title: Nitrotriazole- and imidazole-based amides and sulfonamides as antitubercular agents.
abstract: Twenty-three 3-nitrotriazole-based and 2-nitroimidazole-based amides and sulfonamides were screened for antitubercular (anti-TB) activity in aerobic Mycobacterium tuberculosis H37Rv by using the BacTiter-Glo (BTG) microbial cell viability assay. In general, 3-nitrotriazole-based sulfonamides demonstrated anti-TB activity, whereas 3-nitrotriazole-based amides and 2-nitroimidazole-based amides and sulfonamides were inactive. Three 3-nitrotriazole-based sulfonamides (compounds 4, 2, and 7) demonstrated 50% inhibitory concentration (IC50), IC90, and MIC values of 0.38, 0.43, and 1.56 μM (compound 4), 0.57, 0.98, and 3.13 μM (compound 2), and 0.79, 0.87, and 3.13 μM (compound 7), respectively. For 3-nitrotriazole-based sulfonamides, anti-TB activity increased with lipophilicity, whereas the one-electron reduction potential (E1/2) did not play a role. 2-Nitroimidazole-based analogs, which were inactive in the BTG assay, were significantly more active in the low-oxygen assay and more active than the 3-nitrotriazoles. All active nitrotriazoles in the BTG assay were similarly active or more potent (lower MIC values) against resistant strains, with the exception of compounds 2, 3, 4, and 8, which demonstrated greater MIC values against isoniazid-resistant strains. Five 3-nitrotriazole-based sulfonamides demonstrated activity in infected murine J774 macrophages, causing log reductions similar to those seen with rifampin. However, some compounds caused toxicity in uninfected macrophages. In conclusion, the classes of 3-nitrotriazole-based amides and sulfonamides merit further investigation as potential antitubercular agents.
authors.affiliation: NorthShore University HealthSystem, Department of Radiation Medicine, Evanston, Illinois, USA mpapadopoulou@northshore.org.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Papadopoulou
authors.affiliation: NorthShore University HealthSystem, Department of Radiation Medicine, Evanston, Illinois, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Bloomer
authors.affiliation: Oakton Community College, Des Plaines, Illinois, USA.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Rosenzweig
authors.affiliation: San Diego State University, Department of Chemistry, San Diego, California, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Arena
authors.affiliation: San Diego State University, Department of Chemistry, San Diego, California, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Arrieta
authors.affiliation: San Diego State University, Department of Chemistry, San Diego, California, USA.
authors.forename: Joseph C J
authors.initials: JC
authors.lastname: Rebolledo
authors.affiliation: San Diego State University, Department of Chemistry, San Diego, California, USA.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Smith
mesh_terms: D000577:Amides / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D000995:Antitubercular Agents / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000577:Amides; D000995:Antitubercular Agents; D007093:Imidazoles; D009593:Nitroimidazoles; D013449:Sulfonamides; C029899:imidazole; D007538:Isoniazid