期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 46, 期 6, 页码 2091-2101出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.02.062
关键词
Antimycobacterial; Lipophilicity; N-Substituted-2-[(1E)-alkenyl]-4-(1H)-quinolone; Structure-activity relationship
资金
- Austrian Science Fund (FWF) [P21152-B18]
- Austrian Science Fund (FWF) [P21152] Funding Source: Austrian Science Fund (FWF)
In an effort to improve biological activities and to examine antimycobacterial-lipophilicity relationships of 2-[(1E)-alkenyl)]-4-(1H)-quinolones, we have synthesized a series of 30 quinolones by introducing several alkyl groups, an alkenyl and an alkynyl group at N-1. All synthetic compounds were first tested in vitro against Mycobacterium smegmatis and the most active compounds (MIC values similar to 3.0-7.0 mu M) were further examined against three other rapidly growing strains of mycobacteria using a microtiter broth dilution assay. The Clog P values of the synthetic compounds were calculated to provide an estimate of their lipophilicity. Compounds 18e, 19a and 19b displayed the most potent inhibitory effect against M. smegmatis mc(2)155 with an MIC value of similar to 1.5 mu M, which was twenty fold and thirteen fold more potent than isoniazid and ethambutol, respectively. On the other hand, compounds 17e, 18e and 19a were most active against Mycobacterium fortuitum and Mycobacterium phlei with an MIC value of similar to 3.0 mu M. In the human diploid embryonic lung cell line MRC-5 cytotoxicity assay, the derivatives showed moderate to strong cytotoxic activity. Although the antimycobacterial activity of our synthetic compounds could not be correlated with the calculated log P values, an increase in lipophilicity enhances the antimycobacterial activity and C-13-C-15 total chain length at positions 1 and 2 is required to achieve optimal inhibitory effect against the test strains. (C) 2011 Elsevier Masson SAS. All rights reserved.
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