Antimalarial potential of curcumin derivatives evaluated through experimental and computational approaches.

Malaria remains a leading global health threat, with cases and deaths continually increasing each year. The rising number of drug-resistant cases further diminishes the effectiveness of current antimalarials, highlighting the need for potent and effective new compounds. Curcumin, a natural polyphenol, has been extensively studied for its therapeutic properties. However, its clinical use is limited by poor bioavailability. This study evaluates curcumin derivatives as potential antimalarial agents through in-silico screening and biological assessments, aiming to identify promising candidates for further development. For the first time, we reveal the multi-target mechanisms of action of these derivatives, focusing on their potential for immunomodulatory GSK-3β inhibition and haemin binding. The ten synthesised compounds, which include Knoevenagel condensates, heterocyclic pyrazoles, and monocarbonyl derivatives, show favourable GSK-3β binding and improved specific ADMET parameters compared to curcumin, along with favourable electronic and reactivity profiles. These compounds also demonstrate greater potency than curcumin against both P. falciparum CQ-sensitive 3D7 and multidrug-resistant K1 strains. Notably, monocarbonyl derivative 20 exhibited the most potent EC50 (0.15 ± 0.03 µM for 3D7 and 2.53 ± 1.06 µM for K1), with selective in vitro inhibition of GSK-3β. Most compounds, apart from pyrazole derivatives 17-18, showed higher cytotoxicity potential. Additionally, ITC experiments indicated that curcumin derivatives can spontaneously bind haemin thermodynamically, which may contribute to their increased activity in pLDH assays. Overall, these findings highlight the multifaceted biological potential of structurally derived curcumin compounds for antimalarial development. This research exemplifies efforts to address the urgent need for potent antimalarials capable of overcoming parasite resistance.