2. Academic Validation
  3. New antiplasmodial 4-amino-thieno[3,2-d]pyrimidines with improved intestinal permeability and microsomal stability

New antiplasmodial 4-amino-thieno[3,2-d]pyrimidines with improved intestinal permeability and microsomal stability

  • Eur J Med Chem. 2023 Jan 13;249:115115. doi: 10.1016/j.ejmech.2023.115115.
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,  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, UNICAENs, 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 LCC-CNRS, Université de Toulouse, CNRS UPR 8241, UPS, Toulouse, France; Univ. Grenoble Alpes, CNRS, DPM UMR 5063, F-38041, Grenoble, 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: 36680984 DOI: 10.1016/j.ejmech.2023.115115
Abstract

The increasing number of Plasmodium falciparum strains resistant to current treatments justifies the urgent need to discover new compounds active on several stages of the Parasite development. Based on the structure of Gamhepathiopine, a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one previously identified for its dual activity against the sexual and asexual stages of P. falciparum, 25 new 4-amino-substituted analogues were synthesized and evaluated on the erythrocytic and hepatic stages of Plasmodium. A promising compound, N2-(tert-butyl)-N [4]-(3-(dimethylamino)propyl)-6-(p-tolyl)thieno[3,2-d]pyrimidine-2,4-diamine, showed improved physicochemical properties, intestinal permeability (PAMPA model) and microsomal stability compared to Gamhepathiopine, while maintaining a good antiplasmodial activity on the erythrocytic stage of P. falciparum and on the hepatic stage of P. berghei.

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