Exploring Indole-Dihydropyrimidinone Derivatives: Design, Synthesis, Biological Assessment, SAR Analysis, and Evaluation of Mode of Action in Experimental Visceral Leishmaniasis

The emergence of drug resistance and the non-availability of vaccines encouraged us to identify novel chemical scaffolds as new anti-leishmanial agents. In doing so, a series of thirty-four indole-dihydropyrimidinone hybrid compounds were synthesized using the Biginelli multicomponent reaction. These synthesized compounds were tested against L. donovani in vitro and in vivo in experimental golden hamster model of visceral leishmaniasis. Compounds 4f and 4m were found to have promising anti-leishmanial properties against intracellular amastigotes (IC₅₀ 4.54 & 5.05 μM, respectively) with minimal cytotoxicity against J774.1 macrophage. 4f and 4m were tested in vivo, and only 4f effectively cleared the parasite burden (>65%) in infected golden hamsters. Mode of action studies discloses that 4f induces oxidative stress-mediated mitochondrial dysfunction and impairment of ATP production and triggers apoptosis. SAR and PK studies revealed that compound 4f (indole-dihydropyrimidinone hybrid) may be used as a lead for developing future chemotherapeutic options for VL.