Discovery of dihydropyrrolidones as novel inhibitors against influenza A virus.

More effective prophylactic and therapeutic strategies to combat influenza viruses are urgently required worldwide because the conventional anti-influenza drugs are facing drug resistance. Here, dihydropyrrolidones (DHPs), the products of an efficient multi-components reaction, were found to possess good activities against influenza A virus (IAV). Primary structure-activity relationship indicated that the activities of DHPs were greatly influenced by substituents and four of them had IC50 values lower than 10 μM (DHPs 5–2, 8, 14 and 19: IC50 = 3.11–9.23 μM). The activities against multiple IAV strains and mechanism of DHPs were further investigated by using 5–2 (IC50 = 3.11 μM). It was found that 5–2 possessed antiviral effects against all the investigated subtypes of IAVs with the IC50 values from 3.11 to 7.13 μM. Moreover, 5–2 showed very low cytotoxicity with CC50 > 400 μM. Results of mechanism study indicated that 5–2 could efficiently inhibit replication of IAV, up-regulate the expression of key antiviral cytokines IFN-β and antiviral protein MxA, and suppress the production of the NDAPH oxidase NOX1 in MDCK cells. These results indicated that 5–2 could be used as a potential inhibitor against wide subtypes of IAVs.