Siti Nur Hidayah Jamil, Khairul Azreena Bakar, Amatul Hamizah Ali, Nur Fatin Najihah Marzuki, Fatima Shahid, Fauze Mahmud, Shevin Rizal Feroz, Su Datt Lam, Natsuhisa Oka, Yusmazura Zakaria, Muhamad Imam Muhajir, Rani Maharani, Unang Supratman, Jalifah Latip
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. © The Author(s) 2026.
Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, UKM Bangi, Selangor, Bangi, 43600, Malaysia; International Joint Department of Materials Science and Engineering between, Graduate School of Engineering, National University of Malaysia and Gifu University, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan; Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, UKM Bangi, Selangor, Bangi, 43600, Malaysia; Biomedicine Programme, School of Health Sciences, Universiti Sains Malaysia, Health Campus, Kelantan, Kota Bharu, 16150, Malaysia; Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, UKM Bangi, Selangor, Bangi, 43600, Malaysia; Faculty of Science and Technology, Universiti Malaysia Sabah, Jalan UMS, Kota Kinabalu, 88400, Malaysia; BioAgriTech Research (BioATR) Group, Faculty of Science and Technology, Universiti Malaysia Sabah, Jalan UMS, Kota Kinabalu, 88400, Malaysia; Structural Biology and Protein Engineering Research Group, Universiti Kebangsaan Malaysia, Selangor, Bangi, 43600, Malaysia; Center for Global Health Research (CGHR), Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha Medical College, Saveetha University, Tamil Nadu, Chennai, 602 105, India; Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan; Center for One Medicine Innovative Translational Research (COMIT), Institute for Advanced Study, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan; Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, 501-1193, Japan; Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, West Java, Jatinangor, 45363, Indonesia; Smart Material and Sustainable Product Innovation (SMatSPIn) Research, Universiti Kebangsaan Malaysia, UKM Bangi, Selangor, Bangi, 43600, Malaysia; Department of Chemistry, Faculty of Mathematics and Natural Sciences, State University of Malang (Universitas Negeri Malang), Jl. Semarang No. 5, Malang, 65145, Indonesia
