Design, synthesis and antitubercular potency of 4-hydroxyquinolin-2(1H)-ones

de Macedo, Maíra Bidart; Kimmel, Roman; Urankar, Damijana; Gazvoda, Martin; Peixoto, Antonio; Cools, Freya; Torfs, Eveline; Verschaeve, Luc; Lima, Emerson Silva; Lyčka, Antonín; Milićević, David; Klásek, Antonín; Cos, Paul; Kafka, Stanislav; Košmrlj, Janez; Cappoen, Davie

dc.title	Design, synthesis and antitubercular potency of 4-hydroxyquinolin-2(1H)-ones	en
dc.contributor.author	de Macedo, Maíra Bidart
dc.contributor.author	Kimmel, Roman
dc.contributor.author	Urankar, Damijana
dc.contributor.author	Gazvoda, Martin
dc.contributor.author	Peixoto, Antonio
dc.contributor.author	Cools, Freya
dc.contributor.author	Torfs, Eveline
dc.contributor.author	Verschaeve, Luc
dc.contributor.author	Lima, Emerson Silva
dc.contributor.author	Lyčka, Antonín
dc.contributor.author	Milićević, David
dc.contributor.author	Klásek, Antonín
dc.contributor.author	Cos, Paul
dc.contributor.author	Kafka, Stanislav
dc.contributor.author	Košmrlj, Janez
dc.contributor.author	Cappoen, Davie
dc.relation.ispartof	European Journal of Medicinal Chemistry
dc.identifier.issn	0223-5234 Scopus Sources, Sherpa/RoMEO, JCR
dc.date.issued	2017
utb.relation.volume	138
dc.citation.spage	491
dc.citation.epage	500
dc.type	article
dc.language.iso	en
dc.publisher	Elsevier Masson SAS
dc.identifier.doi	10.1016/j.ejmech.2017.06.061
dc.relation.uri	https://www.sciencedirect.com/science/article/pii/S0223523417305159
dc.subject	mycobacterium tuberculosis	en
dc.subject	tuberculosis	en
dc.subject	4-hydroxyquinolin-2(1H)-ones	en
dc.subject	antibiotic	en
dc.subject	cytotoxicity	en
dc.subject	genotoxicity	en
dc.description.abstract	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. © 2017 Elsevier Masson SAS	en
utb.faculty	Faculty of Technology
dc.identifier.uri	http://hdl.handle.net/10563/1007208
utb.identifier.obdid	43876735
utb.identifier.scopus	2-s2.0-85021723786
utb.identifier.wok	000411297000039
utb.identifier.pubmed	28689097
utb.identifier.coden	EJMCA
utb.source	j-scopus
dc.date.accessioned	2017-09-03T21:40:00Z
dc.date.available	2017-09-03T21:40:00Z
dc.description.sponsorship	CAPES, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; 11912/13-8, MEC, Ministério da Educação; 12N5915N, FWO, Fonds Wetenschappelijk Onderzoek; P1-0230, ARRS, Javna Agencija za Raziskovalno Dejavnost RS
dc.description.sponsorship	Research Foundation Flanders (FWO-Vlaanderen) [12N5915N]; Brazilian Federal Agency; Evaluation of Graduate Education (CAPES) within the Ministry of Education of Brazil [11912/13-8]; Slovenian Research Agency [P1-0230]; TBU in Zlin [IGA/FT/2017/005]
utb.contributor.internalauthor	Kimmel, Roman
utb.contributor.internalauthor	Milićević, David
utb.contributor.internalauthor	Klásek, Antonín
utb.contributor.internalauthor	Kafka, Stanislav
utb.fulltext.affiliation	Maíra Bidart de Macedo a , Roman Kimmel b , Damijana Urankar c , Martin Gazvoda c , Antonio Peixoto d, e , Freya Cools a , Eveline Torfs a , Luc Verschaeve f , Emerson Silva Lima g , Antonín Lyčcka h , David Milićević b , Antonín Klásek b , Paul Cos a , Stanislav Kafka b, * , Janez Košmrlj c, , Davie Cappoen a, * a Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium b Faculty of Technology, Tomas Bata University, Vavrečkova 275, CZ-760 01 Zlín, Czech Republic c Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia d Centre National de la Recherche Scientifique, IPBS, UMR 5089, F-31077 Toulouse, France e Univ. Toulouse, UPS, F-31000 Toulouse, France f Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium g Faculty of Pharmaceutical Sciences, Federal Univeristy of Amazonas, Avenida General Rodrigo Octavio Campo de Jordão, 6200, Coroado, Manaus 69077-000, Amazonas, Brazil h Faculty of Science, University of Hradec Králové, Rokitanského 62, CZ-500 03 Hradec Králové III, Czech Republic * Corresponding author. Corresponding author. * Corresponding author. E-mail addresses: Kafka@ft.utb.cz (S. Kafka), Janez.Kosmrlj@fkkt.uni-lj.si (J. Košmrlj), Davie.Cappoen@uantwerpen.be (D. Cappoen).
