title: Structure-activity relationship studies on 3,5-dinitrophenyl tetrazoles as antitubercular agents.
abstract: In this study, we described the structure-activity relationships of substituted 3,5-dinitrophenyl tetrazoles as potent antitubercular agents. These simple and readily accessible compounds possessed high in vitro antimycobacterial activities against Mycobacterium tuberculosis, including clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with submicromolar minimum inhibitory concentrations (MICs). The most promising compounds showed low in vitro cytotoxicity and negligible antibacterial and antifungal activities, highlighting their highly selective antimycobacterial effects. 2-Substituted 5-(3,5-dinitrophenyl)-2H-tetrazole regioisomers, which are the dominant products of 5-(3,5-dinitrophenyl)-1H-tetrazole alkylation, showed better properties with respect to antimycobacterial activity and cytotoxicity than their 1-substituted counterparts. The 2-substituent of 5-(3,5-dinitrophenyl)-2H-tetrazole can be easily modified and can thus be used for the structure optimization of these promising antitubercular agents. The introduction of a tetrazole-5-thioalkyl moiety at position 2 of the tetrazole further increased the antimycobacterial activity. These compounds showed outstanding in vitro activity against M. tuberculosis (MIC values as low as 0.03 μM) and high activity against non-tuberculous mycobacterial strains.
authors.affiliation: Charles University, 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, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005, Hradec Králové, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Sychra
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005, Hradec Králové, Czech Republic.
authors.forename: Miloslav
authors.initials: M
authors.lastname: Macháček
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove, Sokolská 581, 50005, Hradec Králové, Czech Republic.
authors.forename: Markéta
authors.initials: M
authors.lastname: Benková
authors.affiliation: Charles University, 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, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005, Hradec Králové, Czech Republic.
authors.forename: Klára
authors.initials: K
authors.lastname: Konečná
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005, Hradec Králové, Czech Republic.
authors.forename: Věra
authors.initials: V
authors.lastname: Kavková
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, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005, Hradec Králové, Czech Republic.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Hrabálek
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005, Hradec Králové, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Vávrová
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove, Sokolská 581, 50005, Hradec Králové, Czech Republic.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: Charles University, 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, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005, Hradec Králové, Czech Republic.
authors.forename: Věra
authors.initials: V
authors.lastname: Klimešová
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D013777:Tetrazoles
keywords: Antitubercular agent; Mycobacterium tuberculosis; Regioisomers; Structure-activity relationships; Tetrazole; Tuberculosis