Synthesis, biological evaluation, and molecular modelling studies of novel Ethyl 3-benzoyl-6,8-dichloroindolizine-1-carboxylates against malaria vector <i>Anopheles arabiensis</i>

A series of novel dichloroindolizine carboxylate analogues (<b>4a–n</b>) have been prepared by using 3,5-dichloropyridine, and substituted phenacyl bromide with electron-deficient acetylene <i>via</i> 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 (<b>4a–n</b>) were characterized by ¹H NMR,¹³C NMR, and HRMS spectroscopic techniques. All the final compounds were evaluated for larvicidal activity using Temephos as the reference standard against <i>Anopheles arabiensis</i>. Compound <b>4c</b> exhibited the highest larval mortality of 96.67% after 48 h of exposure, which is on par with the positive control, Temephos. Compounds <b>4e, 4i</b>, <b>4j,</b> and <b>4m</b> 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 <b>4c</b> and <b>4e</b> 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 <b>4c</b> and <b>4e</b> 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.