Novel Catechol Derivatives of Arylimidamides as Antileishmanial Agents

Two novel bis-arylimidamide derivatives with terminal catechol moieties (9a and 10a) and two parent compounds with terminal phenyl groups (DB613 and DB884) were synthesized as dihydrobromide salts (9b and 10b). The designed compounds were hybrid molecules consisting of a catechol functionality embedded in an arylimidamide moiety. All compounds were examined for in vitro antiparasitic activity upon promastigotes of Leishmania major and L. infantum as well as axenic amastigotes of L. major. It was shown that conversion of terminal phenyl groups into catechol moieties resulted in more than 10-fold improvement in potency, coupled with lower cytotoxicity against fibroblast cells, compared to the corresponding parent compounds. The furan-containing analog 9a exhibited the highest activity with submicromolar IC₅₀ values, ranging from 0.29 to 0.36 μm, which is comparable in efficacy to the reference drug amphotericin B (IC₅₀ 0.28 - 0.33 μm). The results justify further study of this class of compounds. It seems that the combination of catechol chelating groups with potent antiparasitic agents could improve the efficacy by presenting novel hybrid compounds.