Selection of a trioxaquine as an antimalarial drug candidate

被引：122

作者：

Cosledan, Frederic ^{[1
]}

Fraisse, Laurent ^{[2
]}

Pellet, Alain ^{[2
]}

Guillou, Francois ^{[3
]}

Mordmueller, Benjamin ^{[4
,5
]}

Kremsner, Peter G. ^{[4
,5
]}

Moreno, Alicia ^{[6
,7
]}

Mazier, Dominique ^{[6
,7
,8
]}

Maffrand, Jean-Pierre ^{[2
]}

Meunier, Bernard ^{[1
]}

机构：

[1] Palumed, F-31682 Labege, France

[2] Sanofi Aventis Rech, F-31036 Toulouse, France

[3] Sanofi Aventis Rech, F-34184 Montpellier, France

[4] Univ Tubingen, Dept Parasitol, D-72074 Tubingen, Germany

[5] Hop Albert Schweitzer, Med Res Unit, Lambarene, Gabon

[6] Univ Paris 06, Unite Mixte Rech 5511, F-75013 Paris, France

[7] INSERM, U511, F-75013 Paris, France

[8] CHU Pitie Salpetriere, AP HP, Serv Parasitol Mycol, F-75013 Paris, France

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 45期

关键词：

curative drug; malaria; Plasmodium; heme; alkglation;

D O I：

10.1073/pnas.0804338105

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：

Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One of these molecules, PA1103/SAR116242, is highly active in vitro on several sensitive and resistant strains of Plasmodium falciparum at nanomolar concentrations (e.g., IC50 value = 10 nM with FcM29, a chloroquine-resistant strain) and also on multidrug-resistant strains obtained from fresh patient isolates in Gabon. This molecule is very efficient by oral route with a complete cure of mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia at 26-32 mg/kg. This compound is also highly effective in humanized mice infected with P. falciparum. Combined with a good drug profile (preliminary absorption, metabolism, and safety parameters), these data were favorable for the selection of this particular trioxaquine for development as drug candidate among 120 other active hybrid molecules.

引用

页码：17579 / 17584

页数：6

共 33 条

[1] Trioxaquines are new antimalarial agents active on all erythrocytic forms, including gametocytes [J].