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

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.

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

“…The mouse monocyte/macrophage cell line RAW 264.7 and L. donovani (MHOM/ET/67/HU3, also called LV9) promastigotes and axenic amastigotes were maintained according to the protocols described in Pomel et al, 2021 …”

“…The mouse monocyte/ macrophage cell line RAW 264.7 and L. donovani (MHOM/ ET/67/HU3, also called LV9) promastigotes and axenic amastigotes were maintained according to the protocols described in Pomel et al, 2021. 69 Evaluation of Compound Cytotoxicity on RAW 264.7 Macrophages. Cytotoxicity was evaluated on RAW 264.7 macrophages using the resazurin method as detailed in Pomel et al, 2021.…”

“…Cytotoxicity was evaluated on RAW 264.7 macrophages using the resazurin method as detailed in Pomel et al, 2021. 69 In Vitro Antileishmanial Evaluation on L. donovani Axenic Amastigotes. This evaluation was performed using the SYBR Green method as previously described.…”

“…The in vitro treatment was applied 24 h post-infection, and the treatment duration was 48 h. The results of the effect of the compounds are given as percentage reduction of parasite growth, measured using the SYBR Green incorporation method. The activity of the compounds is expressed as IC 50 , calculated using the ICEstimator version 1.2 software (Pomel et al, 2021). Miltefosine was used as the reference drug.…”

Synthesis of new 3-acetyl-1,3,4-oxadiazolines combined with pyrimidines as antileishmanial and antiviral agents

“…The mouse monocyte/macrophage cell lines RAW 264.7 and L. donovani (MHOM/ET/67/HU3, also called LV9) promastigotes and axenic amastigotes were kept in accordance with the procedures presented by Pomel et al [ 50 ]…”