In vitro and computational investigations of novel synthetic carboxamide-linked pyridopyrrolopyrimidines with potent activity as SARS-CoV-2-MPro inhibitors.

ABSTRACT

An essential target for COVID-19 is the main protease of SARS-CoV-2 (Mpro). With the objective of targeting this receptor, a novel set of pyrido[1,2-a]pyrrolo[2,3-d]pyrimidines with terminal carboxamide fragments was designed, synthesized, and considered as an initial motif for the creation of effective pan-coronavirus inhibitors. Accordingly, nine derivatives (21-29) have been introduced for in vitro assay to evaluate their antiviral activity and cytotoxicity effect against COVID-19 virus using Vero cells. The obtained data revealed that the majority of these derivatives showed potent cellular anti-COVID-19 activity and prevent viral growth by more than 90% at two different concentrations with weak or even no detectable cytotoxic effect on Vero cells. Extensive molecular docking simulations highlighted proper non-covalent interaction of new compounds within the binding pocket of Mpro as a potential target for their antiviral activity. In vitro assay for all the synthesized derivatives against the viral Mpro target indicated that compounds 25 and 29 have promising inhibitory activity with IC50 values at low micromolar concentrations. The molecular dynamic simulation results predicted the stability of compound 29 in the binding cavity of SARS-CoV-2 Mpro and hence supported the high inhibitory activity shown by the In vitro assay. These results suggested that compounds 25 and 29 merit further investigations as promising drug candidates for the management of SARS-CoV-2.