The development of novel ferrocenyl quinoline-benzimidazole molecular hybrids against cutaneous leishmaniasis

Cutaneous leishmaniasis, the most prevalent form of the parasitic and vector-borne disease of leishmaniasis, is mainly caused by Leishmania major (L. major) in the developing world. With no vaccine available for primary prophylaxis, secondary prophylaxis comprises commercially available therapeutic drugs, such as amphotericin B and miltefosine. However, these agents are associated with parasite-specific drug resistance, severe drug-induced toxicity to the host and high treatment costs. In this study, the strategies of molecular hybridisation of pharmacologically relevant scaffolds and metal incorporation were combined to synthesise a set of novel hybrid compounds containing the quinoline, benzimidazole, ferrocene and triazole scaffolds. The hybrids showed adequate stability at 37 °C over a 48-h incubation period and antileishmanial studies on L. major promastigotes revealed one lead compound (4a) with potent activity (IC₅₀ of 6.63 ± 0.66 μM), comparable with the standard clinical drug amphotericin B (IC₅₀ of 4.96 ± 0.13 μM). In addition, compound 4a showed significant efficacy (IC₅₀ of 15.4 ± 0.5 μM) against L. major amastigotes in murine bone marrow-derived macrophages (BMDMs), albeit less potent than amphotericin B (IC₅₀ of 5.47 ± 0.43 μM). The lead compound was also minimally toxic against murine BMDMs which resulted in a strong selectivity index. Mechanistic profiling in L. major promastigotes further revealed that compound 4a induced a concentration-dependent increase in intracellular reactive oxygen species, mitochondrial membrane depolarisation, and progressive parasitic plasma membrane impairment. Taken together, the hybrid architecture of these compounds may provide opportunities for further derivatisation, optimisation, and structure-activity relationship (SAR) studies to improve potency and selectivity through potential multimodal mechanisms of action, thus representing a nascent roadmap towards novel antileishmanial agents.