%0 Journal Article
%9 ACL : Articles dans des revues avec comité de lecture répertoriées par l'AERES
%A Cohen, A.
%A Suzanne, P.
%A Lancelot, J. C.
%A Verhaeghe, P.
%A Lesnard, A.
%A Basmaciyan, L.
%A Hutter, S.
%A Laget, M.
%A Dumetre, A.
%A Paloque, L.
%A Deharo, Eric
%A Crozet, M. D.
%A Rathelot, P.
%A Dallemagne, P.
%A Lorthiois, A.
%A Sibley, C. H.
%A Vanelle, P.
%A Valentin, A.
%A Mazier, D.
%A Rault, S.
%A Azas, N.
%T Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium
%D 2015
%L fdi:010064628
%G ENG
%J European Journal of Medicinal Chemistry
%@ 0223-5234
%K Thieno[3,2-dlpyrimidin-4(3H)-one ; Pharmacomodulation ; In vitro ; antiplasmodial profile ; Genotoxicity ; Activity against Plasmodium liver stages ; Antiplasmodial mechanism of action
%M ISI:000354139900002
%P 16-28
%R 10.1016/j.ejmech.2015.03.011
%U https://www.documentation.ird.fr/hor/fdi:010064628
%> https://www.documentation.ird.fr/intranet/publi/2015/06/010064628.pdf
%V 95
%W Horizon (IRD)
%X 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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