In silico design, chemical synthesis and biological screening of novel 4‐(1H)‐pyridone‐based antimalarial agents

Identifying novel lead compounds in drug discovery has been challenging because of the rapid rise of drug resistance to the existing chemotherapeutics and a lack of understanding of complex metabolic pathways in the parasite. Integrating computational and experimental approaches has shown to be of great worth in identifying and developing novel promising pharmacophore hybrids. In this present research, a series of new 4‐(1H)‐pyridone‐derived antimalarial agents were designed based on recent reports and our preliminary findings through in silico studies. Two of the 4‐(1H)‐Pyridone derivatives showed potential to bind to the Q0 site of the cytochrome bc1 complex and disrupt the mitochondrial electron transport chain. These compounds, along with previously synthesized compounds, exhibited significant inhibitory activities against the malaria parasite. Presently, seven compounds were successfully synthesized, characterized and these novel compounds have shown promise as antimalarial agents. This research focuses on synthesis of a series of new 4‐(1H)‐pyridone‐derived antimalarial agents, designed via in silico studies. The target compounds 5 and 6 displayed excellent antimalarial activities against Plasmodium falciparum with IC50 values of 0.13 µM (NF54), 0.10 µM (K1) and 0.05 µM (NF54), 0.04 µM (K1), respectively.