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.

本研究报道了3,5-二硝基苯基1,2,4-三唑类化合物的发现，该类化合物对结核分枝杆菌（Mycobacterium tuberculosis）菌株（包括临床分离的多药耐药菌株）展现出优异且具有选择性的抗分枝杆菌活性。针对含3,5-二硝基苯基的1,2,4-三唑类化合物及其三氟甲基类似物开展的系统构效关系研究表明，3,5-二硝基苯基片段的取代位置对其抗结核活性具有关键影响。在所合成的化合物中，S-取代的4-烷基-5-(3,5-二硝基苯基)-4H-1,2,4-三唑-3-硫醇及其3-硝基-5-(三氟甲基)苯基类似物，对结核分枝杆菌H37Rv菌株以及7株临床分离的多药耐药结核分枝杆菌菌株展现出最高的体外抗分枝杆菌活性。此类化合物的最低抑菌浓度可达0.03 μM，优于当前所有一线抗结核药物。此外，几乎所有具备优异抗分枝杆菌活性的化合物，对两种增殖性哺乳动物细胞系均表现出极低的体外细胞毒性。分子对接研究表明，此类化合物可作为癸异戊烯基磷酸基-β-D-呋喃核糖2'-氧化酶的抑制剂，该作用机制已通过两项独立的放射性标记实验得到实验验证。