Design and synthesis of norsesquiterpenoid-1,2,3-triazole derivatives and investigation of their anti-influenza virus activity.

Influenza is a highly contagious, acute respiratory illness caused by the influenza virus. The continual emergence of drug-resistant viral strains has created an urgent need for the development of novel anti-influenza agents. In our previous study, we identified a series of nor-sesquiterpenoids with potent activity against influenza A virus, isolated from the fermentation broth of Streptomyces sp. XM17-an actinobacterial strain derived from fresh panda feces. Building on these findings, we synthesized the core nor-sesquiterpene scaffold and functionalized it by attaching various molecular fragments through a 1,2,3-triazole linker containing heteroatoms, utilizing a click chemistry strategy. This approach aimed to enhance antiviral potency through structural diversification. Among the resulting compounds, 14d demonstrated superior antiviral activity against the influenza virus, along with a low 50 % cytotoxic concentration. Mechanistic studies indicated that compound 14d exerted its antiviral effect during the later stages of viral infection. Notably, it did not inhibit neuraminidase activity. Instead, it disrupted the cellular nuclear factor kappa B signaling pathway and suppressed the virus-induced overexpression of proinflammatory cytokines. Collectively, these results highlight compound 14d as a promising lead candidate for the development of novel therapeutics targeting influenza virus infection.