_1 | 2009-09-03 |
CHEMBL3217730 | nan | 1 | Scientific Literature | Determination of structural requirements of influenza neuraminidase type A inhibitors and binding interaction analysis with the active site of A/H1N1 by 3D-QSAR CoMFA and CoMSIA modeling | nan | 10.1039/C1MD00050K | nan | Murumkar PR, Le L, Truong TN, Yadav MR | 2011 | 2 | 8 | 710 | 719 | PUBLICATION | nan | 61 | 1 | 122 | CHEMBL_20 | 2015-01-14 |
CHEMBL3232938 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Design, synthesis, and biological evaluation of dihydroartemisinin-fluoroquinolone conjugates as a novel type of potential antitubercular agents. | 24684842 | 10.1016/j.bmcl.2014.03.010 | nan | Zhou FW, Lei HS, Fan L, Jiang L, Liu J, Peng XM, Xu XR, Chen L, Zhou CH, Zou YY, Liu CP, He ZQ, Yang DC. | 2014 | 24 | 8 | 1912 | 1917 | PUBLICATION | Tuberculosis remains a global public health problem in recent years. To develop novel type of potential antitubercular agents, twelve novel dihydroartemisinin-fluoroquinolone (DHA-FQ) conjugates (three types of molecules) were gradually designed and conveniently synthesized. All the newly synthesized conjugates were well characterized and evaluated against different Mycobacterium tuberculosis strains in vitro. The screening results showed that five DHA-FQ conjugates were active toward M. tuberculosis H37Rv, and compound 3a exhibited the strongest inhibitory activity (MIC=0.0625 μg/mL), which was comparable to the positive control Moxifloxacin and even stronger than Ofloxacin. Conjugates 2a and 3a also displayed comparable activities against various clinically isolated sensitive and resistant M. tuberculosis strains (MIC=0.125-16 μg/mL) to Moxifloxacin. All target compounds possessed selective anti-M. tuberculosis ability. Preliminary structure-activity relationship demonstrated that short linker between DHA and FQ was favorable for strong antitubercular activity. This study provides a new clue for the development of novel antitubercular lead molecules. | 19 | 5 | 283 | CHEMBL_20 | 2015-01-14 |
CHEMBL1909495 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and kinetic testing of new inhibitors for a metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. | 22051063 | 10.1016/j.ejmech.2011.10.030 | nan | Mohamed MS, Hussein WM, McGeary RP, Vella P, Schenk G, Abd El-Hameed RH. | 2011 | 46 | 12 | 6075 | 6082 | PUBLICATION | There are currently no clinically useful inhibitors against metallo-β-lactamases (MBLs), enzymes that confer resistance against a broad spectrum of commonly used antibiotics and that are produced by an increasing number of bacterial pathogens. New pyrrole derivatives were synthesized and assayed for their inhibitory effect on the catalytic activity of the IMP-1 MBL from Pseudomonas aeruginosa and Klebsiella pneumoniae. Six compounds tested (3a-3c, 5, 7 and 8) show micromolar inhibition constants (K(i) values range from ∼10 to 30 μM). In silico docking was employed to investigate the binding mode of the strongest inhibitor, 3b, in the active site of IMP-1. Implications for further improvements of binding efficiency and specificity are discussed. | 11 | 2 | 42 | CHEMBL_14 | 2012-06-27 |
CHEMBL1914441 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Discovery and optimization of a biphenylacetic acid series of prostaglandin D2 receptor DP2 antagonists with efficacy in a murine model of allergic rhinitis. | 21958540 | 10.1016/j.bmcl.2011.01.024 | nan | Scott JM, Baccei C, Bain G, Broadhead A, Evans JF, Fagan P, Hutchinson JH, King C, Lorrain DS, Lee C, Prasit P, Prodanovich P, Santini A, Stearns BA. | 2011 | 21 | 21 | 6608 | 6612 | PUBLICATION | Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D(2) receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eosinophil shape change assay, as well as good oral bioavailability in rat and dog, and efficacy in a mouse model of allergic rhinitis following oral dosing. | 26 | 11 | 108 | CHEMBL_14 | 2012-06-27 |
CHEMBL3217734 | nan | 1 | Scientific Literature | Sulfonyl-hydrazones of cyclic imides derivatives as potent inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase B (PtpB) | nan | 10.1039/C0MD00253D | nan | Navakoski de Oliveira K, Chiaradia LD, Alves Martins PG, Mascarello A, Sechini Cordeiro MN, Carvalho Guido RV, Andricopulo AD, Yunes RA, Nunes RJ, Vernal J, Terenzi H | 2011 | 2 | 6 | 500 | 504 | PUBLICATION | nan | 17 | 2 | 29 | CHEMBL_20 | 2015-01-14 |
CHEMBL1147029 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Probing binding requirements of NAD kinase with modified substrate (NAD) analogues. | 17258457 | 10.1016/j.bmcl.2007.01.012 | nan | Bonnac L, Chen L, Pathak R, Gao G, Ming Q, Bennett E, Felczak K, Kullberg M, Patterson SE, Mazzola F, Magni G, Pankiewicz KW. | 2007 | 17 | 6 | 1512 | 1515 | PUBLICATION | Synthesis of novel NAD(+) analogues that cannot be phosphorylated by NAD kinase is reported. In these analogues the C2' hydroxyl group of the adenosine moiety was replaced by fluorine in the ribo or arabino configuration (1 and 2, respectively) or was inverted into arabino configuration to give compound 3. Compounds 1 and 2 showed inhibition of human NAD kinase, whereas analogue 3 inhibited both the human and Mycobacterium tuberculosis NAD kinase. An uncharged benzamide adenine dinucleotide (BAD) was found to be the most potent competitive inhibitor (K(i)=90 microM) of the human enzyme reported so far. | 7 | 2 | 24 | CHEMBL_1 | 2009-09-03 |
