Exploring the Efficacy of Halogenated Thioxanthone Derivatives Against Multidrug-Resistant Gram-Positive Bacteria: An In Silico and In Vitro Approach

Abstrak

ABSTRACT. This study conducts a comprehensive analysis of halogenated thioxanthone derivatives through molecular docking, molecular dynamics simulations, and antimicrobial evaluation. The molecular docking analysis against Bacillus subtilis protein demonstrated that the halogenated thioxanthone derivatives (TX1–TX6) exhibited binding energies ranging from −6.22 to −7.35 kcal/mol, in comparison to tetracycline, which displayed a binding energy of −6.63 kcal/mol. Furthermore, the docking study against dihydrofolate reductase (DHFR) Staphylococcus aureus revealed binding energies for these compounds ranging from −6.93 to −7.65 kcal/mol, whereas trimethoprim and tetracycline exhibited binding energies of −7.19 and −7.73 kcal/mol, respectively. The 100 ns molecular dynamics simulation indicated that 2,4-dichloro-1,3-dihydroxythioxanthone (TX3) and 2,4-dibromo-1,3-dihydroxythioxanthone (TX6) maintained significant stability when interacting with B. subtilis and DHFR S. aureus proteins. Compounds TX3 and TX6 were found to exhibit antibacterial activity against Gram-positive bacteria, B. subtilis strain M18, and methicillin-resistant Staphylococcus aureus (MRSA). Among the tested compounds, TX3 exhibited the highest antibacterial activity, with a MIC of 1.98 µg/mL and a MBC of 3.9 µg/mL. In comparison, TX6 demonstrated a MIC of 3.9 µg/mL and an MBC of 7.9 µg/mL. The tetracycline exhibited a MIC value of 3.9 µg/mL and an MBC value of 3.9 µg/mL. Keywords: Bacillus subtilis, Molecular docking, Molecular dynamics, MRSA, Thioxanthone