Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium PMID: 25791675

ADC Targets in Oncology

2026-04-10

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

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: [email protected].
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.

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.