Natural pyrrolo[1,2-a]quinazolinone derivatives: Design, synthesis, characterization, and bio-evaluation as novel antiviral agents

Abstract

As viral infectious diseases increasingly threaten global health, antiviral drug research has become a focus in the medicinal chemistry. Enterovirus has always been an important virus causing infections disease with a high incidence in summer and autumn, such as Enterovirus 71 (EV71) and Coxsackievirus B3 (CVB₃). Currently, no specific antiviral drugs are available for EV71 and CVB₃. So, we designed and synthesized a novel series of quinazolinone derivatives based on the natural pyrrolo[1,2-a]quinazolinone scaffold, which were fully characterized and identified as potential anti-enterovirus agents. Among them, compound B9 exhibited potent anti-CVB₃ activity with an EC₅₀ value of 17.4 ± 3.62 μM, and compound B5 exhibited potent anti-EV71 activity with an EC₅₀ value of 14.8 ± 2.18 μM as confirmed by determining the cytopathic effects, progeny virus titers, viral nucleic acid and protein levels. The potential antiviral mechanisms of compound B5 were also explored. The compound B5 exhibited a powerful therapeutic effect primarily by blocking the post-attachment stage of viral infection. Further experiments demonstrated that compound B5 didn't inhibit the activities of the EV71 2Apro and 3Dpol. Modelling of the molecular binding of the 3Cpro-compound complex revealed that the compound B5 could insert into the substrate-binding pocket of EV71 3Cpro, blocking substrate recognition and possibly inhibiting EV71 3Cpro activity. These researches may provide evidence for the development of these novel pyrrolo[1,2-a]quinazolinone derivatives derived from natural products as potential antiviral agents.

Keywords: Antiviral agents; CVB(3); EV71; Natural product; Pyrrolo[1,2-a]quinazolinone derivatives.