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.

Department of Bacteriology and Mycology Regional Institute of Public Health Partyzánské náměstí 7 70200 Ostrava Czech Republic

Ecole Polytechnique Fédérale de Lausanne Global Health Institute CH 1015 Lausanne Switzerland

Faculty of Military Health Sciences Department of Molecular Pathology and Biology University of Defence Třebešská 1575 50005 Hradec Králové Czech Republic

Faculty of Natural Sciences Department of Biochemistry Comenius University in Bratislava Mlynská dolina Ilkovičova 6 842 15 Bratislava Slovakia

Faculty of Pharmacy in Hradec Králové Charles University Prague Heyrovského 1203 50005 Hradec Králové Czech Republic

000      

00000naa a2200000 a 4500

001      

bmc16027605

003      

CZ-PrNML

005      

20161025104645.0

007      

ta

008      

161005s2016 xxu f 000 0|eng||

009      

AR

024    7_

$a 10.1021/acs.jmedchem.5b00608 $2 doi

024    7_

$a 10.1021/acs.jmedchem.5b00608 $2 doi

035    __

$a (PubMed)26948407

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a xxu

100    1_

$a Karabanovich, Galina $u Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

245    10

$a Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis / $c G. Karabanovich, J. Zemanová, T. Smutný, R. Székely, M. Šarkan, I. Centárová, A. Vocat, I. Pávková, P. Čonka, J. Němeček, J. Stolaříková, M. Vejsová, K. Vávrová, V. Klimešová, A. Hrabálek, P. Pávek, ST. Cole, K. Mikušová, J. Roh,

520    9_

$a 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.

650    _2

$a zvířata $7 D000818

650    _2

$a antituberkulotika $x chemická syntéza $x farmakologie $x toxicita $7 D000995

650    _2

$a Bacteria $x účinky léků $7 D001419

650    _2

$a buněčné linie $7 D002460

650    _2

$a viabilita buněk $x účinky léků $7 D002470

650    _2

$a racionální návrh léčiv $7 D015195

650    _2

$a mnohočetná bakteriální léková rezistence $7 D024901

650    _2

$a houby $x účinky léků $7 D005658

650    _2

$a lidé $7 D006801

650    _2

$a latentní tuberkulóza $x farmakoterapie $x mikrobiologie $7 D055985

650    _2

$a mikrobiální testy citlivosti $7 D008826

650    _2

$a mikrozomy $x metabolismus $7 D008861

650    _2

$a mutageny $x toxicita $7 D009153

650    _2

$a Mycobacterium tuberculosis $x účinky léků $7 D009169

650    _2

$a oxazoly $x chemická syntéza $x farmakologie $7 D010080

650    _2

$a primární buněčná kultura $7 D061251

650    _2

$a rifampin $x farmakologie $7 D012293

650    _2

$a vztahy mezi strukturou a aktivitou $7 D013329

650    _2

$a thiadiazoly $x chemická syntéza $x farmakologie $7 D013830

655    _2

$a časopisecké články $7 D016428

655    _2

$a práce podpořená grantem $7 D013485

700    1_

$a Zemanová, Júlia $u Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava , Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.

700    1_

$a Smutný, Tomáš $u Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

700    1_

$a Székely, Rita $u Ecole Polytechnique Fédérale de Lausanne, Global Health Institute , CH-1015 Lausanne, Switzerland.

700    1_

$a Šarkan, Michal $u Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava , Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.

700    1_

$a Centárová, Ivana $u Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava , Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.

700    1_

$a Vocat, Anthony $u Ecole Polytechnique Fédérale de Lausanne, Global Health Institute , CH-1015 Lausanne, Switzerland.

700    1_

$a Pávková, Ivona $u Faculty of Military Health Sciences, Department of Molecular Pathology and Biology, University of Defence , Třebešská 1575, 50005 Hradec Králové, Czech Republic.

700    1_

$a Čonka, Patrik $u Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

700    1_

$a Němeček, Jan $u Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

700    1_

$a Stolaříková, Jiřina $u Department of Bacteriology and Mycology, Regional Institute of Public Health , Partyzánské náměstí 7, 70200 Ostrava, Czech Republic.

700    1_

$a Vejsová, Marcela $u Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

700    1_

$a Vávrová, Kateřina $u Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

700    1_

$a Klimešová, Věra $u Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

700    1_

$a Hrabálek, Alexandr $u Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

700    1_

$a Pávek, Petr $u Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

700    1_

$a Cole, Stewart T $u Ecole Polytechnique Fédérale de Lausanne, Global Health Institute , CH-1015 Lausanne, Switzerland.

700    1_

$a Mikušová, Katarína $u Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava , Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.

700    1_

$a Roh, Jaroslav $u Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

773    0_

$w MED00010049 $t Journal of medicinal chemistry $x 1520-4804 $g Roč. 59, č. 6 (2016), s. 2362-80

856    41

$u https://pubmed.ncbi.nlm.nih.gov/26948407 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y a $z 0

990    __

$a 20161005 $b ABA008

991    __

$a 20161025105059 $b ABA008

999    __

$a ok $b bmc $g 1165919 $s 952235

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2016 $b 59 $c 6 $d 2362-80 $e 20160315 $i 1520-4804 $m Journal of medicinal chemistry $n J Med Chem $x MED00010049

LZP    __

$a Pubmed-20161005