CHEMBL3232880 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | The chemistry and biology of febrifugine and halofuginone. | 24650700 | 10.1016/j.bmc.2014.02.040 | nan | McLaughlin NP, Evans P, Pines M. | 2014 | 22 | 7 | 1993 | 2004 | PUBLICATION | The trans-2,3-disubstituted piperidine, quinazolinone-containing natural product febrifugine (also known as dichroine B) and its synthetic analogue, halofuginone, possess antimalarial activity. More recently studies have also shown that halofuginone acts as an agent capable of reducing fibrosis, an indication with clinical relevance for several disease states. This review summarizes historical isolation studies and the chemistry performed which culminated in the correct structural elucidation of naturally occurring febrifugine and its isomer isofebrifugine. It also includes the range of febrifugine analogues prepared for antimalarial evaluation, including halofuginone. Finally, a section detailing current opinion in the field of halofuginone's human biology is included. | 12 | 2 | 17 | CHEMBL_20 | 2015-01-14 |
CHEMBL1150067 | Journal of natural products. | 1 | Scientific Literature | Anti-tumor-promoting activities of afromosin and soyasaponin I isolated from Wistaria brachybotrys. | 1294698 | 10.1021/np50090a011 | nan | Konoshima T, Kokumai M, Kozuka M, Tokuda H, Nishino H, Iwashima A. | 1992 | 55 | 12 | 1776 | 1778 | PUBLICATION | Afromosin [1] and soyasaponin I [2] isolated from Wistaria brachybotrys exhibited remarkable inhibitory effects on mouse skin tumor promotion, and afromosin also exhibited a significant inhibitory effect on pulmonary tumor promotion. The combined effects of these compounds on the two-stage skin carcinogenesis were also examined, and it was concluded that the combination of 1 with 2 enhanced the inhibitory effect. | 2 | 1 | 5 | CHEMBL_2 | 2009-11-30 |
CHEMBL3351771 | Journal of medicinal chemistry. | 1 | Scientific Literature | Development of inhibitors of the 2C-methyl-D-erythritol 4-phosphate (MEP) pathway enzymes as potential anti-infective agents. | 25210872 | 10.1021/jm5010978 | nan | Masini T, Hirsch AK. | 2014 | 57 | 23 | 9740 | 9763 | PUBLICATION | Important pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum, the causative agents of tuberculosis and malaria, respectively, and plants, utilize the 2C-methyl-D-erythritol 4-phosphate (MEP, 5) pathway for the biosynthesis of isopentenyl diphosphate (1) and dimethylallyl diphosphate (2), the universal precursors of isoprenoids, while humans exclusively utilize the alternative mevalonate pathway for the synthesis of 1 and 2. This distinct distribution, together with the fact that the MEP pathway is essential in numerous organisms, makes the enzymes of the MEP pathway attractive drug targets for the development of anti-infective agents and herbicides. Herein, we review the inhibitors reported over the past 2 years, in the context of the most important older developments and with a particular focus on the results obtained against enzymes of pathogenic organisms. We will also discuss new discoveries in terms of structural and mechanistic features, which can help to guide a rational development of inhibitors. | 46 | 9 | 61 | CHEMBL_21 | 2016-02-01 |
CHEMBL3414519 | Journal of medicinal chemistry. | 1 | Scientific Literature | Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type I methionine aminopeptidases. | 25699713 | 10.1021/jm501790e | nan | Arya T, Reddi R, Kishor C, Ganji RJ, Bhukya S, Gumpena R, McGowan S, Drag M, Addlagatta A. | 2015 | 58 | 5 | 2350 | 2357 | PUBLICATION | The methionine aminopeptidase (MetAP) family is responsible for the cleavage of the initiator methionine from newly synthesized proteins. Currently, there are no small molecule inhibitors that show selectivity toward the bacterial MetAPs compared to the human enzyme. In our current study, we have screened 20 α-aminophosphonate derivatives and identified a molecule (compound 15) that selectively inhibits the S. pneumonia MetAP in low micromolar range but not the human enzyme. Further bioinformatics, biochemical, and structural analyses suggested that phenylalanine (F309) in the human enzyme and methionine (M205) in the S. pneumonia MetAP at the analogous position render them with different susceptibilities against the identified inhibitor. X-ray crystal structures of various inhibitors in complex with wild type and F309M enzyme further established the molecular basis for the inhibitor selectivity. | 6 | 2 | 30 | CHEMBL_21 | 2016-02-01 |
