Novel thiosemicarbazones of coumarin incorporated isatins: synthesis, structural characterization and antileishmanial activity.

Abstract

Leishmaniasis, a neglected tropical disease affecting 0.7 to 1.3 million people annually, has only a few toxic therapeutic options. This study describes the synthesis, structural characterization, in silico and in vitro assessment of novel thiosemicarbazones of coumarin incorporated isatins (6a-6m) as highly as potent and safe antileishmanial agents. Molecular docking was initially used to determine the binding of these compounds to the active cavity of the target protein (Leishmanolysin gp63) of Leishmania (L.) tropica. Among all the docked compounds, three 6d, 6f and 6l showed high binding affinities due to strong H-bonds and hydrophobic π-interactions. Importantly, the in vitro investigations of thirteen synthesized compounds for antileishmanial activity against L. tropica promastigotes and axenic amastigotes, complemented the docking results. The compound 6d was found to be the most active of the series at micromolar concentrations both against promastigotes (IC₅₀ = 2.985 μmol/L) and axenic amastigotes (IC₅₀ = 13.46 μmol/L) in comparison to the tarter emetic (IC₅₀ = 12.56 μmol/L) and amphotericin B (IC₅₀ = 1.826 μmol/L), respectively. Significantly, all active compounds are much less toxic as compared to the positive control (Triton X-100) and, tartar emetic (TA) and amphotericin B when screened for their toxicity against human erythrocytes. To gain further insight into the interaction dynamics of our target protein on binding with compound 6d, molecular dynamic simulation was performed for a course of 100 ns for both the apo-protein and the protein-ligand complex. The results revealed consistent structural stability for the protein-ligand complex, aligning with characteristics seen in the apo-proteins.