Development of 3,5-Dinitrophenyl-Containing 1,2,4-Triazoles and Their Trifluoromethyl Analogues as Highly Efficient Antitubercular Agents Inhibiting Decaprenylphosphoryl-β-d-ribofuranose 2'-Oxidase.
Karabanovich G, Dušek J, Savková K, Pavliš O, Pávková I, Korábečný J, Kučera T, Kočová Vlčková H, Huszár S, Konyariková Z, Konečná K, Jand'ourek O, Stolaříková J, Korduláková J, Vávrová K, Pávek P, Klimešová V, Hrabálek A, Mikušová K, Roh J.
We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against <i>Mycobacterium tuberculosis</i> strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against <i>M. tuberculosis</i> H<sub>37</sub>Rv and against seven clinically isolated multidrug-resistant strains of <i>M. tuberculosis</i> were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4<i>H</i>-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-β-d-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.