Discovery of monoterpenoid-based benzamides bearing bicyclo[2.2.1]heptane motif as influenza H1N1 virus inhibitors.

The persistent threat of influenza pandemics and the limitations of existing therapies necessitate the discovery of novel antiviral agents. This study investigates a series of monoterpenoid-based benzamides, derived from natural products (+)-camphor and (-)-fenchone, as a new class of inhibitors against influenza A virus (IAV). Building upon previous findings of their activity against orthopoxviruses, we identified several derivatives with potent activity against the A/H1N1 strain. Structure-activity relationship (SAR) analysis revealed that antiviral efficacy is critically dependent on the substituent's nature and position on the aromatic ring, the stereochemistry of the bicyclo[2.2.1]heptane core, and the amide configuration. Key lead compounds demonstrated significant inhibitory activity against the A/Puerto Rico/8/34 (H1N1) strain with high selectivity, and one derivative also showed promising activity against the highly pathogenic A(H7N9) strain. A representative compound demonstrated high metabolic stability in murine blood in vitro and exhibited promising pharmacokinetic properties in vivo following intragastric administration in mice. Mechanistic studies revealed two distinct profiles: one subset of inhibitors likely targets viral entry, while another appears to interfere with a later stage, such as assembly; their action is not mediated by neuraminidase inhibition. These findings establish monoterpenoid benzamides bearing the bicyclo[2.2.1]heptane motif as a promising scaffold for the development of anti-influenza agents, warranting further investigation into their precise molecular target and in vivo efficacy.