title: Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis.
abstract: Herein, we report the discovery and structure-activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as a new class of antituberculosis agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 μM (0.011-0.026 μg/mL). The investigated compounds had a highly selective antimycobacterial effect because they showed no activity against the other bacteria or fungi tested in this study. Furthermore, the investigated compounds exhibited low in vitro toxicities in four proliferating mammalian cell lines and in isolated primary human hepatocytes. Several in vitro genotoxicity assays indicated that the selected compounds have no mutagenic activity. The oxadiazole and thiadiazole derivatives with the most favorable activity/toxicity profiles also showed potency comparable to that of rifampicin against the nonreplicating streptomycin-starved M. tuberculosis 18b-Lux strain, and therefore, these derivatives, are of particular interest.
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Galina
authors.initials: G
authors.lastname: Karabanovich
authors.affiliation: Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava , Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
authors.forename: Júlia
authors.initials: J
authors.lastname: Zemanová
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Smutný
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute , CH-1015 Lausanne, Switzerland.
authors.forename: Rita
authors.initials: R
authors.lastname: Székely
authors.affiliation: Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava , Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
authors.forename: Michal
authors.initials: M
authors.lastname: Šarkan
authors.affiliation: Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava , Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Centárová
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute , CH-1015 Lausanne, Switzerland.
authors.forename: Anthony
authors.initials: A
authors.lastname: Vocat
authors.affiliation: Faculty of Military Health Sciences, Department of Molecular Pathology and Biology, University of Defence , Třebešská 1575, 50005 Hradec Králové, Czech Republic.
authors.forename: Ivona
authors.initials: I
authors.lastname: Pávková
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Patrik
authors.initials: P
authors.lastname: Čonka
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Němeček
authors.affiliation: Department of Bacteriology and Mycology, Regional Institute of Public Health , Partyzánské náměstí 7, 70200 Ostrava, Czech Republic.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Stolaříková
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Marcela
authors.initials: M
authors.lastname: Vejsová
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Vávrová
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Věra
authors.initials: V
authors.lastname: Klimešová
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Hrabálek
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Pávek
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute , CH-1015 Lausanne, Switzerland.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.affiliation: Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava , Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
authors.forename: Katarína
authors.initials: K
authors.lastname: Mikušová
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Roh
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001419:Bacteria / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial; D005658:Fungi / Q000187:drug effects; D006801:Humans; D055985:Latent Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D008861:Microsomes / Q000378:metabolism; D009153:Mutagens / Q000633:toxicity; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D061251:Primary Cell Culture; D012293:Rifampin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D009153:Mutagens; D010080:Oxazoles; D013830:Thiadiazoles; D012293:Rifampin