Clemastine/tamoxifen hybrids as easily accessible antileishmanial drug leads.

Abstract

A library of hybrid molecules is developed based on the common chemical features shared by clemastine and tamoxifen both of which are well known for their antileishmanial activities. In the initial screening against Leishmania major and L. amazonensis promastigotes, as well as cytotoxicity assays using HepG2 cells, several hybrids showed submicromolar activity against the parasite and no toxicity against human cells. The compounds with an EC50 < 2 μM against promastigotes of both species and a selectivity index >10 were further characterized against intracellular amastigotes as well as promastigotes of species that cause both visceral and cutaneous leishmaniasis, such as L. infantum and L. braziliensis, respectively. These sequential screenings revealed the high pan-activity of this class of molecules against these species, with several compounds displaying an EC50 ≤ 2 μM against both promastigotes and intracellular amastigotes. Two of them were identified as the potential templates for lead optimization of this series having shown the highest activities against all species in both stages of parasite. The present findings can serve as a good starting point in the search for novel antileishmanial compounds that are easy to access and highly active.