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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.

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