CHEMBL3120115 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and biological evaluation of 2-oxonicotinonitriles and 2-oxonicotinonitrile based nucleoside analogues. | 24486419 | 10.1016/j.ejmech.2013.12.055 | nan | Abou-Elkhair RA, Moustafa AH, Haikal AZ, Ibraheem AM. | 2014 | 74 | nan | 388 | 397 | PUBLICATION | Drug resistance and emergence of new pathogens highlight the need for developing new therapeutic agents. We focused on 2-oxonicotinonitrile (2-ONN) as derivative of the natural product 2-pyridinone.(1) Herein, we describe the synthesis of 2-ONNs bearing two aryl groups, which we coupled with organohalides, including three glycosyl bromides, to prepare the nucleoside analogues. Coupling occurred mostly at the 2-ONN ring nitrogen to give the aimed targets, and in a few cases, it happened at the 2-oxo position giving O-alkylation products. Free 2-ONNs and their acetylated nucleosides were tested against a number of viruses. The nucleoside analogue 2a(Ac) showed good anti SARS-CoV and anti influenza A (H₅N₁) activities. Additionally, 7b had good activity against Gram positive bacterium, Bacillis subtilis. | 27 | 12 | 197 | CHEMBL_19 | 2014-07-03 |
CHEMBL3124766 | ACS medicinal chemistry letters. | 1 | Scientific Literature | Metabolomics Reveal d-Alanine:d-Alanine Ligase As the Target of d-Cycloserine in Mycobacterium tuberculosis. | 24478820 | 10.1021/ml400349n | nan | Prosser GA, de Carvalho LP. | 2013 | 4 | 12 | 1233 | 1237 | PUBLICATION | Stable isotope-mass spectrometry (MS)-based metabolomic profiling is a powerful technique for following changes in specific metabolite pool sizes and metabolic flux under various experimental conditions in a test organism or cell type. Here, we use a metabolomics approach to interrogate the mechanism of antibiotic action of d-cycloserine (DCS), a second line antibiotic used in the treatment of multidrug resistant Mycobacterium tuberculosis infections. We use doubly labeled (13)C α-carbon-(2)H l-alanine to allow tracking of both alanine racemase and d-alanine:d-alanine ligase activity in M. tuberculosis challenged with DCS and reveal that d-alanine:d-alanine ligase is more strongly inhibited than alanine racemase at equivalent DCS concentrations. We also shed light on mechanisms surrounding d-Ala-mediated antagonism of DCS growth inhibition and provide evidence for a postantibiotic effect for this drug. Our results illustrate the potential of metabolomics in cellular drug-target engagement studies and consequently have broad implications in future drug development and target validation ventures. | 3 | 4 | 18 | CHEMBL_19 | 2014-07-03 |
CHEMBL1955755 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Novel imidazo[2,1-b][1,3,4]thiadiazole carrying rhodanine-3-acetic acid as potential antitubercular agents. | 22325950 | 10.1016/j.bmcl.2012.01.052 | nan | Alegaon SG, Alagawadi KR, Sonkusare PV, Chaudhary SM, Dadwe DH, Shah AS. | 2012 | 22 | 5 | 1917 | 1921 | PUBLICATION | The increase in the prevalence of multi drug-resistant and extensively drug-resistant strains of Mycobacteriumtuberculosis case demonstrates the urgent need of discovering new promising compounds with antimycobacterial activity. As part of our research program and with a aim of identifying new antitubercular drug candidates, a new class of 2-(trifluoromethyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazole derivatives has been synthesized by both conventional as well as microwave assisted method and evaluated for their in vitro antitubercular activity against M. tuberculosis H(37)Rv. Moreover, various drug-likeness properties of new compounds were predicted. Seven compounds from the series exhibited good activity with MIC in range 3.12-1.56μg/ml. The present study suggests that compounds 6b, 6c, 6d, 6e and 6f may serve as promising lead scaffolds for further generation of new anti-TB agents. | 23 | 1 | 23 | CHEMBL_14 | 2012-06-27 |
CHEMBL1133010 | Journal of medicinal chemistry. | 1 | Scientific Literature | Structure-function studies of polymyxin B nonapeptide: implications to sensitization of gram-negative bacteria. | 10956216 | 10.1021/jm0000057 | nan | Tsubery H, Ofek I, Cohen S, Fridkin M. | 2000 | 43 | 16 | 3085 | 3092 | PUBLICATION | Polymyxin B nonapeptide (PMBN), a cationic cyclic peptide derived by enzymatic processing from the naturally occurring peptide polymyxin B, is able to increase the permeability of the outer membrane of Gram-negative bacteria toward hydrophobic antibiotics probably by binding to the bacterial lipopolysaccharide (LPS). We have synthesized 11 cyclic analogues of PMBN and evaluated their activities compared to that of PMBN. The synthetic peptides were much less potent than PMBN in their capacity to sensitize Escherichia coli and Klebsiella pneumoniae toward novobiocin and to displace dansyl-PMBN from Escherichia coli LPS. Moreover, unlike PMBN, none of the analogues were able to inhibit the growth of Pseudomonas aeruginosa. The structural-functional features of PMBN were characterized and identified with regard to the ring size, the distance between positive charges and peptide backbone, the chirality of the DPhe-Leu domain, and the nature of the charged groups. Apparently, the structure of PMBN is highly specific for efficient perturbation of the outer membrane of Gram-negative bacteria as well as for LPS binding. The present study further increases our understanding of the complex PMBN-LPS and may, potentially, enable the design of compounds having enhanced permeabilization potency of the Gram-negative outer membrane. | 14 | 3 | 61 | CHEMBL_1 | 2009-09-03 |
