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

被引：21

作者：

de Macedo, Maira Bidart ^{[1
]}

Kimmel, Roman ^{[2
]}

Urankar, Damijana ^{[3
]}

Gazvoda, Martin ^{[3
]}

Peixoto, Antonio ^{[4
,5
]}

Cools, Freya ^{[1
]}

Torfs, Eveline ^{[1
]}

Verschaeve, Luc ^{[6
]}

Lima, Emerson Silva ^{[7
]}

Lycka, Antonin ^{[8
]}

Milicevic, David ^{[2
]}

Klasek, Antonin ^{[2
]}

Cos, Paul ^{[1
]}

Kafka, Stanislav ^{[2
]}

Kosmrlj, Janez ^{[3
]}

Cappoen, Davie ^{[1
]}

机构：

[1] Univ Antwerp, LMPH, Fac Pharmaceut Biomed & Vet Sci, S7,Univ Pl 1, B-2610 Antwerp, Belgium

[2] Tomas Bata Univ, Fac Technol, Vavreckova 275, CZ-76001 Zlin, Czech Republic

[3] Univ Ljubljana, Fac Chem & Chem Technol, Vecna Pot 113, SI-1000 Ljubljana, Slovenia

[4] CNRS, IPBS, UMR 5089, F-31077 Toulouse, France

[5] Univ Toulouse, UPS, F-31000 Toulouse, France

[6] Univ Antwerp, Dept Biomed Sci, Univ Pl 1, B-2610 Antwerp, Belgium

[7] Univ Fed Amazonas, Fac Pharmaceut Sci, Ave Gen Rodrigo Otavio Campos de Jordao 6200, BR-69077000 Manaus, Amazonas, Brazil

[8] Univ Hradec Kralove, Fac Sci, Rokitanskeho 62, CZ-50003 Hradec Kralove 3, Czech Republic

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 138卷

关键词：

Mycobacterium tuberculosis; Tuberculosis; 4-Hydroxyquinolin-2(1H)-ones; Antibiotic; Cytotoxicity; Genotoxicity; NONNUCLEOSIDE INHIBITORS; POLYMERASE; DERIVATIVES; REARRANGEMENT; BENZOFURANES; DISCOVERY; SPECTRA; DRUGS;

D O I：

10.1016/j.ejmech.2017.06.061

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M and against Mycobacterium bovis AN5A below 15 mu M 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 (TM) 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 mu M and a CC50 against MRC-5 of 67.4 mu M. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：491 / 500

页数：10

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