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

European Journal of Medicinal Chemistry
Anita CohenNadine Azas

Abstract

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 μM) 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.

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Citations

Dec 8, 2015·Journal of Medicinal Chemistry·Bogdan A ŠolajaDonatella Taramelli
Sep 13, 2015·Toxicon : Official Journal of the International Society on Toxinology·Anderson M KayanoAndreimar M Soares
Sep 2, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Dyhia AmraneNicolas Primas
Sep 17, 2019·European Journal of Medicinal Chemistry·Anudeep K NarulaLalit M Nainwal

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