CHEMBL1932915 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Synthesis and biological evaluation of sialic acid derivatives containing a long hydrophobic chain at the anomeric position and their C-5 linked polymers as potent influenza virus inhibitors. | 22100261 | 10.1016/j.bmc.2011.10.064 | nan | Suzuki K, Koyama T, Yingsakmongkon S, Suzuki Y, Hatano K, Matsuoka K. | 2012 | 20 | 1 | 446 | 454 | PUBLICATION | Conversions of the C-5 acetamide group in sialic acid into two kinds of C=C double bond substituents were accomplished under Shotten-Baumann conditions. The polymerizable glycomonomers also contain a hydrophobic chain or hydroxyl group at the anomeric position. Radical polymerizations of the fully protected glycomonomers were carried out with acryl amide in the presence of ammonium persulfate (APS) and N,N,N',N'-tetramethylethylenediamine (TEMED), followed by deprotection to furnish water-soluble glycopolymers. The activities of the deprotected glycopolymers and glycomonomers against human influenza viruses (H1N1 and H3N2) and avian influenza virus (H5N3) were evaluated. Biological evaluations showed that the glycomonomers containing a long hydrophobic chain at the anomeric position had both hemagglutination and neuraminidase inhibitory activities. | 3 | 6 | 18 | CHEMBL_14 | 2012-06-27 |
CHEMBL1150956 | Journal of natural products. | 1 | Scientific Literature | Antitubercular natural products: berberine from the roots of commercial Hydrastis canadensis powder. Isolation of inactive 8-oxotetrahydrothalifendine, canadine, beta-hydrastine, and two new quinic acid esters, hycandinic acid esters-1 and -2. | 9784149 | 10.1021/np9701889 | nan | Gentry EJ, Jampani HB, Keshavarz-Shokri A, Morton MD, Velde DV, Telikepalli H, Mitscher LA, Shawar R, Humble D, Baker W. | 1998 | 61 | 10 | 1187 | 1193 | PUBLICATION | Berberine (4) is responsible for the activity of an extract of a commercial root sample of Hydrastis canadensis against multiply drug resistant Mycobacterium tuberculosis. Two new quinic acid feruloyl esters, compounds 2 and 3, have been isolated from the same source along with canadine (1c), 8-oxotetrahydrothalifendine (1), and beta-hydrastine (5). These were found to be inactive. The structures of the new compounds were elucidated from spectral (1H, 13C, HMQC, HMBC, and H-H COSY) and chemical evidences. | 13 | 9 | 62 | CHEMBL_2 | 2009-11-30 |
CHEMBL1142851 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | An efficient synthesis of aryloxyphenyl cyclopropyl methanones: a new class of anti-mycobacterial agents. | 16087335 | 10.1016/j.bmcl.2005.07.007 | nan | Dwivedi N, Tewari N, Tiwari VK, Chaturvedi V, Manju YK, Srivastava A, Giakwad A, Sinha S, Tripathi RP. | 2005 | 15 | 20 | 4526 | 4530 | PUBLICATION | An efficient, high yield and one-pot synthesis of phenyl cyclopropyl methanones by reaction of different aryl alcohols with 4'-fluoro-4-chloro-butyrophenone in THF/DMF in the presence of NaH/TBAB is reported. Most of the methanones were further reduced to respective alcohols or methylenes. All the compounds were evaluated for their anti-tubercular activities against M. tuberculosis H37Rv in vitro displaying MICs ranging from 25 to 3.125 microg/mL. The most active compounds showed activity against MDR strains and two of them (14 and 16) showed marginal enhancement of MST in mice. | 29 | 1 | 58 | CHEMBL_1 | 2009-09-03 |
CHEMBL1150350 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery. | 18462943 | 10.1016/j.bmc.2008.04.015 | nan | Nordqvist A, Nilsson MT, Röttger S, Odell LR, Krajewski WW, Evalena Andersson C, Larhed M, Mowbray SL, Karlén A. | 2008 | 16 | 10 | 5501 | 5513 | PUBLICATION | A combination of a literature survey, structure-based virtual screening and synthesis of a small library was performed to identify hits to the potential antimycobacterial drug target, glutamine synthetase. The best inhibitor identified from the literature survey was (2S,5R)-2,6-diamino-5-hydroxyhexanoic acid (4, IC(50) of 610+/-15microM). In the virtual screening 46,400 compounds were docked and subjected to a pharmacophore search. Of these compounds, 29 were purchased and tested in a biological assay, allowing three novel inhibitors containing an aromatic scaffold to be identified. Based on one of the hits from the virtual screening a small library of 15 analogues was synthesized producing four compounds that inhibited glutamine synthetase. | 37 | 3 | 48 | CHEMBL_2 | 2009-11-30 |
