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
相关论文
共 34 条
[1]   Multiple-component condensation strategies for combinatorial library synthesis [J].
Armstrong, RW ;
Combs, AP ;
Tempest, PA ;
Brown, SD ;
Keating, TA .
ACCOUNTS OF CHEMICAL RESEARCH, 1996, 29 (03) :123-131
[2]   Antimalarials: Synthesis of 4-aminoquinolines that circumvent drug resistance in malaria parasites [J].
De, DY ;
Byers, LD ;
Krogstad, DJ .
JOURNAL OF HETEROCYCLIC CHEMISTRY, 1997, 34 (01) :315-320
[3]   Structure-activity relationships for antiplasmodial activity among 7-substituted 4-aminoquinolines [J].
De, DYD ;
Krogstad, FM ;
Byers, LD ;
Krogstad, DJ .
JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (25) :4918-4926
[4]   Recent advances in isocyanide-based multicomponent chemistry [J].
Dömling, A .
CURRENT OPINION IN CHEMICAL BIOLOGY, 2002, 6 (03) :306-313
[5]  
Dömling A, 2000, ANGEW CHEM INT EDIT, V39, P3168, DOI 10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO
[6]  
2-U
[7]   APPLICATIONS OF COMBINATORIAL TECHNOLOGIES TO DRUG DISCOVERY .1. BACKGROUND AND PEPTIDE COMBINATORIAL LIBRARIES [J].
GALLOP, MA ;
BARRETT, RW ;
DOWER, WJ ;
FODOR, SPA ;
GORDON, EM .
JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (09) :1233-1251
[8]   Liquid-phase combinatorial synthesis of alicyclic β-lactams via Ugi four-component reaction [J].
Gedey, S ;
Van der Eycken, J ;
Fulöp, F .
ORGANIC LETTERS, 2002, 4 (11) :1967-1969
[9]   Anti-malarial activity of N6-substituted adenosine derivatives.: Part I [J].
Golisade, A ;
Wiesner, J ;
Herforth, C ;
Jomaa, H ;
Link, A .
BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (03) :769-777
[10]   Synthesis and structure-activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi [J].
Greenbaum, DC ;
Mackey, Z ;
Hansell, E ;
Doyle, P ;
Gut, J ;
Caffrey, CR ;
Lehrman, J ;
Rosenthal, PJ ;
McKerrow, JH ;
Chibale, K .
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (12) :3212-3219
1234