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; Univ Toulouse UPS F 31000 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

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