Identification of novel inhibitors from as anti-leishmanial agents targeting DDX3-DEAD box RNA helicase of .

Unlabelled: Visceral leishmaniasis (VL), caused by , remains challenging to treat due to severe side effects and increasing drug resistance associated with current chemotherapies. Our study investigates the anti-leishmanial potential of from Uttarakhand, India, with extracts prepared from leaves and stems using ethanol and hexane. Advanced GC-MS analysis identified over 100 bioactive compounds, which were screened using molecular docking to assess their binding to LdHEL-67, a DDX3-DEAD box RNA helicase of donovani. Our results spotlighted nine major compounds with high binding energy, which were then further analyzed for ADMET properties and toxicity predictions, demonstrating their promising pharmacokinetic profiles. Among these, clionasterol emerged as the standout compound, displaying superior results in all in silico analyses compared to Amphotericin B (the control). Notably, clionasterol was present in significant proportions across all the mentioned extracts. Subsequent treatment with these extracts led to a remarkable reduction in the intracellular amastigote and axenic amastigote, and promastigote forms of and non-toxic to THP-1-derived macrophages. Moreover, the extracts induced apoptotic effects, as evidenced by the fragmentation of parasitic genomic DNA. This study marks a significant leap in developing herbal-based, target-specific inhibitors against VL. Hence, our findings highlight the immense potential of as a natural treatment for VL.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04183-4.