Furanyl-Chalcones as antimalarial agent: synthesis, <i>in vitro</i> study, DFT, and docking analysis of P <i>f</i> DHFR inhibition

Abstract Malaria continues to pose a significant threat to global health, demanding the development of novel antimalarial agents. This study investigated the antimalarial potential of eleven (11) furanyl-chalcone derivatives synthesized from two distinct furan sources: 2-acetylfuran and furfuraldehyde with Claisen–Schmidt condensation under base conditions, and successfully synthesized target compound with yields ranging from 67 % to 94 %. Structural characterization was achieved using spectroscopic techniques, including NMR, IR, and GC-MS. Our findings revealed that compounds derived from 2-acetylfuran exhibited superior antimalarial activity compared to their furfuraldehyde counterparts. Compounds B1 and B4 demonstrated the most promising activity with IC 50 values of 1.01 μM and 1.04 μM, respectively against P.falciparum FCR-3 strain. Our analysis revealed that B4 forms a stable hydrogen bond with Ser108 in the active site of wild-type P f DHFR, with a binding affinity of −6.7 kcal/mol. Importantly, this interaction was preserved even in the presence of a mutation at this residue, with B4 forming a hydrogen bond with Asn108 in the mutant enzyme, exhibiting a binding affinity of −7.0 kcal/mol. This suggests that B4 has the potential to overcome pyrimethamine resistance. Further analysis, utilizing DFT calculations and MEP, identified B4 as the most reactive compound within the series. The reactive site was located in the carbonyl group, with enhanced reactivity attributed to the presence of the electron-rich furan ring and the ortho -methoxy substituent.