title: 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 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.
authors: Aix-Marseille Université, MD, Infections Parasitaires, Transmission, Pharmacologie et Thérapeutique IP-TPT UMR MD3, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France. Electronic address: anita.cohen@univ-amu.fr.
authors: Anita
authors: A
authors: Cohen
authors: UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie-FR CNRS INC3M - SF ICORE, Université de Caen Basse-Normandie, UFR des Sciences Pharmaceutiques, Bd Becquerel), CS14032, F-14032 Caen, France.
authors: Peggy
authors: P
authors: Suzanne
authors: UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie-FR CNRS INC3M - SF ICORE, Université de Caen Basse-Normandie, UFR des Sciences Pharmaceutiques, Bd Becquerel), CS14032, F-14032 Caen, France.
authors: Jean-Charles
authors: JC
authors: Lancelot
authors: Université Paul Sabatier, CNRS, UPR-CNRS 8241 Laboratoire de Chimie de Coordination, Faculté des Sciences Pharmaceutiques, BP 44099, 205 Route de Narbonne, 31077 Toulouse Cedex 4, France.
authors: Pierre
authors: P
authors: Verhaeghe
authors: UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie-FR CNRS INC3M - SF ICORE, Université de Caen Basse-Normandie, UFR des Sciences Pharmaceutiques, Bd Becquerel), CS14032, F-14032 Caen, France.
authors: Aurélien
authors: A
authors: Lesnard
authors: Aix-Marseille Université, MD, Infections Parasitaires, Transmission, Pharmacologie et Thérapeutique IP-TPT UMR MD3, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors: Louise
authors: L
authors: Basmaciyan
authors: Aix-Marseille Université, MD, Infections Parasitaires, Transmission, Pharmacologie et Thérapeutique IP-TPT UMR MD3, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors: Sébastien
authors: S
authors: Hutter
authors: Aix-Marseille Université, MD, Infections Parasitaires, Transmission, Pharmacologie et Thérapeutique IP-TPT UMR MD3, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors: Michèle
authors: M
authors: Laget
authors: Aix-Marseille Université, MD, Infections Parasitaires, Transmission, Pharmacologie et Thérapeutique IP-TPT UMR MD3, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors: Aurélien
authors: A
authors: Dumètre
authors: Université Paul Sabatier, IRD, UPS PHARMA-DEV, Equipe BIOCID UMR 152, Faculté des Sciences Pharmaceutiques, 35 Chemin des Maraîchers, 31400 Toulouse, France.
authors: Lucie
authors: L
authors: Paloque
authors: Université Paul Sabatier, IRD, UPS PHARMA-DEV, Equipe BIOCID UMR 152, Faculté des Sciences Pharmaceutiques, 35 Chemin des Maraîchers, 31400 Toulouse, France.
authors: Eric
authors: E
authors: Deharo
authors: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de PharmacoChimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors: Maxime D
authors: MD
authors: Crozet
authors: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de PharmacoChimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors: Pascal
authors: P
authors: Rathelot
authors: UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie-FR CNRS INC3M - SF ICORE, Université de Caen Basse-Normandie, UFR des Sciences Pharmaceutiques, Bd Becquerel), CS14032, F-14032 Caen, France.
authors: Patrick
authors: P
authors: Dallemagne
authors: Université Pierre et Marie Curie, INSERM, Immunité et Infection, UMR S945, Faculté de Médecine: CHU Pitié-Salpétrière, 91 Boulevard de l'Hôpital, 75013 Paris, France.
authors: Audrey
authors: A
authors: Lorthiois
authors: WorldWide Antimalarial Resistance Network (WWARN) and Department of Genome Sciences, University of Washington, Foege Building S-250, Box 355065, 3720 15th Avenue NE, Seattle, WA 98195-5065, USA.
authors: Carol Hopkins
authors: CH
authors: Sibley
authors: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de PharmacoChimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors: Patrice
authors: P
authors: Vanelle
authors: Université Paul Sabatier, IRD, UPS PHARMA-DEV, Equipe BIOCID UMR 152, Faculté des Sciences Pharmaceutiques, 35 Chemin des Maraîchers, 31400 Toulouse, France.
authors: Alexis
authors: A
authors: Valentin
authors: Université Pierre et Marie Curie, INSERM, Immunité et Infection, UMR S945, Faculté de Médecine: CHU Pitié-Salpétrière, 91 Boulevard de l'Hôpital, 75013 Paris, France.
authors: Dominique
authors: D
authors: Mazier
authors: UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie-FR CNRS INC3M - SF ICORE, Université de Caen Basse-Normandie, UFR des Sciences Pharmaceutiques, Bd Becquerel), CS14032, F-14032 Caen, France.
authors: Sylvain
authors: S
authors: Rault
authors: Aix-Marseille Université, MD, Infections Parasitaires, Transmission, Pharmacologie et Thérapeutique IP-TPT UMR MD3, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors: Nadine
authors: N
authors: Azas
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D004912:Erythrocytes / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D053058:Trophozoites / Q000187:drug effects
chemical_list: D000962:Antimalarials; D011743:Pyrimidines; C476003:thienopyrimidine
keywords: Activity against Plasmodium liver stages; Antiplasmodial mechanism of action; Genotoxicity; In vitro antiplasmodial profile; Pharmacomodulation; Thieno[3,2-d]pyrimidin-4(3H)-one