Exploring ferrocenyl-quinoline hybrids as in vitro agents against Leishmania major promastigotes

• Ferrocenyl-quinolines have been prepared. • The amino-alkyl linked ferrocenyl-quinolines showed good in vitro activity against Leishmania major . • The lead compound showed better activity than the clinical drug, amphotericin B, but slightly more cytotoxic. Currently available drugs for cutaneous leishmaniasis are sub-optimal due to parasite-specific drug resistance, drug-induced host toxicity and lengthy treatment. Repurposing existing drugs/compounds with established biological activity provides an attractive measure for antileishmanial drug development. Quinoline is a ubiquitous scaffold for targeting parasitic infections, particularly malaria, showing enhanced activity when combined with metal complexes, such as the iron-containing compound ferrocene. Concomitantly, this study evaluates the potential of ferrocenyl-quinoline compounds as potential drug candidates for treating cutaneous leishmaniasis caused by Leishmania major , focusing on in vitro antipromastigote activity and cytotoxicity, using murine and cell-based models of the disease. Four ferrocenyl-quinoline compounds containing various linkers (imino-alkyl, amino-alkyl, triazole-amine and phenyl-alkene) were synthesized, with the triazole-amine and phenyl-alkene compounds being new. The four compounds and their respective precursors were assessed for their antileishmanial activity against only the promastigote form of L. major LV39, as well as their cytotoxicity in the RAW 264.7 murine macrophage cell line. The amino-alkyl and triazole amine-linked compounds were the most active against L. major LV39 promastigotes (IC 50 = 1.16 and 8.83 μM, respectively), with the former being more active than the clinical drug, amphotericin B (IC 50 = 2.10 μM). All four ferrocenyl-quinoline compounds were more cytotoxic than amphotericin B (CC 50 < 54 μM). However, both the amino-alkyl and triazole amine-linked compounds showed higher CC 50 values than their respective IC 50 values, suggesting a higher selectivity toward L. major promastigotes than their other counterparts (SI > 1). The triazole amine-linked compound, in particular, had an SI of 2.11, making it a more promising antileishmanial agent worthy of further investigation. This preliminary study not only delineates structure-based trends on antipromastigote activity but also demonstrates the significance of incorporating metals in drug design to enhance potency. Additional future studies are necessary to examine the potency of these compounds against L. major amastigotes, as well as their efficacy in vivo and mechanism of action.