Structural modifications of toxyloxanthone C and macluraxanthone isolated from Maclura cochinchinensis: cytotoxicity, antibacterial activity, and in silico studies

Abstract

Toxyloxanthone C and macluraxanthone, isolated from the roots of Maclura cochinchinensis, have been reported to exhibit promising cytotoxic and antibacterial activities. Accordingly, thirteen xanthone derivatives were synthesized from these two parent xanthones by simple acylation, alkylation, sulfonylation, and bromination reactions. All derivatives were evaluated for their cytotoxicity against three cancer cell lines, HelaS3, A549, and HepG2, and their antibacterial activity against four Gram-positive bacterial strains, namely methicillin-resistant Staphylococcus aureus, S. aureus, Bacillus subtilis, and Bacillus cereus. 5,6-Diacetoxytoxyloxanthone C (1a) displayed cytotoxicity against three cancer cells with IC₅₀ values ranging from 12.20 to 22.61 μM. Additionally, 1a demonstrated potent cytotoxicity against A549 cells with IC₅₀ = 12.20 μM, without showing cytotoxicity toward Vero cells. Moreover, 1,5,6-tripentanoyloxytoxyloxanthone C (1b) and 4-bromotoxyloxanthone C (1f) exhibited significant cytotoxicity against A549 cells with IC₅₀ values of 5.77 and 7.52 μM, respectively. In addition, 1a and 1f showed potent antibacterial activity against all bacteria tested with the same MIC value of 4 μg mL⁻¹, which was stronger than the parent xanthone 1. Molecular docking studies revealed that 1a, 1b, and 1f interacted with CDK2 through a competitive inhibition mechanism. Additionally, the binding conformations of 1a and 1f within the active sites of key enzymes involved in bacterial cell wall synthesis were similar to that of the tetracycline drug. The in silico physicochemical investigation indicated that 1a and 1f exhibited a favorable drug-likeness. Based on this finding, 1a represents a promising lead candidate for further study as an anticancer and an antibacterial agent.