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

We report herein the discovery of
3,5-dinitrophenyl 1,2,4-triazoles
with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis 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 M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant
strains of M. tuberculosis were found
with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-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.