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Article Dans Une Revue Journal of Antimicrobial Chemotherapy Année : 2021

An adamantamine derivative as a drug candidate for the treatment of visceral leishmaniasis

Sébastien Pomel
  • Fonction : Auteur
Sandrine Cojean
  • Fonction : Auteur
Valérie Pons
  • Fonction : Auteur
Jean-Christophe Cintrat
  • Fonction : Auteur
Joël Vacus
  • Fonction : Auteur
Alain Pruvost
  • Fonction : Auteur
Daniel Gillet
Philippe Loiseau
  • Fonction : Auteur

Résumé

Abstract Background This study aimed to investigate compounds acting on the host cell machinery to impair parasite installation with the possible advantage of limiting drug resistance. The strategy therefore consisted of selecting compounds that are poorly active on the axenic parasite, but very active on the intramacrophage form of Leishmania. Objectives To identify a drug candidate from focused screening of adamantamine derivatives that can inhibit the development of Leishmania infantum in macrophages. Methods In vitro screening was performed on a library of 142 adamantamine derivatives with axenic and intramacrophage forms of L. infantum, as well as cytotoxicity assays, allowing selection of the most promising compound. Absorption, distribution, metabolism and excretion (ADME) experiments, including pharmacokinetics and microsomal stability, were performed and finally the physicochemical stability of the compound was investigated to assess its suitability for further drug development. Results VP343 was identified first in vitro, with a CC50 value of 63.7 μM and an IC50 value of 0.32 μM for L. infantum intramacrophage amastigotes and then in vivo, with a 59% reduction of the liver parasite burden after oral administration at 10 mg/kg/day for 5 days. In addition, the ADME data were compatible with moving this compound further through the antileishmanial drug candidate pipeline. Conclusions VP343 has the properties of a good drug candidate and merits further investigations.

Dates et versions

hal-04433354 , version 1 (01-02-2024)

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Citer

Sébastien Pomel, Sandrine Cojean, Valérie Pons, Jean-Christophe Cintrat, Anvi Laetitia Nguyen, et al.. An adamantamine derivative as a drug candidate for the treatment of visceral leishmaniasis. Journal of Antimicrobial Chemotherapy, 2021, 76 (10), pp.2640-2650. ⟨10.1093/jac/dkab226⟩. ⟨hal-04433354⟩
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