Design, synthesis and structure-activity relationship of dihydrobenzoquinolines as novel inhibitors against influenza A virus

Abstract

Novel dihydrobenzo[h]quinolines (DHBQs), the products of an efficient catalyst-free three-component reaction (3CR) recently developed by us, possess useful and strong aggregation-induced emission (AIE) characteristic. Here, a series of new dihydrobenzo[h]quinolines (h-DHBQs 4-1-34) and dihydrobenzo[f]quinolines (f-DHBQs 5a-e) were designed and synthesized by the 3CR to study their bioactivities as novel inhibitors against the influenza A (H1N1) virus. The structure-activity relationship (SAR) indicates that the antiviral activities of DHBQs depend on the combination of substituents and three of h-DHBQs (4-12, 4-25 and 4-27) show potent antiviral activity with IC₅₀ = 2.52-3.79 μM. These potent h-DHBQs have low toxicity to MDCK and A549 cells (CC50 > 100 μM for 4-12 and > 50/100 μM for 4-25 and 4-27). The primary mechanism of the antiviral activities of DHBQs was studied using the most potent h-DHBQ 4-12, which indicated that 4-12 could efficiently inhibit virus-induced plaque formation and NP/PB2 protein expression in a dose-dependent way. DHBQs with simple synthetic method, useful AIE characteristic and antiviral activities are expected to be developed into potential inhibitors against influenza A virus, at the same time acting as chemical/biological fluorescent probe.

Keywords: Design and synthesis; Dihydrobenzoquinolines; Influenza A virus; Multicomponent reaction; Structure-activity relationship.