Synthesis, Antibacterial Activity, and  In Silico  Analysis of Hydroxyxanthone Derivatives Targeting Gram-Positive and Gram-Negative Bacteria

Enny Fachriyah; Muhammad Badrul Huda; Purbowatiningrum Ria Sarjono; Faris Hermawan; Reinhard Sharon Lase; Nanik Wijayati; Jumina Jumina; Yudhi Dwi Kurniawan; Muhammad Eka Prastya

doi:10.22146/ijc.113042

Synthesis, Antibacterial Activity, and In Silico Analysis of Hydroxyxanthone Derivatives Targeting Gram-Positive and Gram-Negative Bacteria

https://doi.org/10.22146/ijc.113042

Enny Fachriyah⁽¹⁾, Muhammad Badrul Huda^(2*), Purbowatiningrum Ria Sarjono⁽³⁾, Faris Hermawan⁽⁴⁾, Reinhard Sharon Lase⁽⁵⁾, Nanik Wijayati⁽⁶⁾, Jumina Jumina⁽⁷⁾, Yudhi Dwi Kurniawan⁽⁸⁾, Muhammad Eka Prastya⁽⁹⁾

(1) Department of Chemistry, Faculty of Science and Mathematics, Diponegoro University, Jl. Prof. Soedharto SH, Tembalang, Semarang 50275, Indonesia
(2) Department of Chemistry, Faculty of Science and Mathematics, Diponegoro University, Jl. Prof. Soedharto SH, Tembalang, Semarang 50275, Indonesia
(3) Department of Chemistry, Faculty of Science and Mathematics, Diponegoro University, Jl. Prof. Soedharto SH, Tembalang, Semarang 50275, Indonesia
(4) Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), KST BJ Habibie, Setu, Tangerang Selatan 15314, Indonesia
(5) Department of Chemistry, Universitas Negeri Semarang, Kampus Sekaran, Gunungpati, Semarang 50229, Indonesia
(6) Department of Chemistry, Semarang State University, 50229 Semarang, Indonesia
(7) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(8) Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), KST BJ Habibie, Setu, Tangerang Selatan 15314, Indonesia
(9) Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), KST BJ Habibie, Setu, Tangerang Selatan 15314, Indonesia
(*) Corresponding Author

Abstract

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.

Keywords

antibacterial; xanthone; synthesis; molecular docking; molecular dynamics

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DOI: https://doi.org/10.22146/ijc.113042