Larvicidal activity, molecular docking, and structural analysis of methoxyindolizine-1-carboxylate derivatives

Abstract

A series of sixteen ethyl 3-(4-substitutedbenzoyl)-7-methoxyindolizine-1-carboxylate derivatives (1a-1p) were assessed for their larvicidal study against Anopheles arabiensis using a standard WHO larvicidal assay, with Temephos (4 μg/mL) as the standard, to evaluate the nature of substitutions on the indolizine pharmacophore. Compounds 1h and 1l demonstrated excellent larvicidal activity at 48 h, achieving mean mortality rates of 98 % and 80 %, respectively, while the other compounds showed lower to moderate activity. Additionally, we report two single crystal structures of 1i and 1m from this series to investigate their structural characteristics. To establish a plausible mechanism of action and correlate it with the observed larvicidal activity, we employed computational approaches, including molecular docking and molecular dynamics simulations, to identify potential targets for the compound series. The results revealed that compounds 1h and 1l exhibited strong binding affinities with PDB ID: 6ARY (acetylcholinesterase mutant from the malaria vector) and PDB ID: 4JBV (calciumdependent protein kinase 1). Their strong binding affinities align with their observed larvicidal effectiveness. The stability of the protein-ligand complexes was further validated from molecular dynamics insights through RMSD, RMSF, hydrogen bond analysis, and 2D interaction plots. In addition, ADMET predictions highlighted compounds 1h and 1l as promising candidates, providing a foundation for the development of novel larvicidal agents.