期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 69, 期 -, 页码 338-347出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.08.046
关键词
Antimalarial; Plasmodium falciparum; beta-Haematin; Structure-activity relationships; Resistance
资金
- South African Malaria Initiative (SAMI)
- National Research Foundation
- Medical Research Council of South Africa
- University of Cape Town
A novel series of quinoline triazole amide analogues (38-51) has been synthesized. Analogues 38-44 had a Cl substituent at the 7-position of the quinoline ring, while 45-51 had a CN substituent at this position. Compounds 40,45 and 49 were found to be the most active in the series against the Plasmodium falciparum chloroquine-sensitive D10 strain, with IC50 values in the range of 349-1247 nM, with 40 and 45, but not 49 also exhibiting similar activity against the chloroquine-resistant 1(1 strain of parasite. Quinoline triazoles 40 and 44 were the most active beta-haematin inhibitors, with 50% inhibitory concentrations of 14.7 and 8.9 1tM respectively. In vitro antimalarial activity of the 7-C1 bearing analogues 38 -44 exhibited a strong linear dependence of log(1/IC50) on log P. Thus, the more lipophilic, the more active it was found be. The 7-CN series 45-51 showed no such dependence. The resistance index (IC50 K1 /IC50 D10) also exhibited a linear dependence on log P, with a substantially steeper slope in the case of the 7-CI series. The findings demonstrate the feasibility of producing hydrophilic analogues with strong activity and low cross-resistance with chloroquine. (C) 2013 Elsevier Masson SAS. All rights reserved.
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