CHEMBL1149604 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Disaccharide analogs as probes for glycosyltransferases in Mycobacterium tuberculosis. | 17544276 | 10.1016/j.bmc.2007.04.012 | nan | Pathak AK, Pathak V, Seitz L, Gurcha SS, Besra GS, Riordan JM, Reynolds RC. | 2007 | 15 | 16 | 5629 | 5650 | PUBLICATION | Glycosyltransferases (GTs) play a crucial role in mycobacterial cell wall biosynthesis and are necessary for the survival of mycobacteria. Hence, these enzymes are potential new drug targets for the treatment of tuberculosis (TB), especially multiple drug-resistant TB (MDR-TB). Herein, we report the efficient syntheses of Araf(alpha 1-->5)Araf, Galf(beta 1-->5)Galf, and Galf(beta 1-->6)Galf disaccharides possessing a 5-N,N-dimethylaminonaphthalene-1-sulfonamidoethyl (dansyl) unit that were prepared as fluorescent disaccharide acceptors for arabinosyl- and galactosyl-transferases, respectively. Such analogs may offer advantages relative to radiolabeled acceptors or donors for studying the enzymes and for assay development and compound screening. Additionally, analogs possessing a 5-azidonaphthalene-1-sulfonamidoethyl unit were prepared as photoaffinity probes for their potential utility in studying active site labeling of the GTs (arabinosyl and galactosyl) in Mycobacterium tuberculosis (MTB). Beyond their preparation, initial biological testing and kinetic analysis of these disaccharides as acceptors toward glycosyltransferases are also presented. | 6 | 1 | 6 | CHEMBL_1 | 2009-09-03 |
CHEMBL1136997 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | An atom economic synthesis and antitubercular evaluation of novel spiro-cyclohexanones. | 19473840 | 10.1016/j.bmcl.2009.05.018 | nan | Ranjith Kumar R, Perumal S, Manju SC, Bhatt P, Yogeeswari P, Sriram D. | 2009 | 19 | 13 | 3461 | 3465 | PUBLICATION | The 1,3-dipolar cycloaddition of azomethine ylides derived from acenaphthenequinone and alpha-amino acids viz. sarcosine, phenylglycine, 1,3-thiazolane-4-carboxylic acid and proline to a series of 2,6-bis[(E)-arylmethylidene]cyclohexanones afforded novel spiro-heterocycles chemo-, regio- and stereoselectively in quantitative yields. These compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Two compounds, 4-(2,4-dichlorophenyl)-5-phenylpyrrolo(spiro[2.2'']acenaphthene-1''-one)spiro[3.2']-6'-(2,4-dichlorophenylmethylidene)cyclohexanone (4i) and spiro[5.2'']acenaphthene-1''-onespiro[6.2']-6'-(2,4-dichlorophenylmethylidene)cyclohexanone-7-(2,4-dichlorophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole (5i) display maximum activity in vitro with a MIC value of 0.40microg/mL against MTB and were 4 and 15.6 times more potent than ethambutol and pyrazinamide, respectively. | 28 | 1 | 28 | CHEMBL_2 | 2009-11-30 |
CHEMBL1158339 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and anti-microbial screening of some Schiff bases of 3-amino-6,8-dibromo-2-phenylquinazolin-4(3H)-ones. | 18603337 | 10.1016/j.ejmech.2008.04.010 | nan | Panneerselvam P, Rather BA, Ravi Sankar Reddy D, Ramesh Kumar N. | 2009 | 44 | 5 | 2328 | 2333 | PUBLICATION | In the present study, a series of novel Schiff bases were synthesized by condensation of 3-amino-6,8-dibromo-2-phenylquinazolin-4(3H)-ones with different aromatic aldehydes via cyclized intermediate 6,8-dibromo-2-phenyl benzoxazin-4-one. The chemical structures were confirmed by means of IR, (1)H NMR, (13)C NMR, Mass spectral and Elemental analysis. These compounds were screened for anti-bacterial (Staphylococcus aureus ATCC-9144, Staphylococcus epidermidis ATCC-155, Micrococcus luteus ATCC-4698, Bacillus cereus ATCC-11778, Escherichia coli ATCC-25922, Pseudomonas aeruginosa ATCC-2853, and Klebsiella pneumoniae ATCC-11298) and anti-fungal (Aspergillus niger ATCC-9029 and Aspergillus fumigatus ATCC-46645) activities by paper disc diffusion technique. The minimum inhibitory concentrations (MICs) of the compounds were also determined by agar streak dilution method. Among the synthesized compounds 3-(3,4,5-trimethoxybenzylideneamino)-6,8-dibromo-2-phenylquinazolin-4(3H)-one 10 was found to be the most potent anti-microbial activity with MICs of 18.9, 19.1, 18.8, 21.7, 18.2, 19.3, 16.7, 8.6 and 10.1 microg/ml against above mentioned respective strains. Compounds were found to exhibit more anti-fungal than anti-bacterial activity. | 14 | 9 | 234 | CHEMBL_3 | 2010-04-16 |
