Application of multicomponent reactions to antimalarial drug discovery.: Part 2:: New antiplasmodial and antitrypanosomal 4-aminoquinoline γ- and δ-lactams via a 'catch and release' protocol

被引：71
作者：
Musonda, Chitalu C.
Gut, Jiri
Rosenthal, Philip J.
Yardley, Vanessa
De Souza, Renata C. Carvalho
Chibale, Kelly [1 ]
机构：
[1] Univ Cape Town, Dept Chem, ZA-7701 Cape Town, South Africa
[2] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA
[3] Univ London London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1E 7HT, England
[4] Fiocruz MS, Ctr Pesquisas Rene Rachou, BR-30190002 Belo Horizonte, MG, Brazil
[5] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Cape Town, South Africa
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2006年 / 14卷 / 16期
基金：
新加坡国家研究基金会; 美国国家卫生研究院;
关键词：
D O I：
10.1016/j.bmc.2006.04.035
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
A parallel synthesis of a new series of 4-aminoquinoline gamma- and delta-lactams synthesized via the Ugi 3-component 4-centre multicomponent reaction is described. The basicity of the quinoline nitrogen was exploited in the purification of compounds via a 'catch and release' protocol. Yields ranging from 60% to 77% and purities as high as 96% were obtained. Compound 29, the most active against a chloroquine-resistant W2 strain of Plasmodium falciparum with an IC50 of 0.096 mu M, also inhibited recombinant falcipain-2 in vitro (IC50 = 17.6 mu M). Compound 17 inhibited the growth of Trypanosoma brucei with an ED50 of 1.44 mu M whilst exhibiting a favourable therapeutic index of 409 against a human KB cell line. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码：5605 / 5615
页数：11
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