Clofazimine analogs as antimalarial drugs

Abstract

Clofazimine is a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy (MDT) for the treatment of leprosy. Tetramethylpiperidine \u2013substituted phenazines, structurally related to clofazimine, have been described to be endowed with activity against multidrug resistant strains of Plasmodium falciparum.1 With the aim to study more thorougly the antimalarial potentialities of this kind of structures, we synthesized a set of novel aminophenazines bearing a monocyclic or bicyclic basic head linked through a short alkylic chain to the imino nitrogen in position 2 on the phenazine nucleus. The new compounds inhibited the growth of cloroquine sensitive (CQ-S) and chloroquine resistant (CQ-R) strains of P. falciparum with IC50 in low micromolar or submicromolar range. Among the compounds so far synthesized, the quinolizidinyl derivatives were the most active. In this series, activity and resistance index improved with the elongation of the alkyl spacer . Compound VB 667 showing IC50=123 nM against D-10 (CQ-S) strain and IC50=62.6 nM against W-2 (CQ-R) strain, represents our new lead compound worthy of further studies focused on its optimisation