Systems pharmacology aiding benzimidazole scaffold as potential lead compounds against leishmaniasis for functional therapeutics.

Systems pharmacology helps to understand the complex relationships between biological systems, drugs, and infection model; Leishmania major being one of them. It has aided the drug discovery process by addressing the concerns about economic stress, drug toxicity, and the emergence of resistance. Two million new leishmaniasis cases are reported annually, and >350 million people are at risk globally due to the parasite Leishmania. Trypanothione reductase (TryR) from the parasite-specific redox metabolism is a promising target. In the discipline of medicinal chemistry, benzimidazole is a strong pharmacophore and exhibits a broad range of biological activities. In the current study, benzimidazole derivatives were explored using computational, enzyme kinetics, biological activity, cytotoxic impact characterization, and in-silico ADME-Tox predictions, followed by their confirmation through in-vitro and animal experiments to discover novel inhibitors for TryR from Leishmania major. During rigorous in-silico screening, two benzimidazole derivatives were chosen for further experimentation. In-vitro testing revealed that compound C1 has a higher binding affinity for the TryR protein. Treatment with compound C1 caused significant morphological changes in the parasite, including size reduction, membrane blebbing, loss of motility, and improved anti-leishmanial efficacy. The compound C1 had significant anti-leishmanial potential against L. major promastigotes and demonstrated apoptosis-mediated leishmanicidal activity (apoptosis-like cell death). Furthermore, BALB/c female mice treated with C1 reduced parasite burden. Our findings depicts that C1 successfully lowered the parasite load and has a therapeutic impact on infected mice making C1 as a promising lead compound that, with additional modifications, may be exploited to create novel anti-leishmanial therapies.