Synthesis, Biological Evaluation, Structure–Activity Relationship, and Mechanism of Action Studies of Quinoline–Metronidazole Derivatives Against Experimental Visceral Leishmaniasis

In our efforts to identify novel
chemical scaffolds for the development
of antileishmanial agents, a series of quinoline–metronidazole
hybrid compounds was synthesized and tested against the murine model
of visceral leishmaniasis. Among all synthesized derivatives, 15b and 15i showed significant antileishmanial
efficacy against both extracellular promastigote (IC50 9.54
and 5.42 μM, respectively) and intracellular amastigote (IC50 9.81 and 3.75 μM, respectively) forms of Leishmania donovani with negligible cytotoxicity
toward the host (J774 macrophages, Vero cells). However, compound 15i effectively inhibited the parasite burden in the liver
and spleen (>80%) of infected BALB/c mice. Mechanistic studies
revealed
that 15i triggers oxidative stress which induces bioenergetic
collapse and apoptosis of the parasite by decreasing ATP production
and mitochondrial membrane potential. Structure–activity analyses
and pharmacokinetic studies suggest 15i as a promising
antileishmanial lead and emphasize the importance of quinoline–metronidazole
series as a suitable platform for the future development of antileishmanial
agents.