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

作者：Cohen Anita^*; Suzanne Peggy; Lancelot Jean Charles; Verhaeghe Pierre; Lesnard Aurelien; Basmaciyan Louise; Hutter Sebastien; Laget Michele; Dumetre Aurelien; Paloque Lucie; Deharo Eric; Crozet Maxime D; Rathelot Pascal; Dallemagne Patrick; Lorthiois Audrey; Sibley Carol Hopkins; Vanelle Patrice; Valentin Alexis; Mazier Dominique; Rault Sylvain; Azas Nadine

来源：European Journal of Medicinal Chemistry, 2015, 95: 16-28.

DOI：10.1016/j.ejmech.2015.03.011

• Thieno[3,2-dlpyrimidin-4(3H)-one
• Pharmacomodulation
• In vitro antiplasmodial profile
• Genotoxicity
• Activity against Plasmodium liver stages
• Antiplasmodial mechanism of action

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.

• 出版日期2015-5-5