Spiroindolones, a Potent Compound Class for the Treatment of Malaria

被引：1023

作者：

Rottmann, Matthias ^{[2
,3
]}

McNamara, Case ^{[1
]}

Yeung, Bryan K. S. ^{[4
]}

Lee, Marcus C. S. ^{[5
]}

Zou, Bin ^{[4
]}

Russell, Bruce ^{[6
,7
]}

Seitz, Patrick ^{[2
,3
]}

Plouffe, David M. ^{[1
]}

Dharia, Neekesh V. ^{[8
]}

Tan, Jocelyn ^{[4
]}

Cohen, Steven B. ^{[1
]}

Spencer, Kathryn R. ^{[8
]}

Gonzalez-Paez, Gonzalo E. ^{[8
]}

Lakshminarayana, Suresh B. ^{[4
]}

Goh, Anne ^{[4
]}

Suwanarusk, Rossarin ^{[6
]}

Jegla, Timothy ^{[9
,10
]}

Schmitt, Esther K. ^{[11
]}

Beck, Hans-Peter ^{[2
,3
]}

Brun, Reto ^{[2
,3
]}

Nosten, Francois ^{[12
,13
,14
]}

Renia, Laurent ^{[6
]}

Dartois, Veronique ^{[4
]}

Keller, Thomas H. ^{[4
]}

Fidock, David A. ^{[5
,15
]}

Winzeler, Elizabeth A. ^{[1
,8
]}

Diagana, Thierry T. ^{[4
]}

机构：

[1] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

[2] Swiss Trop & Publ Hlth Inst, CH-4002 Basel, Switzerland

[3] Univ Basel, CH-4003 Basel, Switzerland

[4] Novartis Inst Trop Dis, Singapore 138670, Singapore

[5] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA

[6] ASTAR, Singapore Immunol Network, Lab Malaria Immunobiol, Biopolis 138648, Singapore

[7] Natl Univ Singapore, Dept Microbiol, Singapore 117597, Singapore

[8] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA

[9] Penn State Univ, Dept Biol, University Pk, PA 16802 USA

[10] Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA

[11] Novartis Pharma AG, Nat Prod Unit, CH-4002 Basel, Switzerland

[12] Shoklo Malaria Res Unit, Mae Sot 63110, Tak, Thailand

[13] Mahidol Univ, Fac Trop Med, Bangkok, Thailand

[14] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford OX3 7LJ, England

[15] Columbia Univ, Med Ctr, Dept Med, Div Infect Dis, New York, NY 10032 USA

来源：

SCIENCE | 2010年 / 329卷 / 5996期

基金：

英国惠康基金;

关键词：

PARASITE PLASMODIUM-FALCIPARUM; CALCIUM-PUMP; DRUG-RESISTANCE; SARCOPLASMIC-RETICULUM; ARTEMISININ; VIVAX; IDENTIFICATION; ANTIMALARIALS; ERADICATION; CHLOROQUINE;

D O I：

10.1126/science.1193225

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Recent reports of increased tolerance to artemisinin derivatives-the most recently adopted class of antimalarials-have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.

引用

页码：1175 / 1180

页数：6

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