An Adamantamine Derivative As A Drug Candidate For The Treatment Of Visceral Leishmaniasis

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 mu M and an IC50 value of 0.32 mu M for L. infantum intramacrophage amastigotes and then in vivo, with a 59% reduction of the liver parasite burden after oral administration at 10mg/kg/day for 5days. 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.