Mangubhai_2025_J.Biomol.Struct.Dyn__1

A series of novel dichloroindolizine carboxylate analogues (4a-n) have been prepared by using 3,5-dichloropyridine, and substituted phenacyl bromide with electron-deficient acetylene via a [3 + 2] cycloaddition reaction. This methodology features a reaction that is free from transition metal or catalyst, providing an eco-friendly synthesis for developing dichloroindolizines. All the synthesized products (4a-n) were characterized by (1)H NMR,(13)C NMR, and HRMS spectroscopic techniques. All the final compounds were evaluated for larvicidal activity using Temephos as the reference standard against Anopheles arabiensis. Compound 4c exhibited the highest larval mortality of 96.67% after 48 h of exposure, which is on par with the positive control, Temephos. Compounds 4e, 4i, 4j, and 4m were moderately toxic, resulting in 70.00%, 74.44%, 73.33%, and 70.00% mortality, respectively, after 48 h of exposure. To validate the biological activity and elucidate a plausible mechanism of action of these compounds molecular docking studies were carried out against six known antimalarial targets. Potential compounds 4c and 4e showed significant binding affinities and correlation of larvicidal activity against the targets calcium-dependent protein kinase-1 (4JBV) and acetylcholinesterase from malaria vector (6ARY). Molecular dynamics studies (300 ns) further supported the stability of these compounds 4c and 4e inside the binding pockets of 4JBV and 6ARY, as evidenced by the RMSD, RMSF, H-bonding, and other stable interactions. Therefore, these novel indolizines can be considered as potential multi-targeting lead molecules for further optimization to combat malaria.