title: 1-Substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles and their isosteric analogs: A new class of selective antitubercular agents active against drug-susceptible and multidrug-resistant mycobacteria.
abstract: In this work, a new class of highly potent antituberculosis agents, 1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles and their oxa and selanyl analogs, is described. The minimal inhibitory concentration (MIC) values reached 1 μM (0.36-0.44 μg/mL) against Mycobacterium tuberculosis CNCTC My 331/88 and 0.25-1 μM against six multidrug-resistant clinically isolated strains of M. tuberculosis. The antimycobacterial effects of these compounds were highly specific because they were ineffective against all eight bacterial strains and eight fungal strains studied. Furthermore, these compounds exhibited low in vitro toxicity in four mammalian cell lines (IC50 > 30 μM). We also examined the structure-activity relationships of the compounds, particularly the effects on antimycobacterial activity of the number and position of the nitro groups, the linker between tetrazole and benzyl moieties, and the tetrazole itself. Relatively high variability of substituent R(1) on the tetrazole in the absence of negative effects on antimycobacterial activity allows further structural optimization with respect to toxicity and the ADME properties of the 1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles lead compounds.
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Galina
authors.initials: G
authors.lastname: Karabanovich
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic. Electronic address: jaroslav.roh@faf.cuni.cz.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Roh
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Smutný
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Němeček
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Vicherek
authors.affiliation: Regional Institute of Public Health, Department of Bacteriology and Mycology, Partyzánské náměstí 7, 70200 Ostrava, Czech Republic.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Stolaříková
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Marcela
authors.initials: M
authors.lastname: Vejsová
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Ida
authors.initials: I
authors.lastname: Dufková
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Vávrová
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Pávek
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Věra
authors.initials: V
authors.lastname: Klimešová
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Hrabálek
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009578:Nitrobenzenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D009578:Nitrobenzenes; D014230:Triazoles
keywords: Antituberculosis drug; Mycobacterium; Selectivity; Structure–activity relationships; Tetrazole; Tuberculosis