AN OVERVIEW ON 1,2,4-TRIAZOLE AND 1,3,4-THIADIAZOLE DERIVATIVES AS POTENTIAL ANESTHESIC AND ANTI-INFLAMMATORY AGENTS

data on the synthesis and structural modification of heterocy clic systems with triazole and thiadiazole fragments in molecules as promising objects in bioorganic and medicinal chemistry. Synthetic research allows to propose a whole number of new molecular design directions of biological active triazole and/or thiadiazole derivatives, as well as to obtain directed library that include hundreds of new compounds. This review is an effort to summarize data of its analgesic and anti-inflammatory activity over the last decade. We summarized and analyzed the series of triazole and/or thiadiazole derivatives and provided data of their struc-ture-activity relationship. For optimization and rational design of highly active molecules with optimal «drug-like» characteristics and discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were summarized. Conclusions . It has been shown that heterocyclic systems containing fragments of triazole and/or thiadiazole are a significant source of promising analgesic and/or anti-inflammatory agents. It has been established that the mentioned heterocyclic derivatives have a high selectivity of action, low toxicity and an effect commensurate with standard drugs


Introduction
In recent years, heterocyclic compounds and their analogues are of considerable interest due to the wide range of their useful biological and pharmacological properties. Thus, different classes of heterocyclic systems underlie most existing drugs or compounds that are in the final stages of preclinical trials [1][2][3][4][5]. The particular interest in this context is the study of heterocyclic compounds based on azole core, which has significant synthetic and pharmacological potential [6][7][8][9][10]. The uniqueness of these heterocycle systems is based on easy functionalization with the possibility of obtaining various condensed [11][12][13][14][15][16][17] and non-condensed derivatives [18][19][20][21][22][23]. In addition, the use of modern approaches for studying this class heterocycles such as target-oriented [24][25][26] and diversity-oriented synthesis (DOS) approaches [27][28][29][30] are an opportunity to obtain combinatorial libraries to effectively searching new drugs or drug candidates.
The aim of the study was to analyze the literature data about the synthesis and biological activity evaluation of heterocyclic compounds with triazole and thiadiazole fragments in molecules.

Materials and methods
Bibliosemantic and analytical methods were used in the study. During the literature review were used also bibliographic and abstract databases (Pubmed), as well as databases of chemical compounds (PubChem, Reaxys and SciFinder).
The authors [57] observed moderate antiexudative and significant antinociceptive activity of 3-β-[(N-benzenesulfonyl/tosyl)-4-phenylamino]ethyl-4-amino-5mercapto-4(H)-1,2,4-triazoles 4. Studied derivatives also showed a significant anti-exudative effect in the model of carrageenan edema in rats at the level of acetylsalicylic acid, as well as in the model of cotton granuloma. Moreover, the synthesized compounds did not have ulcerogenic action in experimental animals. The significant activity of these derivatives was demonstrated in the model of thermal nociceptive stimulation of tail flick, with 81.02-120.72 % inhibition compared with aspirin (49.39 % inhibition). The authors established the analgesic effect of target compounds related with a presence of biologically active sulfonamide fragment in the structure.
Synthesized 5-carbomethoxy-2-substituted-7H-1,2,4-triazolo[3,2-b]-1,3-thiazin-7-one derivatives 5 showed pronounced anti-inflammatory activity under oral administration in low doses (10 and 20 mg/kg) in models of carrageenan and serotonin edema which were equal or higher to diclofenac sodium. It should be noted that the anti-exudative activity correlated with the analgesic effect in the model of acetic acid-induced writhing response in mice. In addition, these biological effects were not accompanied by gastric lesions [58].
Condensed 1,2,4-triazoles with a 2,4-dichlorophenoxyl moiety in molecules 7 showed anti-inflammatory activity under intragastrically administration in equal doses to indomethacin [60]. These compounds showed a dose-dependent anti-inflammatory effect in carrageenan and histamine edema models. Condensed derivatives with 2,4-dichlorophenoxyl group at position 6 showed the highest activity comparable to indomethacin, with 36-56 % inhibition of exudative inflammation.
3-(N-substituted carboxamidoethylthio)-4H-1,2,4-triazole derivatives 8 under administration intraperitoneally to rats at a dose of 40 mg/kg showed a significant antiexudative effect in the model of formalin edema with 25.92 %-44.44 % inhibition which exceeds reference drug diclofenac sodium (23.14 %). The anti-exudative effect of the studied compounds depends on the presence of chloro-, nitro-, methyl-or methoxy groups in the phenyl substituent. Several mentioned compounds also showed an antinociceptive effect on the hot plate model (up to 303.4 %), which exceeds the parameters of tramadol (169.4 %). In addition, the most active derivatives did not show anxiolytic activity [61]. The authors [62] studied 1,3,4-thiadiazole and 1,2,4-triazole derivatives containing a phenylalanine moiety 9. The studied derivatives had low toxicity (LD 50 1025-5010 mg/kg when administered intragastrically). When administered target derivatives at doses of 1/10 LD50 and 1/5 LD50 in the nystatin edema model, the compounds generally exeeded acetylsalicylic acid and phenylbutazone at the respective doses, but possess less activity than indomethacin.
Triazole-containing tetracyclic thienopyrimidines have proven to be promising as potential anti-inflammatory and analgesic agents [63]. The administration orally of mentioned compounds at doses of 10 mg/kg, predominate or are equivalent in analgesic and antiexudative activity diclofenac sodium in carrageenan edema (edema inhibition from -31.2 % to -56.1 %) and acetic acid-induced writhing response (degree of inhibition from 45.3 % -up to 71.7 %) models in mice. It worth mentioned that the tested compounds did not have ulcerogenic effect.
The authors [69] reported in vitro and in vivo screening for the anti-inflammatory activity of a series of pyridine-substituted triazoles and thiadiazoles 13 on carrageenan-induced paw edema model. In vivo experiments were performed on albino rats using indomethacin as a reference drug. sessed significant antiexudative activity on carrageenan-induced paw edema and serotonin edema models comparable to reference drug diclofenac sodium.
Interesting data are given by the authors [72], who report the study of the activity of numerous triazole and thiadiazole derivatives 16. The synthesized compounds were studied for analgesic activity in the hot plate model. The results of a study of recently synthesized derivatives of triazolethiadiazole and triazolothiadiazines 17, including 3-nitronaphtho[2,1-b]furan moiety, showed a significant antinociceptive effect of these heterocyclic compounds [73] (Fig. 3). The activity of the synthesized derivatives was comparable to the standard drug (tramadol). In addition, triazolethiadiazole and triazolothiadiazine derivatives possess other types of biological activities, namely anticancer [74][75][76], antileishmanial [77] and antimicrobial [78][79][80][81][82][83].

Conclusion
We reviewed data on the anti-inflammatory and analgesic activity of compounds containing triazole and/or thiadiazole fragment in molecules. Data analysis showed that these derivatives are characterized by significant antinociceptive and antiexudative effects, which are often accompanied by low toxicity, lack of ulcerogenic action, which reveal the significant interest to pharmacy and medicine. The activity profile of these derivatives is based on the nature of the substituent of the basic triazole and/or thiadiazole core. The use of the obtained literature data and their systematic analysis could be promising for the rational design of potential biologically active molecules and further study of the pharmacological effect of mentioned derivatives.

Conflict of interests
The authors declare there is no conflict of interests.

Financing
The research leading to these results has received funding from the Ministry of Health of Ukraine, under the project number: 0121U100690, and the National Research Foundation of Ukraine, under the project number: 2020.02/0035.