Enny Fachriyah, Muhammad Badrul Huda, Purbowatiningrum Ria Sarjono, Faris Hermawan, Reinhard Sharon Lase, Nanik Wijayati, Jumina Jumina, Yudhi Dwi Kurniawan, Muhammad Eka Prastya
The global rise of antibiotic-resistant bacteria poses a critical health challenge, necessitating the discovery of new antibacterial agents. In this study, three hydroxyxanthone derivatives, 1,5-dihydroxyxanthone (HX1), 1,6-dihydroxyxanthone (HX2), and 1,7-dihydroxyxanthone (HX3) were synthesized in 3.5, 38.2, and 17.54% yields, respectively. In vitro assays revealed that all compounds were inactive against Escherichia coli (MIC > 1000 μg/mL) but exhibited potent inhibition of Pseudomonas aeruginosa (MIC 15.62 μg/mL). Compounds HX1 and HX3 also demonstrated strong activity against Staphylococcus aureus and Bacillus subtilis (MICs of 15.62 μg/mL), while HX2 showed moderate activity (MIC of 31.25 μg/mL). Molecular docking indicated favorable binding energies (–6.23 to –6.68 kcal/mol) toward DHFR from E. coli and S. aureus, surpassing those of trimethoprim and tetracycline. Molecular dynamics simulations confirmed stable ligand–protein interactions, and ADMET analyses potential drug-likeness and pharmacokinetic profiles. Overall, HX1 and HX3 emerge as promising lead scaffolds for the development of novel DHFR-targeted antibacterial agents against both Gram-positive and Gram-negative pathogens. © 2026, Gadjah Mada University. All rights reserved.
Department of Chemistry, Faculty of Science and Mathematics, Diponegoro University, Jl. Prof. Soedharto SH, Tembalang, Semarang, 50275, Indonesia; Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), KST BJ Habibie, Setu, Tangerang Selatan, 15314, Indonesia; Department of Chemistry, Universitas Negeri Semarang, Kampus Sekaran, Gunungpati, Semarang, 50229, Indonesia; Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta, 55281, Indonesia
