Sexually transmitted infections (STIs) remain a major global health concern, contributing significantly to morbidity and facilitating the co-transmission of other pathogens. Recent outbreaks of Monkeypox virus (MPXV) have further underscored the urgent need for broad-spectrum antiviral agents effective against emerging and re-emerging sexually transmissible viruses. We report here the design and synthesis of a series of 3-cyanoquinoline-based Src inhibitors to evaluate their antimicrobial efficacy against sexually transmitted pathogens. Among them, compound 7d demonstrated potent inhibitory activity against MPXV, Herpes simplex virus types 1 and 2, Hepatitis C virus, Human immunodeficiency virus, and Chlamydia trachomatis at non-toxic concentrations. Owing to its broad-spectrum profile and favorable cytotoxicity profile, compound 7d represents a promising candidate for development as a topical microbicide for the prevention and treatment of STIs. Interestingly, the screening also identified compound 7g, which, despite lacking Src inhibitory activity, exhibited selective antiviral activity against members of the Poxviridae family, suggesting the involvement of alternative host-dependent mechanisms that can be further exploited. Both compounds were non-toxic in relevant epithelial and mucosal tissue models. Collectively, these findings highlight the therapeutic potential of 3-cyanoquinoline derivatives as scaffolds for the development of novel broad-spectrum microbicides targeting a range of sexually transmitted pathogens.
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