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
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Alcohol Oxidoreductases antagonists & inhibitors metabolism MeSH
- Antitubercular Agents chemical synthesis chemistry pharmacology MeSH
- Bacterial Proteins antagonists & inhibitors metabolism MeSH
- Dinitrobenzenes chemical synthesis chemistry pharmacology MeSH
- Hydrocarbons, Fluorinated chemical synthesis chemistry pharmacology MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Mycobacterium tuberculosis drug effects enzymology MeSH
- Triazoles chemical synthesis chemistry pharmacology MeSH
- Drug Development * MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Alcohol Oxidoreductases MeSH
- Antitubercular Agents MeSH
- Bacterial Proteins MeSH
- Dinitrobenzenes MeSH
- DprE1 protein, Mycobacterium tuberculosis MeSH Browser
- Hydrocarbons, Fluorinated MeSH
- Triazoles MeSH
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.
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