Exploring the dual effect of novel 1,4-diarylpyranopyrazoles as antiviral and anti-inflammatory for the management of SARS-CoV-2 and associated inflammatory symptoms.

COVID-19 and associated substantial inflammations continue to threaten humankind triggering death worldwide. So, the development of new effective antiviral and anti-inflammatory medications is a major scientific goal. Pyranopyrazoles have occupied a crucial position in medicinal chemistry because of their biological importance. Here, we report the design and synthesis of a series of sixteen pyranopyrazole derivatives substituted with two aryl groups at N-1 and C-4. The designed compounds are suggested to show dual activity to combat the emerging Coronaviruses and associated substantial inflammations. All compounds were evaluated for their in vitro antiviral activity and cytotoxicity against SARS-CoV infected Vero cells. As well, the in vitro assay of all derivatives against the SARS-CoV Mpro target was performed. Results revealed the potential of three pyranopyrazoles (22, 27, and 31) to potently inhibit the viral main protease with IC50 values of 2.01, 1.83, and 4.60 µM respectively compared with 12.85 and 82.17 µM for GC-376 and lopinavir. Additionally, in vivo anti-inflammatory testing for the most active compound 27 proved its ability to reduce levels of two cytokines (TNF-α and IL-6). Molecular docking and dynamics simulation revealed consistent results with the in vitro enzymatic assay and indicated the stability of the putative complex of 27 with SARS-CoV-2 Mpro. The assessment of metabolic stability and physicochemical properties of 27 have also been conducted. This investigation identified a set of metabolically stable pyranopyrazoles as effective anti-SARS-CoV-2 Mpro and suppressors of host cell cytokine release. We believe that the new compounds deserve further chemical optimization and evaluation for COVID-19 treatment.

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.

Public Awareness, Attitudes, and Adherence to COVID-19 Quarantine and Isolation in Saudi Arabia.

BACKGROUND: This study aims to assess the general population's awareness, attitude, and adherence regarding COVID-19 and quarantine in Saudi Arabia. METHODS: A descriptive cross-sectional design with a consecutive sampling method was used in this study. All accessible Saudi population during the study period were invited to participate in the survey from 1st April to 25th April 2020. The study questionnaire was constructed by the researchers based on experts' consultation. RESULTS: A total sample of 1998 respondents with complete data was included in the survey. A total of 1936 participants reported that they were aware of regarding COVID-19 outbreak (96.9%). The most identified symptom was fever (92.3%; 1843), followed by respiratory distress (90.8%; 1813). About 81% of the participants reported that quarantine should be applied with travel or contact with infected persons. Also, 98.3% of the participants reported that the quarantine period should be a minimum of 14 days. In total, more than three-quarters of the participants had good awareness levels regarding COVID-19 and quarantine. CONCLUSION: This study showed that the Saudi population had very high levels of awareness, adherence regarding COVID-19 quarantine and isolation measures.

Clinical Characteristics and Laboratory Abnormalities of Hospitalized and Critically Ill Children with Coronavirus Disease 2019: A Retrospective Study from Saudi Arabia.

BACKGROUND: COVID-19 was reported in several studies characterized by milder clinical course, benign disease, and peculiar epidemiologic patterns among pediatric patients compared to adults' disease. However, other studies indicated that critical cases also exist and are associated with preexisting cardiopulmonary comorbidities and concurrent multisystem inflammatory syndrome in children. METHODS: The study period was six months, May-October 2020. Data on demographics, clinical manifestations, laboratory abnormalities were extracted from the patients' hospital records. During the study period, 644 pediatric patients attended the hospital. They were all screened for SARS-CoV-2 using RT-PCR. Only the confirmed positive patients were included in the subsequent study analysis. They were hospitalized either in the general pediatric wards (GPW) or pediatric intensive care unit (PICU). RESULTS: Out of the total patients screened, 79 (12.3%) children were confirmed to have COVID-19 infection. All the confirmed COVID-19 patients were either admitted to the general pediatric wards (58; 73.4%) or PICU (21; 26.6%). The admission diagnoses for these children were acute gastroenteritis (22.85%), acute pneumonia (19%), clinical sepsis (17.7%), and multisystem inflammatory syndrome in children (10.1%). A significantly higher percentage of the PICU admitted patients showed shortness of breath (SOB) (P= 0.016). Respiratory insufficiencies, prematurity, and congenital heart diseases are the most reported comorbid conditions among the admitted children. The oxygen saturation was significantly lower among PICU patients than those in GPW (P=0.001). The total hospital stays differ significantly between the two groups, which were ten days for the PICU group compared to 4.5 days for the GPW group with a statistical significance noted (P= 0.001). CONCLUSION: Despite the observable variations in the clinical and laboratory findings among the hospitalized pediatric COVID-19 patients, no serious consequences among all patients were observed. The history of SOB and the initial oxygen saturation level were significantly associated with PICU admissions.