Evaluation of the Antiviral Activity of Monomeric, Dimeric, and Oligomeric Flavonoids against Chikungunya and Mayaro Viruses.

This study evaluated a panel of structurally diverse flavonoids, including monomeric, dimeric, and oligomeric compounds, to investigate the influence of structural complexity on antiviral activity against Chikungunya (CHIKV) and Mayaro (MAYV) viruses. CHIKV and MAYV, which are both members of the genus Alphavirus, represent a growing public health concern in Brazil. This is owing to rising arboviral infections and the potential for cotransmission by shared urban vectors. Effective control requires integrated strategies, including antivirals. Therefore, this study evaluated the cytotoxicity, antiviral activity, and in silico pharmacokinetic/toxicological profiles of nine structurally diverse compounds. Accordingly, procyanidins A2 (PA2), C1 (PC1), and genistein (GNT) displayed the most promising antiviral activity against CHIKV. Moreover, these compounds exhibited selectivity index (SI) values of 5.9, 10.4, and 2.6, with half maximal effective concentrations of 56.7, 50.2, and 64.4 μM, respectively. Furthermore, for the anti-MAYV activity, PA2 and PC1 exhibited SI values of 4.1 and 61, with EC50 values of 81.7 and 8.8 μM, respectively. In addition, GNT induced a 5-log reduction of CHIKV replication, whereas PC1 caused a 4-log reduction of MAYV replication. In virucidal assays, PA2 and PC1 nearly abolished (∼100%) CHIKV infectivity and reduced MAYV infectivity by approximately 80%.In silico analysis indicated that GNT had favorable pharmacokinetics and high toxicological safety, whereas PC1 demonstrated strong safety despite limited oral bioavailability. These results identify PC1 as the most promising candidate for future preclinical development, whereas GNT and PA2 should be considered lead compounds for further optimization strategies aimed at improving selectivity and safety profiles.