CHEMBL3085639 | European journal of medicinal chemistry. | 1 | Scientific Literature | Novel camphane-based anti-tuberculosis agents with nanomolar activity. | 24177364 | 10.1016/j.ejmech.2013.10.015 | nan | Stavrakov G, Valcheva V, Philipova I, Doytchinova I. | 2013 | 70 | nan | 372 | 379 | PUBLICATION | A series of new amidoalcohols and amidodiols were designed on the base of the camphor scaffold and evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv and MDR strain 43. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. Small structural changes in the side chain shift the activity from micromolar to nanomolar inhibitory concentrations. Quantitative structure-activity relationship (QSAR) model is derived to guide the further lead optimization. Two hydrogen bond donors and up to three rings in the molecules are optimal for nanomolar activity. The camphane-based amides present novel promising scaffolds for antimycobacterial agents. | 14 | 1 | 39 | CHEMBL_19 | 2014-07-03 |
CHEMBL3045705 | Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents. | 1 | Scientific Literature | Thermal, kinetic, spectroscopic studies and anti-microbial, anti-tuberculosis, anti-oxidant properties of clioquinol and benzo-coumarin derivatives mixed complexes with copper ion | nan | 10.1007/s00044-013-0576-6 | nan | Dholariya HR, Patel KS, Patel JC, Patel AK, Patel KD | 2013 | 22 | 12 | 5848 | 5860 | PUBLICATION | nan | 14 | 7 | 84 | CHEMBL_19 | 2014-07-03 |
CHEMBL1687831 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Novel insights into the mode of inhibition of class A SHV-1 beta-lactamases revealed by boronic acid transition state inhibitors. | 21041505 | 10.1128/aac.00930-10 | nan | Ke W, Sampson JM, Ori C, Prati F, Drawz SM, Bethel CR, Bonomo RA, van den Akker F. | 2011 | 55 | 1 | 174 | 183 | PUBLICATION | Boronic acid transition state inhibitors (BATSIs) are potent class A and C β-lactamase inactivators and are of particular interest due to their reversible nature mimicking the transition state. Here, we present structural and kinetic data describing the inhibition of the SHV-1 β-lactamase, a clinically important enzyme found in Klebsiella pneumoniae, by BATSI compounds possessing the R1 side chains of ceftazidime and cefoperazone and designed variants of the latter, compounds 1 and 2. The ceftazidime and cefoperazone BATSI compounds inhibit the SHV-1 β-lactamase with micromolar affinity that is considerably weaker than their inhibition of other β-lactamases. The solved crystal structures of these two BATSIs in complex with SHV-1 reveal a possible reason for SHV-1's relative resistance to inhibition, as the BATSIs adopt a deacylation transition state conformation compared to the usual acylation transition state conformation when complexed to other β-lactamases. Active-site comparison suggests that these conformational differences might be attributed to a subtle shift of residue A237 in SHV-1. The ceftazidime BATSI structure revealed that the carboxyl-dimethyl moiety is positioned in SHV-1's carboxyl binding pocket. In contrast, the cefoperazone BATSI has its R1 group pointing away from the active site such that its phenol moiety moves residue Y105 from the active site via end-on stacking interactions. To work toward improving the affinity of the cefoperazone BATSI, we synthesized two variants in which either one or two extra carbons were added to the phenol linker. Both variants yielded improved affinity against SHV-1, possibly as a consequence of releasing the strain of its interaction with the unusual Y105 conformation. | 4 | 1 | 8 | CHEMBL_11 | 2011-08-01 |
CHEMBL2429741 | Journal of medicinal chemistry. | 1 | Scientific Literature | IspC as target for antiinfective drug discovery: synthesis, enantiomeric separation, and structural biology of fosmidomycin thia isosters. | 24032981 | 10.1021/jm4012559 | nan | Kunfermann A, Lienau C, Illarionov B, Held J, Gräwert T, Behrendt CT, Werner P, Hähn S, Eisenreich W, Riederer U, Mordmüller B, Bacher A, Fischer M, Groll M, Kurz T. | 2013 | 56 | 20 | 8151 | 8162 | PUBLICATION | The emergence and spread of multidrug-resistant pathogens are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the synthesis and properties of 'reverse' thia analogs of fosmidomycin, which inhibit the first committed enzyme of a metabolic pathway that is essential for the causative agents of tuberculosis and malaria but is absent in the human host. Notably, IspC displays a high level of enantioselectivity for an α-substituted fosmidomycin derivative. | 25 | 3 | 121 | CHEMBL_18 | 2014-03-12 |
CHEMBL2424522 | European journal of medicinal chemistry. | 1 | Scientific Literature | Demonic axe-like conjugated alkynes in combating microbes. | 23973825 | 10.1016/j.ejmech.2013.07.013 | nan | Komsani JR, Koppireddi S, Avula S, Koochana PK, Yadla R. | 2013 | 68 | nan | 132 | 138 | PUBLICATION | A new series of disubstituted alkynes was obtained by microwave induced internal splitting of the corresponding β-oxo-alkylidenetriphenylphosphoranes. The antimicrobial potential of these conjugated alkynes and phosphoranes was assayed in vitro against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Staphylococcus epidermidis), three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and five fungal strains (Aspergillus niger, Candida albicans, Aspergillus flavus, Candida rugosa, Saccharomyces cerevisiae). The 3-pyridylalkyne derivatives viz., 3-(6-chloropyridin-3-yl)propynenitrile (6a), 3-(2-chloropyridin-3-yl)propynenitrile (6b), ethyl 3-(6-chloropyridin-3-yl)propiolate (6c), iso-propyl 3-(6-chloropyridin-3-yl)propiolate (6d) and 3-(2,6-dichloro-5-fluoropyridin-3-yl)propynenitrile (6e) were found to be highly potent towards all tested microorganisms except E. coli. | 27 | 11 | 321 | CHEMBL_18 | 2014-03-12 |
