4-Substituted Thieno[3,2-d]pyrimidines as Dual-Stage Antiplasmodial Derivatives

Prisca Lagardère (1) , Romain Mustière (2) , Nadia Amanzougaghene (3) , Sébastien Hutter (4) , Jean-François Franetich (3) , Nadine Azas (4) , Patrice Vanelle (2, 5) , Pierre Verhaeghe (6, 7) , Nicolas Primas (2, 5) , Dominique Mazier (3) , Nicolas Masurier (1) , Vincent Lisowski (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 ICR - Institut de Chimie Radicalaire
3 CIMI - Centre d'Immunologie et des Maladies Infectieuses
4 VITROME - Vecteurs - Infections tropicales et méditerranéennes
5 LA CONCEPTION - Hôpital de la Conception [CHU - APHM]
6 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
7 LCC - Laboratoire de chimie de coordination

Malaria remains one of the major health problems worldwide. The increasing resistance of Plasmodium to approved antimalarial drugs requires the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Based on the structure of Gamhepathiopine, a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hit, active on the sexual and asexual stages of the parasite and thanked for the introduction of various substituents at position 4 of the thienopyrimidine core by nucleophilic aromatic substitution and pallado-catalyzed coupling reactions, a series of 4-substituted thieno[3,2-d]pyrimidines were identified as displaying in vitro activities against both the erythrocytic stage of P. falciparum and the hepatic stage of P. berghei. Among the 28 compounds evaluated, the chloro analogue of Gamhepathiopine showed good activity against the erythrocytic stage of P. falciparum, moderate toxicity on HepG2, and better activity against hepatic P. berghei parasites, compared to Gamhepathiopine.

Mots clés: Malaria; Thienopyrimidine; Erythocytic; Hepatic; Plasmodium

Domaines: Chimie thérapeutique; Maladies infectieuses

Prisca Lagardère, Romain Mustière, Nadia Amanzougaghene, Sébastien Hutter, Jean-François Franetich, et al.. 4-Substituted Thieno[3,2-d]pyrimidines as Dual-Stage Antiplasmodial Derivatives. Pharmaceuticals, 2022, 15 (7), pp.820. ⟨10.3390/ph15070820⟩. ⟨hal-03725749⟩