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

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 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.
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https://hal-amu.archives-ouvertes.fr/hal-01460555
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Submitted on : Tuesday, February 7, 2017 - 5:01:30 PM
Last modification on : Wednesday, August 19, 2020 - 12:08:17 PM

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Anita Cohen, Peggy Suzanne, Jean-Charles Lancelot, Pierre Verhaeghe, Aurélien Lesnard, et al.. Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium. European Journal of Medicinal Chemistry, Elsevier, 2015, 95, pp.16-28. ⟨10.1016/j.ejmech.2015.03.011⟩. ⟨hal-01460555⟩

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