title: S-substituted 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols as highly efficient antitubercular agents.
abstract: Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.03 μM. Furthermore, these compounds had a highly selective antimycobacterial effect because they were completely inactive against 4 gram positive and 4 gram negative bacteria and eight fungal strains and had low in vitro toxicity for four mammalian cell lines, including hepatic cell lines HepG2 and HuH7. Although the structure-activity relationship study showed that the presence of two nitro groups is highly beneficial for antimycobacterial activity, the analogues with a trifluoromethyl group instead of one of the nitro groups maintained a high antimycobacterial activity, which indicates the possibility for further structural optimization of this class of antitubercular agents.
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czechia.
authors.forename: Galina
authors.initials: G
authors.lastname: Karabanovich
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czechia.
authors.forename: Jan
authors.initials: J
authors.lastname: Němeček
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czechia.
authors.forename: Lenka
authors.initials: L
authors.lastname: Valášková
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czechia.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Carazo
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czechia.
authors.forename: Klára
authors.initials: K
authors.lastname: Konečná
authors.affiliation: Regional Institute of Public Health, Department of Bacteriology and Mycology, Partyzánské náměstí 7, 70200 Ostrava, Czechia.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Stolaříková
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czechia.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Hrabálek
authors.affiliation: Military Health Institute, Biological Defense Department, Techonin, Czechia.
authors.forename: Oto
authors.initials: O
authors.lastname: Pavliš
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czechia.
authors.forename: Petr
authors.initials: P
authors.lastname: Pávek
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czechia.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Vávrová
authors.affiliation: Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czechia. 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, Czechia.
authors.forename: Věra
authors.initials: V
authors.lastname: Klimešová
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D015195:Drug Design; D004351:Drug Resistance / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D010069:Oxadiazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013777:Tetrazoles / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D000995:Antitubercular Agents; D010069:Oxadiazoles; D013438:Sulfhydryl Compounds; D013777:Tetrazoles; C583463:1,3,4-oxadiazole
keywords: Antitubercular agent; Mycobacterium tuberculosis; Oxadiazole; Structure-activity relationships; Tetrazole; Tuberculosis