utb.fulltext.dates	Received 30 April 2017 Received in revised form 16 June 2017 Accepted 28 June 2017 Available online 29 June 2017
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utb.fulltext.sponsorship	This work was partially supported by the Research Foundation Flanders (FWO-Vlaanderen) DC: Fellowship 12N5915N. The authors acknowledge the financial support from the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES) within the Ministry of Education of Brazil (grant No. 11912/13-8), the Slovenian Research Agency (research core funding No. P1-0230), and TBU in Zlín (internal grant no. IGA/FT/2017/005, funded from the resources of specific university research). We dedicate this paper to our colleague, Professor Sandra Apers, who passed away much too early on February 5th, 2017.
utb.wos.affiliation	[de Macedo, Maira Bidart; Cools, Freya; Torfs, Eveline; Cos, Paul; Cappoen, Davie] Univ Antwerp, LMPH, Fac Pharmaceut Biomed & Vet Sci, S7,Univ Pl 1, B-2610 Antwerp, Belgium; [Kimmel, Roman; Milicevic, David; Klasek, Antonin; Kafka, Stanislav] Tomas Bata Univ, Fac Technol, Vavreckova 275, CZ-76001 Zlin, Czech Republic; [Urankar, Damijana; Gazvoda, Martin; Kosmrlj, Janez] Univ Ljubljana, Fac Chem & Chem Technol, Vecna Pot 113, SI-1000 Ljubljana, Slovenia; [Peixoto, Antonio] CNRS, IPBS, UMR 5089, F-31077 Toulouse, France; [Peixoto, Antonio] Univ Toulouse, UPS, F-31000 Toulouse, France; [Verschaeve, Luc] Univ Antwerp, Dept Biomed Sci, Univ Pl 1, B-2610 Antwerp, Belgium; [Lima, Emerson Silva] Univ Fed Amazonas, Fac Pharmaceut Sci, Ave Gen Rodrigo Otavio Campos de Jordao 6200, BR-69077000 Manaus, Amazonas, Brazil; [Lycka, Antonin] Univ Hradec Kralove, Fac Sci, Rokitanskeho 62, CZ-50003 Hradec Kralove 3, Czech Republic
utb.scopus.affiliation	Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium; Faculty of Technology, Tomas Bata University, Vavrečkova 275, Zlín, Czech Republic; Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, Ljubljana, Slovenia; Centre National de la Recherche Scientifique, IPBS, UMR 5089, Toulouse, France; Univ. Toulouse, UPS, Toulouse, France; Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium; Faculty of Pharmaceutical Sciences, Federal Univeristy of Amazonas, Avenida General Rodrigo Otávio Campos de Jordão, 6200, Coroado, Manaus, Amazonas, Brazil; Faculty of Science, University of Hradec Králové, Rokitanského 62, Hradec Králové III, Czech Republic