Original article Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium Anita Cohen a, * , Peggy Suzanne b , Jean-Charles Lancelot b , Pierre Verhaeghe c , Aur  elien Lesnard b , Louise Basmaciyan a ,S  ebastien Hutter a , Mich  ele Laget a , Aur  elien Dum  etre a , Lucie Paloque d , Eric Deharo d , Maxime D. Crozet e , Pascal Rathelot e , Patrick Dallemagne b , Audrey Lorthiois f , Carol Hopkins Sibley g , Patrice Vanelle e , Alexis Valentin d , Dominique Mazier f, * , Sylvain Rault b, * , Nadine Azas a, * a Aix-Marseille Universit e, MD, Infections Parasitaires, Transmission, Pharmacologie et Th erapeutique IP-TPT UMR MD3, Facult e de Pharmacie, 27 Boulevard Jean Moulin e CS30064, 13385 Marseille Cedex 05, France b UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le M edicament de Normandie-FR CNRS INC3M e SF ICORE, Universit e de Caen Basse-Normandie, UFR des Sciences Pharmaceutiques, Bd Becquerel), CS14032, F-14032 Caen, France c Universit e Paul Sabatier, CNRS, UPR-CNRS 8241 Laboratoire de Chimie de Coordination, Facult e des Sciences Pharmaceutiques, BP 44099, 205 Route de Narbonne, 31077 Toulouse Cedex 4, France d Universit e Paul Sabatier, IRD, UPS PHARMA-DEV, Equipe BIOCID UMR 152, Facult e des Sciences Pharmaceutiques, 35 Chemin des Maraîchers, 31400 Toulouse, France e Aix-Marseille Universit e, CNRS, ICR UMR 7273, Laboratoire de PharmacoChimie Radicalaire, Facult e de Pharmacie, 27 Boulevard Jean Moulin e CS30064, 13385 Marseille Cedex 05, France f Universit e Pierre et Marie Curie, INSERM, Immunit e et Infection, UMR S945, Facult e de M edecine: CHU Piti e-Salp etri ere, 91 Boulevard de l'H^ opital, 75013 Paris, France g WorldWide Antimalarial Resistance Network (WWARN) and Department of Genome Sciences, University of Washington, Foege Building S-250, Box 355065, 372015th Avenue NE, Seattle, WA 98195-5065, USA article info Article history: Received 28 November 2014 Received in revised form 3 March 2015 Accepted 4 March 2015 Available online 10 March 2015 Keywords: Thieno[3,2-d]pyrimidin-4(3H)-one Pharmacomodulation In vitro antiplasmodial profile Genotoxicity Activity against Plasmodium liver stages Antiplasmodial mechanism of action 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 Plasmo- dium falciparum. Then, 120 new derivatives were synthesized and evaluated in vitro; compared to drug references, 40 showed good activity toward chloroquine sensitive (IC 50 35e344 nM) and resistant (IC 50 45e800 nM) P. falciparum strains. They were neither cytotoxic (CC 50 15e50 mM) toward HepG2 and CHO cells, nor mutagenic. Structureeactivity relationships were defined. The lead-compound also appeared active against the Plasmodium liver stages (Plasmodium yoelii IC 50 ¼ 35 nM) and a preliminary in vivo evaluation indicated the in vitro activity was preserved (45% reduction in parasitemia compared to un- treated 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. 1. Introduction Malaria is a devastating pathology, which in 2012 affected 207 million people worldwide (range 135e287 million) and caused 627,000 deaths (range 473,000e789,000) [1]. This infection, transmitted via the bite of the female Anopheles mosquito, is caused by five species of protozoan parasites belonging to the Plasmodium genus, namely falciparum, malariae, vivax, ovale and knowlesi. Plasmodium falciparum is the most virulent [2], causing more than 95% of malaria-related morbidity and mortality. According to the WHO [1], important and durable progress has been recorded in recent years, with the estimated incidence of malaria globally * Corresponding authors. E-mail address: anita.cohen@univ-amu.fr (A. Cohen). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2015.03.011 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 95 (2015) 16e28