Design and Development of Xanthone Hybrid for Potent Anti-Inflammatory Effects: Synthesis and Evaluation

Abstract

Inflammatory responses, while essential for host defence, can precipitate chronic pathologies when sustained. The polyphenolic entity xanthone is distinguished by its capacity to modulate inflammation, notably via the inhibition of the COX-2 enzyme and associated inflammatory pathways. Additionally, heterocyclic frameworks such as pyrazole, triazole, and imidazole are recognised for their anti-inflammatory attributes. This investigation was conducted to engineer and synthesise a series of novel hybrid-xanthone molecules with enhanced anti-inflammatory capabilities. Utilising computational docking strategies, these hybrid-xanthone variants were virtually screened against the COX-2 enzyme structure (PDB ID:1CX2), and the 10 leading candidates were identified based on their binding affinities. These selected entities were synthesised through an optimised three-stage synthetic route. Subsequent in vitro assessments were performed using the Egg albumin denaturation assay at incremental concentrations. Complementary in vivo experiments involved the Carrageenan-induced paw edema protocol in Wistar rats, administered at 200 mg/kg to evaluate the anti-inflammatory response over a period of 6 h. The best percentage inhibition was shown by compound A127(3-(5′(1,2,4-Triazole)-pentyloxy)-1,6,8-trihydroxy xanthone), A11(3-(1′-(1,2,4-Triazole)-methyloxy)-1,6,8-trihydroxy xanthone) and A119(3-(1′-(1,2,4-Triazole)-methyloxy)-1,6,8-trihydroxy xanthone) as 60 ± 0.31, 58.57 ± 0.023, and 57.14 ± 0.21 respectively. Spectroscopic characterisation of the compounds was achieved through UV, IR, NMR, and Mass spectrometry techniques. The investigation revealed that out of the synthesised cohort, nine compounds exhibited favourable in silico profiles, and half of these manifested substantial anti-inflammatory efficacy in both in vitro and in vivo models, outperforming the reference standard. These hybrid-xanthone molecules demonstrated precise COX-2 inhibition and maintained an acceptable safety margin in vivo, underscoring their therapeutic promise as anti-inflammatory agents.