Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium

被引：32

作者：

Cohen, Anita ^{[1
]}

Suzanne, Peggy ^{[2
]}

Lancelot, Jean-Charles ^{[2
]}

Verhaeghe, Pierre ^{[3
]}

Lesnard, Aurelien ^{[2
]}

Basmaciyan, Louise ^{[1
]}

Hutter, Sebastien ^{[1
]}

Laget, Michele ^{[1
]}

Dumetre, Aurelien ^{[1
]}

Paloque, Lucie ^{[4
]}

Deharo, Eric ^{[4
]}

Crozet, Maxime D. ^{[5
]}

Rathelot, Pascal ^{[5
]}

Dallemagne, Patrick ^{[2
]}

Lorthiois, Audrey ^{[6
]}

Sibley, Carol Hopkins ^{[7
,8
]}

Vanelle, Patrice ^{[5
]}

Valentin, Alexis ^{[4
]}

Mazier, Dominique ^{[6
]}

Rault, Sylvain ^{[2
]}

Azas, Nadine ^{[1
]}

机构：

[1] Aix Marseille Univ, Fac Pharm, Infect Parasitaires Transmiss Pharmacol & Therape, MD, F-13385 Marseille 05, France

[2] Univ Caen Basse Normandie, UNICAEN, CERMN, FR CNRS INC3M,SF ICORE,UFR Sci Pharmaceut, F-14032 Caen, France

[3] Univ Toulouse 3, CNRS, Fac Pharmaceut Sci, UPR CNRS 8241,Lab Chim Coordinat,CNRS, F-31077 Toulouse 4, France

[4] Univ Toulouse 3, Fac Pharmaceut Sci, Equipe BIOCID UMR 152, UPS PHARMA DEV,IRD, F-31400 Toulouse, France

[5] Aix Marseille Univ, CNRS, Fac Pharm, Lab PharmacoChim Radicalaire,ICR UMR 7273, F-13385 Marseille 05, France

[6] Univ Paris 06, INSERM, Fac Med, CHU Pitie Salpetriere,Immunite & Infect,UMR S945, F-75013 Paris, France

[7] Univ Washington, WorldWide Antimalarial Resistance Network, Seattle, WA 98195 USA

[8] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 95卷

关键词：

Thieno[3,2-dlpyrimidin-4(3H)-one; Pharmacomodulation; In vitro antiplasmodial profile; Genotoxicity; Activity against Plasmodium liver stages; Antiplasmodial mechanism of action; DIHYDROFOLATE-REDUCTASE; ANTIPLASMODIAL ACTIVITY; TOXOPLASMA-GONDII; DRUG ACTIVITY; MALARIA; FALCIPARUM; PYRIMETHAMINE; SUSCEPTIBILITY; MUTAGENESIS; ATOVAQUONE;

D O I：

10.1016/j.ejmech.2015.03.011

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A preliminary in vitro screening of compounds belonging to various chemical families from our library revealed the thieno[3,2-d]pyrimidin-4(3H)-one scaffold displayed a promising profile against Plasmodium falciparum. Then, 120 new derivatives were synthesized and evaluated in vitro; compared to drug references, 40 showed good activity toward chloroquine sensitive (IC50 35-344 nM) and resistant (IC50 45-800 nM) P. falciparum strains. They were neither cytotoxic (CC50 15-50 mu M) toward HepG2 and CHO cells, nor mutagenic. Structure activity relationships were defined. The lead-compound also appeared active against the Plasmodium liver stages (Plasmodium yoelii IC50 = 35 nM) and a preliminary in vivo evaluation indicated the in vitro activity was preserved (45% reduction in parasitemia compared to untreated infected mice). A mechanistic study demonstrated these molecules do not involve any of the pathways described for commercial drugs and exert a specific activity on the ring and trophozoite stages. 2015 Elsevier Masson SAS. All rights reserved.

引用

页码：16 / 28

页数：13

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