Novel α-mangostin derivatives as promising antiviral agents: Isolation, synthesis, and evaluation against chikungunya virus.

Investigations into fruit and vegetable processing residues (FVPRs) offer huge opportunities to discover novel therapeutics against many diseases. In this study, detailed investigation of Garcinia mangostana fruit peel extract led to the isolation and identification of ten known compounds (1-10). Further, a new series of α-mangostin derived sulphonyl piperzines, aryl alkynes and 1,2,3-triazole derivatives were synthesized using Huisgen 1,3-dipolar cyclo-addition reaction ("click" chemistry). Both isolated compounds and synthetic derivatives were evaluated for their anti-chikungunya activity (CHIKV). Isolated compounds, gartanin (1), mangostenone-F (4), 1-isomangostin (5), mangostenone-D (6), epicatechin (7) and derivatives 14, 15c, 15d, 15e, 15f, 17d, 17f, and 18h exerted anti-CHIKV activity. Compounds 17d, 17f and 18h manifested higher antiviral activity (>2 log reduction in virus titer) with a selectivity index (SI) > 50. The compounds with higher antiviral activity were evaluated further with various assays, time of addition assay, entry and entry bypass assay and were also subjected to molecular docking with viral proteins. The results revealed that 17d, 17f and 18h affect multiple stages of virus life cycle through probable interaction with envelope proteins and nsP3 macrodomain of CHIKV. Overall, this study provides evidence for anti-CHIKV activity of natural xanthones from Garcinia mangostana L and their derivatives which could be further investigated for development of therapeutics against chikungunya.