Nitro ( triazole / imidazole ) - based amides / sulfonamides 1 as antitubercular agents

Twenty-three (3-nitrotriazole/2-nitroimidazole)-based amides and sulfonamides were 20 screened for antitubercular activity in aerobic Mycobacterium tuberculosis H37Rv (Mtb H37Rv), 21 by using the BacTiter-GloTM Microbial Cell Viability (BTG) assay. In general, 3-nitrotriazole22 based sulfonamides demonstrated anti-TB activity, whereas 3-nitrotriazole-based amides and 223 nitroimidazole-based amides/sulfonamides were inactive. Three 3-nitrotriazole-based 24 sulfonamides (compounds 4, 2 and 7) demonstrated IC50, IC90 and MIC values of 0.38, 0.43, 1.56 25 ; 0.57, 0.98, 3.13 and 0.79, 0.87, 3.13 μM, respectively. For 3-nitrotriazole-based sulfonamides, 26 anti-TB activity increased with lipophilicity whereas one electron reduction potential (E1/2) did 27 not play a role. 2-Nitroimidazole-based analogs, which were inactive in the BTG assay, were 28 significantly more active in the Low Oxygen assay and more active than the 3-nitrotriazoles. All 29 active nitrotriazoles in the BTG assay were similarly active or more potent (lower MIC values) 30 against resistant strains with the exception of compounds 2, 3, 4 and 8 which demonstrated 31 greater MIC values against isoniazid resistant strains. Five 3-nitrotriazole-based sulfonamides 32 demonstrated activity in infected murine J774 macrophage, causing log reduction similar to that 33 of rifampin. However, some compounds caused toxicity in uninfected macrophages. In 34 conclusion, the classes of 3-nitrotriazole-based amides/sulfonamides merit further investigation 35 as potential anti-tubercular agents. 36 37