The persistent global burden of viral diseases, exemplified by endemic infections and pandemic outbreaks such as COVID-19, underscores the critical need for effective antiviral therapies. While current agents such as nucleoside analogs and direct-acting antivirals (DAAs) have improved the treatment of infections like HIV, hepatitis C, and influenza, they face limitations including narrow target specificity, resistance development, and adverse effects. These challenges are intensified by the rise of emerging zoonotic viruses driven by climate change, globalization, and urbanization, creating an urgent demand for broad-spectrum antivirals with novel mechanisms of action. Mannich base (MB) derivatives have emerged as promising scaffolds in antiviral drug discovery due to their synthetic accessibility, structural diversity, and ability to enhance solubility, permeability, and bioactivity. In addition to these advantages, MBs exhibit broad-spectrum antiviral activity through unique mechanisms, including viral fusion inhibition and allosteric modulation of viral polymerases, distinguishing them from traditional antivirals and offering potential solutions to resistance. Their capacity to target both RNA and DNA viruses further underscores their therapeutic promise. Recent studies have demonstrated the antiviral efficacy of MBs against a wide range of viruses, including yellow fever virus (YFV), respiratory syncytial virus (RSV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), bovine viral diarrhea virus (BVDV), influenza A, and SARS-CoV-2. Structure–activity relationship (SAR) analyses have highlighted the importance of core scaffolds, ring substitutions, amine types, substitution sites, and linker flexibility in modulating antiviral activity. Electron-withdrawing groups (e.g., Cl, Br, NO2, F) generally enhance potency, while electron-donating groups such as OCH3 have shown variable effects. This review presents a comprehensive analysis of MB-based antivirals developed over the past two decades, with a focus on SAR insights, mechanistic understanding, and their potential in next-generation antiviral development.
Magar et al. (Mon,) studied this question.