In vitro and computational investigations of novel synthetic carboxamide-linked pyridopyrrolopyrimidines with potent activity as SARS-CoV-2-MPro inhibitors† † Electronic supplementary information (ESI) available. See https://doi.org/10.1039/d2ra04015h

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. An essential target for COVID-19 is the main protease of SARS-CoV-2 (Mpro).

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

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.

The early mortality rate of people infected with coronavirus (COVID-2019) in Wuhan, China: Review of three retrospective studies.

BACKGROUND: The infection with coronavirus and non-survivor cases have been escalated since the first inception between January and March 2020. Therefore, reviewing the collated clinical characteristics of non-survivors might assist in current preventive efforts, triaging, and management of survivors. The aim of this review was to summarize the clinical characteristics of non-survivor cases due to the infection caused by a novel coronavirus and to identify the relevant data that might put the new cases at increased mortality. MATERIALS AND METHODS: We have identified three published articles on novel coronavirus reported during December 01, 2020, to March 15, 2020, which have described the mortality rate in Wuhan, Hubei, China. RESULTS: The mean duration of studies (i.e., the three retrospective studies with 278 cases) was 24.7 days, and the duration of onset to dyspnea was variable between 8 and 5 days. The main reported complications were acute respiratory distress, pneumonia, acute kidney injury, and acute cardiac disease. The overall major comorbidity reported was cardiovascular diseases at 23.7% (66 of 278). The reported overall mortality rate was 8.3% (23 of 278), with the highest mortality rate of 15.0% (6 of 41) reported in Jin Yintan Hospital at Wuhan city. CONCLUSIONS: The clinical characteristics of the non-survivors from the novel coronavirus included adult males, aged older than 50 years, having comorbidities of cardiovascular disease, respiratory distress syndrome, acute kidney injury, and diabetes with higher admission to the intensive care unit. The mortality rate was high in two of the reported studies (15.0% and 11.0%), which was decreased in the later-dated study to 3.4%.