In this study, a 50-membered library of substituted 4-hydroxyquinolin-2(1H)-ones and two closely related analogues was designed, scored in-silico for drug likeness and subsequently synthesized. Thirteen derivatives, all sharing a common 3-phenyl substituent showed minimal inhibitory concentrations against Mycobacterium tuberculosis H37Ra below 10 μM and against Mycobacterium bovis AN5A below 15 μM but were inactive against faster growing mycobacterial species. None of these selected derivatives showed significant acute toxicity against MRC-5 cells or early signs of genotoxicity in the Vitotox™ assay at the active concentration range. The structure activity study relation provided some insight in the further favourable substitution pattern at the 4-hydroxyquinolin-2(1H)-one scaffold and finally 6-fluoro-4-hydroxy-3-phenylquinolin-2(1H)-one (38) was selected as the most promising member of the library with a MIC of 3.2 μM and a CC50 against MRC-5 of 67.4 μM.

Centre National de la Recherche Scientifique IPBS UMR 5089 F 31077 Toulouse France

Department of Biomedical Sciences University of Antwerp Universiteitsplein 1 B 2610 Wilrijk Belgium

Faculty of Chemistry and Chemical Technology University of Ljubljana Večna pot 113 SI 1000 Ljubljana Slovenia

Faculty of Pharmaceutical Sciences Federal Univeristy of Amazonas Avenida General Rodrigo Otávio Campos de Jordão 6200 Coroado Manaus 69077 000 Amazonas Brazil

Faculty of Science University of Hradec Králové Rokitanského 62 CZ 500 03 Hradec Králové 3 Czech Republic

Faculty of Technology Tomas Bata University Vavrečkova 275 CZ 760 01 Zlín Czech Republic

Laboratory of Microbiology Parasitology and Hygiene S7 Faculty of Pharmaceutical Biomedical and Veterinary Sciences University of Antwerp Universiteitsplein 1 B 2610 Wilrijk Belgium

Univ Toulouse UPS F 31000 Toulouse France

000      

00000naa a2200000 a 4500

001      

bmc17030699

003      

CZ-PrNML

005      

20171030121937.0

007      

ta

008      

171025s2017 fr f 000 0|eng||

009      

AR

024    7_

$a 10.1016/j.ejmech.2017.06.061 $2 doi

035    __

$a (PubMed)28689097

040    __

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

041    0_

$a eng

044    __

$a fr

100    1_

$a de Macedo, Maíra Bidart $u Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.

245    10

$a Design, synthesis and antitubercular potency of 4-hydroxyquinolin-2(1H)-ones / $c MB. de Macedo, R. Kimmel, D. Urankar, M. Gazvoda, A. Peixoto, F. Cools, E. Torfs, L. Verschaeve, ES. Lima, A. Lyčka, D. Milićević, A. Klásek, P. Cos, S. Kafka, J. Košmrlj, D. Cappoen,

520    9_

$a In this study, a 50-membered library of substituted 4-hydroxyquinolin-2(1H)-ones and two closely related analogues was designed, scored in-silico for drug likeness and subsequently synthesized. Thirteen derivatives, all sharing a common 3-phenyl substituent showed minimal inhibitory concentrations against Mycobacterium tuberculosis H37Ra below 10 μM and against Mycobacterium bovis AN5A below 15 μM but were inactive against faster growing mycobacterial species. None of these selected derivatives showed significant acute toxicity against MRC-5 cells or early signs of genotoxicity in the Vitotox™ assay at the active concentration range. The structure activity study relation provided some insight in the further favourable substitution pattern at the 4-hydroxyquinolin-2(1H)-one scaffold and finally 6-fluoro-4-hydroxy-3-phenylquinolin-2(1H)-one (38) was selected as the most promising member of the library with a MIC of 3.2 μM and a CC50 against MRC-5 of 67.4 μM.

650    _2

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

650    _2

$a vztah mezi dávkou a účinkem léčiva $7 D004305

650    12

$a racionální návrh léčiv $7 D015195

650    _2

$a lidé $7 D006801

650    _2

$a mikrobiální testy citlivosti $7 D008826

650    _2

$a molekulární struktura $7 D015394

650    _2

$a Mycobacterium bovis $x účinky léků $x růst a vývoj $7 D009163

650    _2

$a Mycobacterium tuberculosis $x účinky léků $x růst a vývoj $7 D009169

650    _2

$a chinolony $x chemická syntéza $x chemie $x farmakologie $7 D015363

650    _2

$a vztahy mezi strukturou a aktivitou $7 D013329

655    _2

$a časopisecké články $7 D016428

700    1_

$a Kimmel, Roman $u Faculty of Technology, Tomas Bata University, Vavrečkova 275, CZ-760 01 Zlín, Czech Republic.

700    1_

$a Urankar, Damijana $u Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia.

700    1_

$a Gazvoda, Martin $u Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia.

700    1_

$a Peixoto, Antonio $u Centre National de la Recherche Scientifique, IPBS, UMR 5089, F-31077 Toulouse, France; Univ. Toulouse, UPS, F-31000 Toulouse, France.

700    1_

$a Cools, Freya $u Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.

700    1_

$a Torfs, Eveline $u Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.

700    1_

$a Verschaeve, Luc $u Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.

700    1_

$a Lima, Emerson Silva $u Faculty of Pharmaceutical Sciences, Federal Univeristy of Amazonas, Avenida General Rodrigo Otávio Campos de Jordão, 6200, Coroado, Manaus 69077-000, Amazonas, Brazil.

700    1_

$a Lyčka, Antonín $u Faculty of Science, University of Hradec Králové, Rokitanského 62, CZ-500 03 Hradec Králové III, Czech Republic.

700    1_

$a Milićević, David $u Faculty of Technology, Tomas Bata University, Vavrečkova 275, CZ-760 01 Zlín, Czech Republic.

700    1_

$a Klásek, Antonín $u Faculty of Technology, Tomas Bata University, Vavrečkova 275, CZ-760 01 Zlín, Czech Republic.

700    1_

$a Cos, Paul $u Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.

700    1_

$a Kafka, Stanislav $u Faculty of Technology, Tomas Bata University, Vavrečkova 275, CZ-760 01 Zlín, Czech Republic. Electronic address: Kafka@ft.utb.cz.

700    1_

$a Košmrlj, Janez $u Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia. Electronic address: Janez.Kosmrlj@fkkt.uni-lj.si.

700    1_

$a Cappoen, Davie $u Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium. Electronic address: Davie.Cappoen@uantwerpen.be.

773    0_

$w MED00001628 $t European journal of medicinal chemistry $x 1768-3254 $g Roč. 138, č. - (2017), s. 491-500

856    41

$u https://pubmed.ncbi.nlm.nih.gov/28689097 $y Pubmed

910    __

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

990    __

$a 20171025 $b ABA008

991    __

$a 20171030122026 $b ABA008

999    __

$a ok $b bmc $g 1254292 $s 991726

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2017 $b 138 $c - $d 491-500 $e 20170629 $i 1768-3254 $m European journal of medicinal chemistry $n Eur J Med Chem $x MED00001628

LZP    __

$a Pubmed-20171025