Amatul Hamizah Ali, Rini Retnosari, Siti Nur Hidayah Jamil, Nur Aqilah Zahirah Norazmi, Nabel Darwish Zuhaidi, Su Datt Lam, Sylvia Chieng, Hani Kartini Agustar, Kuhan Chandru, Nurhezreen Md Iqbal, Lau Yee Ling, Jalifah Latip
Background: Thymol, a natural phenol with antimicrobial and antioxidant activities, and its derivatives offer promising scaffolds for antimalarial drug development, potentially helping overcome resistance. Materials and Methods: In this study, thymol derivatives were synthesized and assessed as antiplasmodial agents against both resistant and sensitive strains of P. falciparum, as well as Plasmodium knowlesi. The ligand molecules were assessed with Plasmodium falciparum chloroquine resistance transporter (PfCRT)’s potential using in silico molecular docking and ADMET analysis. The parent compound, thymol, was chemically modified through esterification and conjugation with hydroxybenzoic acid and cinnamic acid derivatives to generate analogs with varied substitution patterns. Results: The findings showed that among seven successfully synthesized thymol derivatives, compounds 4 and 6 exhibited notable potency against Plasmodium falciparum 3D7 (EC50 = 6.01 ± 1.7 µM and 6.8 ± 1.1 µM, respectively) with high SI values (16.5 and 14.6, respectively), indicating improved selectivity relative to thymol. The cytotoxicity evaluation against HCF mammalian cells revealed that most thymol derivatives were non-toxic, with CC50 values greater than 99 µM, except for compound 3 (CC50 = 71.4 ± 4.5 µM) and compound 1 (CC50 = 58.4 ± 2.3 µM), which exhibited moderate cytotoxic effects. The molecular docking results showed that compounds 3 (−8.4 kcal/mol), 4 (−8.3 kcal/mol), and 6 (−8.3 kcal/mol) exhibited strong binding affinities toward the PfCRT protein. Conclusions: Therefore, thymol derivative compounds 4 and 6 exhibited stronger antiplasmodial activity in vitro against P. falciparum and P. knowlesi with safety profiles against mammalian cells, targeting PfCRT, highlighting their potential as lead antimalarial candidates. © 2026 by the authors.
Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), 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; International Joint Department of Materials Science and Engineering, Between National University of Malaysia and Gifu University, Graduate School of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan; Department of Parasitology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, 50603, Malaysia; Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Selangor, Bangi, 43600, Malaysia; Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Selangor, Bangi, 43600, Malaysia; Department of Earth Science and Environment, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Selangor, Bangi, 43600, Malaysia; Space Science Center (ANGKASA), Institute of Climate Change, Level 3, Research Complex, Universiti Kebangsaan Malaysia (UKM), Selangor, Bangi, 43600, Malaysia; Malaysia Genome and Vaccine Institute, Jalan Bangi Lama, Selangor, Kajang, 43000, Malaysia
