Benzimidazole derivatives endowed with potent antileishmanial activity

Abstract

Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC₅₀ values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles.

Graphical Abstract

Keywords:

• Leishmania tropica and infantum
• promastigotes
• anti-leishmania agents
• alkyl benzimidazolium salts
• 2-benzyl-1-lupinylbenzimidazole derivatives

Acknowledgments

This work was in part supported by Ministero dell?Istruzione, dell’Università e della Ricerca (PRIN) Projects 2010C2LKKJ_006; 20154JRJPP_004.

Disclosure statement

All authors declare no conflicts of interest.