Synthesis and Assessment of Imidazo-Fused β-Carbolines as Antileishmanial Agents

Visceral leishmaniasis is a life-threatening neglected tropical disease that predominantly affects the liver and spleen. The widespread emergence of drug resistance, along with the continued absence of an effective vaccine, underscores the urgent need to explore novel chemical scaffolds with potent antileishmanial activity. In this context, we report the discovery of a new series of imidazo-fused β-carbolines synthesized via the Groebke-Blackburn-Bienaymé reaction of substituted 3-amino-β-carboline with aldehyde and isonitrile, which exhibited significant antileishmanial activity against Leishmania donovani in both in vitro and in vivo models. Among the synthesized compounds, 11ab and 11ad emerged as the most potent, displaying IC₅₀ values of 0.662 μM and 0.652 μM, respectively, against the amastigote stage, along with favorable safety indices. In the in vivo evaluation, both compounds achieved greater than 80% parasite suppression in the L. donovani-infected golden hamster model. Mechanistic investigations revealed that compound 11ad exerts its antileishmanial activity through the inhibition of histone deacetylase (Silent Information Regulator 2) activity. Furthermore, 11ad induces elevated intracellular levels of reactive oxygen species, leading to oxidative stress that triggers mitochondrial membrane depolarization and cytochrome-c release. These events ultimately result in phosphatidylserine-like membrane alteration and lead to apoptosis-like cell death. Compound 11ad also activates a host immune response by inducing Th1 cytokines and nitric oxide, which are crucial for killing the parasite. Thus, it was apparent that the compound potentially kills the parasite directly as well as by activating the host immune response.