Identification of N- and C-3-Modified Laudanosoline Derivatives as Novel Influenza PA N Endonuclease Inhibitors

Influenza PA inhibitors are of particular importance in current efforts to develop a new generation of antiviral drugs due to the growing emergence of highly pathogenic influenza viruses and the resistance to existing antiviral inhibitors. Herein, we design and synthesize a set of 1,3-cis- -substituted-1,2,3,4-tetrahydroisoquinoline derivatives to enhance their potency by further exploiting the pockets 3 and 4 in the PA endonuclease based on the hit d,l-laudanosoline. Particularly, the lead compound exhibited potent and broad anti-influenza virus effects with EC values ranging from 0.43 to 1.12 μM and good inhibitory activity in a mouse model. Mechanistic studies demonstrated that could bind tightly to the PA endonuclease of RNA-dependent RNA polymerase, thus blocking the viral replication to exert antiviral activity. Overall, our study might establish the importance of 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based derivatives for the development of novel PA inhibitors of influenza viruses.