Antiviral amide derivatives from Uvaria siamensis

A screening of 824 plant extracts from Rutaceae and Annonaceae species against a human alphacoronavirus (HCoV-229E-Luc) identified Uvaria siamensis (Scheff.) L.L.Zhou, Y·C·F.Su & R.M.K.Saunders (Annonaceae) as a promising source of bioactive metabolites. Subsequent bioassay-guided fractionation of its ethyl acetate and methanol leaf extracts led to the isolation of three previously undescribed amide derivatives, melodamides B-D (3-5), together with melodamide A (2), uvariadiamide (6), (+)- and (-)-toussaintine C (1), and five known polyphenols (7-11). The structures of compounds 1-11 were characterized by comprehensive spectroscopic analysis and comparison with literature data. In HCoV-229E-infected Huh-7 cells, (+)-toussaintine C (1) and melodamide C (4) were the most potent metabolites, with IC₅₀ values of 1.4 and 1.8 μM and selectivity indices of 43 and 39, respectively, while melodamide A (2) also displayed notable activity, with an IC₅₀ of 4.2 μM and an SI of 11. In contrast, polyphenols 7-11 displayed weaker antiviral effects restricted to the low- to mid-micromolar range. Extension of the profiling to a pandemic clinical isolate of SARS-CoV-2 in Vero cells, showed that both enantiomers of toussaintine C, as well as melodamides A and C, retained measurable inhibition in the mid-micromolar range, whereas most polyphenols lost activity. Taken together, these results identify amide derivatives from U. siamensis as antiviral scaffolds with preferential activity against an alphacoronavirus model, and highlight this species as a valuable source of small-molecule coronavirus inhibitors.