CHEMBL2157880 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis, antimycobacterial and antibacterial activity of ciprofloxacin derivatives containing a N-substituted benzyl moiety. | 22884110 | 10.1016/j.bmcl.2012.07.040 | nan | Wang S, Jia XD, Liu ML, Lu Y, Guo HY. | 2012 | 22 | 18 | 5971 | 5975 | PUBLICATION | We report herein the design and synthesis of a series of novel ciprofloxacin (CPFX) derivatives with remarkable improvement in lipophilicity by introducing a substituted benzyl moiety to the N atom on the C-7 piperazine ring of CPFX. Antimycobacterial and antibacterial activity of the newly synthesized compounds was evaluated. Results reveal that compound 4f has good in vitro activity against all of the tested Gram-positive strains including MRSA and MRSE (MICs: 0.06-32 μg/mL) which is two to eightfold more potent than or comparable to the parent drug CPFX (MICs: 0.25-128 μg/mL), Gram-negative bacteria P. aeruginosa (MICs: 0.5-4 μg/mL) and M. tuberculosis H37Rv ATCC 27294 (MIC: 1 μg/mL). | 17 | 9 | 664 | CHEMBL_16 | 2013-05-07 |
CHEMBL3112403 | European journal of medicinal chemistry. | 1 | Scientific Literature | Design, synthesis and evaluation of second generation MurF inhibitors based on a cyanothiophene scaffold. | 24384549 | 10.1016/j.ejmech.2013.11.031 | nan | Hrast M, Anderluh M, Knez D, Randall CP, Barreteau H, O'Neill AJ, Blanot D, Gobec S. | 2014 | 73 | nan | 83 | 96 | PUBLICATION | MurF ligase is a crucial enzyme that catalyses the ultimate intracellular step of bacterial peptidoglycan biosynthesis, and thus represents an attractive target for antibacterial drug discovery. We designed, synthesized and evaluated a new series of cyanothiophene-based inhibitors of MurF enzymes from Streptococcus pneumoniae and Escherichia coli. The target compounds had increased polarity compared to the first generation of inhibitors, with demonstrated enzyme inhibitory potencies in the low micromolar range. Furthermore, the best inhibitors displayed promising antibacterial activities against selected Gram-positive and Gram-negative strains. These results represent an important step towards the development of new antibacterial agents targeting peptidoglycan biosynthesis. | 39 | 4 | 286 | CHEMBL_19 | 2014-07-03 |
CHEMBL3392963 | European journal of medicinal chemistry. | 1 | Scientific Literature | Piperazine derivatives: synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase and SAR studies. | 25461892 | 10.1016/j.ejmech.2014.11.034 | nan | Rotta M, Pissinate K, Villela AD, Back DF, Timmers LF, Bachega JF, de Souza ON, Santos DS, Basso LA, Machado P. | 2015 | 90 | nan | 436 | 447 | PUBLICATION | The Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein reductase (MtInhA) catalyzes hydride transfer to long-chain enoyl thioester substrates. MtInhA is a member of the mycobacterial type II dissociated fatty acid biosynthesis system, and is the bona fide target for isoniazid, the most prescribed drug for tuberculosis treatment. Here, a series of piperazine derivatives was synthesized and screened as MtInhA inhibitors, which resulted in the identification of compounds with IC50 values in the submicromolar range. A structure-activity relationship (SAR) evaluation indicated the importance of the chemical environment surrounding the carbonyl group for inhibition. In addition, the structure of one selected compound was supported by crystallographic studies, and experimental geometrical values were compared with semi-empirical quantum chemical calculations. Furthermore, the mode of inhibition and inhibitory dissociation constants were determined for the nine most active compounds. These findings suggest that these 9H-fluoren-9-yl-piperazine-containing compounds interact with MtInhA at the enoyl thioester (2-trans-dodecenoyl-CoA) substrate binding site. | 25 | 2 | 67 | CHEMBL_21 | 2016-02-01 |
CHEMBL2034954 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antimycobacterial activity of novel 1,3-dimethylisocyanurate derivatives. | 22578509 | 10.1016/j.ejmech.2012.04.014 | nan | Shulaeva MM, Fattakhov SG, Saifina LF, Chestnova RV, Valijev RSh, Mingaleev DN, Voloshina AD, Reznik VS. | 2012 | 53 | nan | 300 | 307 | PUBLICATION | A series of novel 1,3-dimethylisocyanurates has been synthesized as potential inhibitors of β-ketoacyl synthase in mycobacteria. Most of the 25 compounds described and tested for their activity against M. tuberculosis have a bacteriostatic effect, comparable and even higher that of first-line antituberculosis drugs. These compounds are nontoxic, species-specific, exhibiting no activity against other bacterial species. | 28 | 9 | 207 | CHEMBL_15 | 2013-01-23 |
