Evaluation of Antiviral Activity of <i>N</i> -Phenyl-2-Phenoxyacetamides Derived from Carvacrol against Mayaro Virus: <i>In Vitro</i> Analyses and <i>In Silico</i> Insights

Mayaro virus (MAYV), a member of the <i>Togaviridae</i> family and <i>Alphavirus</i> genus, is an emerging and neglected arbovirus that causes Mayaro fever, which can be severely debilitating disease. Although it is responsible for sporadic outbreaks in forested areas of Latin American countries, MAYV has the potential to emerge in an urban transmission cycle, as mosquitoes of the <i>Aedes</i> genus are capable of transmitting the virus, potentially leading to epidemics. Despite this threat, there are currently no licensed vaccines or antiviral drugs available, highlighting the urgent need for effective antiviral compounds. In this study, the antiviral activity of eight <i>N</i>-phenyl-2-phenoxyacetamide derivatives of carvacrol against Mayaro virus was evaluated. Among the tested compounds, compound <b>9</b> demonstrated the greatest potential, preserving 97% of cell viability following viral infection. Plaque reduction assays revealed that compound <b>9</b> interacts directly with the viral particle, interfering with the adsorption and internalization steps of the viral replication cycle. This hypothesis was further supported by <i>in silico</i> analyses, which demonstrated the compound's ability to interact with regions of the viral glycoproteins E1 and E2 involved in receptor binding and membrane fusion. Taken together, these findings highlight compound <b>9</b> as a promising candidate for the development of effective antiviral therapies against Mayaro virus.