<i>In vitro</i>and computational investigations of novel synthetic carboxamide-linked pyridopyrrolopyrimidines with potent activity as SARS-CoV-2-M^Proinhibitors

Abstract

An essential target for COVID-19 is the main protease of SARS-CoV-2 (M^pro). With the objective of targeting this receptor, a novel set of pyrido[1,2-<i>a</i>]pyrrolo[2,3-<i>d</i>]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 <i>in vitro</i> 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 M^pro as a potential target for their antiviral activity. <i>In vitro</i> assay for all the synthesized derivatives against the viral M^pro 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 M^pro and hence supported the high inhibitory activity shown by the <i>In vitro</i> assay. These results suggested that compounds 25 and 29 merit further investigations as promising drug candidates for the management of SARS-CoV-2.