Synthesis, antimalarial activity, and molecular docking of some novel pyridinone derivatives containing benzylpiperazine substituents

In developing countries, malaria is still one of the major health problems. The resistance of the malaria parasite (Plasmodium) to existing drugs necessitates the introduction of novel antimalarial agents. In light of reports on several pyridinone-based compounds as antimalarial agents, this study presents new antimalarial derivatives of this heterocyclic ring containing benzylpiperazine substituents. The compounds were synthesized with appropriate chemical methods and structurally confirmed with different techniques. The antimalarial activity of the synthesized compounds was evaluated through β-hematin inhibition assay which showed satisfactory activity for 5-(benzyloxy)-2-((4-(4-cholrobenzyl)-1-piperazyl) methyl)-1-methyl-4-pyridinone (9e) with 84 % Heme inhibition activity compare to Chloroquine (90 %) as reference. In addition, the interaction of these compounds with the Heme sheet was evaluated through a docking study to identify the theoretical potential of the designed compounds to inhibit β-hematin formation, a key step in the malaria life cycle. The docking results showed good interactions between the compounds and the Heme sheet, particularly for the 9d and 9e compounds. The physicochemical properties of the synthesized compounds predicted by the SwissADME web server, were within acceptable limits. Finally, the MTT assay showed that compounds 9d and 9e did not display noteworthy cytotoxicity on the L929 fibroblast cell line. The obtained results suggest further study on the 9e compound as a potential antimalarial agent.