2. Academic Validation
  3. Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium

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

  • Eur J Med Chem. 2015 May 5:95:16-28. doi: 10.1016/j.ejmech.2015.03.011.
Anita Cohen 1,  Peggy Suzanne 2,  Jean-Charles Lancelot 2,  Pierre Verhaeghe 3,  Aurélien Lesnard 2,  Louise Basmaciyan 4,  Sébastien Hutter 4,  Michèle Laget 4,  Aurélien Dumètre 4,  Lucie Paloque 5,  Eric Deharo 5,  Maxime D Crozet 6,  Pascal Rathelot 6,  Patrick Dallemagne 2,  Audrey Lorthiois 7,  Carol Hopkins Sibley 8,  Patrice Vanelle 6,  Alexis Valentin 5,  Dominique Mazier 7,  Sylvain Rault 2,  Nadine Azas 4
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 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.
  • 5 Université Paul Sabatier, IRD, UPS PHARMA-DEV, Equipe BIOCID UMR 152, Faculté des Sciences Pharmaceutiques, 35 Chemin des Maraîchers, 31400 Toulouse, France.
  • 6 Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de PharmacoChimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
  • 7 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.
  • 8 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.
PMID: 25791675 DOI: 10.1016/j.ejmech.2015.03.011
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.

Keywords

Activity against Plasmodium liver stages; Antiplasmodial mechanism of action; Genotoxicity; In vitro antiplasmodial profile; Pharmacomodulation; Thieno[3,2-d]pyrimidin-4(3H)-one.

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