2. Academic Validation
  3. Novel thienopyrimidones targeting hepatic and erythrocytic stages of Plasmodium parasites with increased microsomal stability

Novel thienopyrimidones targeting hepatic and erythrocytic stages of Plasmodium parasites with increased microsomal stability

  • Eur J Med Chem. 2023 Dec 5:261:115873. doi: 10.1016/j.ejmech.2023.115873.
Prisca Lagardère 1,  Romain Mustière 2,  Nadia Amanzougaghene 3,  Sébastien Hutter 4,  Marion Casanova 4,  Jean-François Franetich 3,  Shahin Tajeri 3,  Aurélie Malzert-Fréon 5,  Sophie Corvaisier 5,  Marc Since 5,  Nadine Azas 4,  Patrice Vanelle 6,  Pierre Verhaeghe 7,  Nicolas Primas 6,  Dominique Mazier 3,  Nicolas Masurier 8,  Vincent Lisowski 9
Affiliations

Affiliations

  • 1 Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, ENSCM, UFR des Sciences Pharmaceutiques et Biologiques, Montpellier, France.
  • 2 Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 13385 Marseille cedex 05, France.
  • 3 Centre d'Immunologie et des Maladies Infectieuses (CIMI), INSERM, CNRS, Sorbonne Université, Paris, France.
  • 4 Aix Marseille Université, IRD, AP-HM, SSA, VITROME, Marseille, France.
  • 5 CERMN, Université de Caen Normandie, UNICAEN, France.
  • 6 Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 13385 Marseille cedex 05, France; AP-HM, Hôpital Conception, Service Central de la Qualité et de l'Information Pharmaceutiques, 13005, Marseille, France.
  • 7 Univ. Grenoble Alpes, CNRS, DPM UMR 5063, F-38041, Grenoble, France; LCC-CNRS Université de Toulouse, CNRS, UPS, Toulouse, France; CHU de Nîmes, Service de Pharmacie, Nîmes, France.
  • 8 Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, ENSCM, UFR des Sciences Pharmaceutiques et Biologiques, Montpellier, France. Electronic address: [email protected].
  • 9 Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, ENSCM, UFR des Sciences Pharmaceutiques et Biologiques, Montpellier, France. Electronic address: [email protected].
PMID: 37857143 DOI: 10.1016/j.ejmech.2023.115873
Abstract

Based on the structure of a previously identified hit, Gamhepathiopine 1, which showed promising antiplasmodial activity, but poor microsomal stability, several strategies were investigated to improve the metabolic stability of the compounds. This included the introduction of fluorine or deuterium atoms, as well as carbocyclic groups. Among the new compounds, the 2-aminocyclobutyl derivative 5g demonstrated enhanced microsomal stability compared to compound 1, while retaining antiplasmodial activity against erythrocytic and hepatic stages of Plasmodium, without significant cytotoxicity against primary hepatocytes.

Figures
Products