Design, synthesis and evaluation of 3-methylene-substituted indolinones as antimalarials

被引：33

作者：

Kumar, S. Praveen ^{[1
]}

Gut, Jiri ^{[2
]}

Guedes, Rita C. ^{[1
]}

Rosenthal, Philip J. ^{[2
]}

Santos, Maria M. M. ^{[1
]}

Moreira, Rui ^{[1
]}

机构：

[1] Univ Lisbon, Fac Pharm, Res Inst Med & Pharmaceut Sci iMed UL, P-1649003 Lisbon, Portugal

[2] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 46卷 / 03期

关键词：

Indolin-2-ones; Falcipain inhibitor; Antiplasmodial activity; Malaria; ANTIPLASMODIAL ACTIVITY; KINASE INHIBITORS; GENETIC ALGORITHM; FALCIPAIN-2; OXINDOLE; DERIVATIVES; DISCOVERY;

D O I：

10.1016/j.ejmech.2011.01.008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design, synthesis and evaluation of 3-methylene-substituted indolinones as falcipain inhibitors and antiplasmodial agents are described. These compounds react readily with thiols via an addition-elimination mechanism, indicating their potential as cysteine protease inhibitors. Several indolinones containing a Leu-i-amyl recognition moiety were found to be moderate inhibitors of the Plasmodium falciparum cysteine protease falcipain-2, but not of the related protease falcipain-3, and displayed antiplasmodial activity against the chloroquine-resistant P falciparum W2 strain in the low micromolar range. Coupling a 7-chloroquinoline moiety to the 3-methylene-substituted indolinone scaffold led to a significant improvement in antiplasmodial activity. (C) 2011 Elsevier Masson SAS. All rights reserved.

引用

页码：927 / 933

页数：7

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