CHEMBL2021789 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Molecular docking and enzymatic evaluation to identify selective inhibitors of aspartate semialdehyde dehydrogenase. | 22464683 | 10.1016/j.bmc.2012.03.013 | nan | Luniwal A, Wang L, Pavlovsky A, Erhardt PW, Viola RE. | 2012 | 20 | 9 | 2950 | 2956 | PUBLICATION | Microbes that have gained resistance against antibiotics pose a major emerging threat to human health. New targets must be identified that will guide the development of new classes of antibiotics. The selective inhibition of key microbial enzymes that are responsible for the biosynthesis of essential metabolites can be an effective way to counter this growing threat. Aspartate semialdehyde dehydrogenases (ASADHs) produce an early branch point metabolite in a microbial biosynthetic pathway for essential amino acids and for quorum sensing molecules. In this study, molecular modeling and docking studies were performed to achieve two key objectives that are important for the identification of new selective inhibitors of ASADH. First, virtual screening of a small library of compounds was used to identify new core structures that could serve as potential inhibitors of the ASADHs. Compounds have been identified from diverse chemical classes that are predicted to bind to ASADH with high affinity. Next, molecular docking studies were used to prioritize analogs within each class for synthesis and testing against representative bacterial forms of ASADH from Streptococcus pneumoniae and Vibrio cholerae. These studies have led to new micromolar inhibitors of ASADH, demonstrating the utility of this molecular modeling and docking approach for the identification of new classes of potential enzyme inhibitors. | 13 | 1 | 28 | CHEMBL_15 | 2013-01-23 |
CHEMBL2021808 | European journal of medicinal chemistry. | 1 | Scientific Literature | Chemical synthesis and biological evaluation of triazole derivatives as inhibitors of InhA and antituberculosis agents. | 22483635 | 10.1016/j.ejmech.2012.03.029 | nan | Menendez C, Chollet A, Rodriguez F, Inard C, Pasca MR, Lherbet C, Baltas M. | 2012 | 52 | nan | 275 | 283 | PUBLICATION | A series of triazoles have been prepared and evaluated as inhibitors of InhA as well as inhibitors of Mycobacterium tuberculosis H(37)R(v). Several of these new compounds possess a good activity against InhA, particularly compounds 17 and 18 for which molecular docking has been performed. Concerning their activities against M. tuberculosis H(37)R(V) strain, two of them, 3 and 12, were found to be good inhibitors with MIC values of 0.50 and 0.25 μg/mL, respectively. Particularly, compound 12 presenting the best MIC value of all compounds tested (0.6 μM) is totally inactive against InhA. | 32 | 2 | 62 | CHEMBL_15 | 2013-01-23 |
CHEMBL1944567 | Journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis, biological evaluation, and molecular modeling of chalcone derivatives as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatases (PtpA and PtpB). | 22136336 | 10.1021/jm2012062 | nan | Chiaradia LD, Martins PG, Cordeiro MN, Guido RV, Ecco G, Andricopulo AD, Yunes RA, Vernal J, Nunes RJ, Terenzi H. | 2012 | 55 | 1 | 390 | 402 | PUBLICATION | Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure-activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC(50) values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs. | 104 | 5 | 394 | CHEMBL_14 | 2012-06-27 |
CHEMBL1955865 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis of novel spirooxindole derivatives by one pot multicomponent reaction and their antimicrobial activity. | 22405285 | 10.1016/j.ejmech.2012.02.024 | nan | Bhaskar G, Arun Y, Balachandran C, Saikumar C, Perumal PT. | 2012 | 51 | nan | 79 | 91 | PUBLICATION | A series of novel spirooxindoles have been synthesized through 1,3-dipolar cycloaddition of an azomethine ylide generated from isatin and sarcosine or l-proline with the dipolarophile 1,4-naphthoquinone followed by spontaneous dehydrogenation. Synthesised compounds were evaluated for their antimicrobial activities against eight bacteria and three fungi. All the spirooxindole derivatives exhibited significant antibacterial activity against Staphylococcus aureus, S. aureus (MRSA), Enterobacter aerogens, Micrococcus luteus, Proteus vulgaris, Klebsiella pneumonia, Salmonella typhimurium, Salmonella paratyphi-B and anti-fungal activity against Malassesia pachydermatis, Candida albicans and Botyritis cinerea organisms. Among 23 compounds screened, 1'-acetyl-2,5'-dimethyl-2,3-dihydrospiro[benzo[f]isoindole-1,3'-indoline]-2',4,9-trione was found to be more active against tested bacteria and fungi. | 27 | 10 | 412 | CHEMBL_14 | 2012-06-27 |
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