Design, synthesis and evaluation of novel ß-carboline ester analogues as potential anti-leishmanial agents.

Leishmaniasis is one of today's most neglected diseases. The emergence of new anti-leishmanial therapies emphasizes several study groups funded by the World Health Organization. The present investigation will focus on the research to determine a few new potential derivatives of ß-carboline ester derivatives against leishmaniasis. The in-silico predicted ADMET properties of most of the titled compounds are in an acceptable range and having drug like properties. Among all the tested analogs, compound ES-3 (EC50 3.36 µM; SI > 29.80) showed comparable and equipotent anti-leishmanial activity as that of standard drug miltefosine (EC50 4.80 µM; SI > 20.80) against amastigote forms of the tested L. infantum strain. Two compounds ES-6 and ES-10 exhibited significant activity with EC50 10.16, 13.56 µM; SI > 4.90, 7.37, respectively. In-silico based molecular docking and dynamics study of the significantly active analog also performed to study the putative binding mode, interaction pattern at the active site of the target leishmanial trypanothione reductase enzyme as well as stability of the target-ligand complex. The changes in the conformation of molecules during MD (frame wise trajectory analysis) provided new insights for the development of novel potent molecules. These findings will further give insight that will help modify the compound ES-3 for better potency and the design of novel inhibitors for leishmaniasis.Communicated by Ramaswamy H. Sarma.

Recent evolution on synthesis strategies and anti-leishmanial activity of ß-carboline derivatives - An update.

Leishmaniasis is the most widespread pathogenic disease in several countries. Currently, no effective vaccines are available, and the control of Leishmaniasis primarily relies on decade-old chemotherapy. The treatment for the Leishmaniasis is not up to the mark. Current therapy for Leishmaniasis is ancient and requires hospitalization for the administration. These medications are also highly toxic and resistant. ß-carboline, a natural indole containing alkaloid, holds a vital position in the field of medicinal chemistry with a diversified pharmacological action. The current review focuses mainly on the anti-leishmanial effects of ß-carboline analogs and their synthetic strategies, structural activity relationship studies (SAR). The past ten years alterations unveiled by ß-carboline analogs present in phytoconstituents and various derivatives of synthesized analogs with the mechanism of action were briefly shortlisted and illustrated.