Design, synthesis, docking, and antiviral evaluation of some novel pyrimidinone-based α-aminophosphonates as potent H1N1 and HCoV-229E inhibitors.

Dialkyl/aryl aminophosphonates, 3a-g and 4a-e were synthesized using the LiClO4 catalyzed Kabachnic Fields-type reaction straightforwardly and efficiently. The synthesized phosphonates structures were characterized using elemental analyses, FT-IR, 1H NMR, 13C NMR, and MS spectroscopy. The new compounds were subjected to in-silico molecular docking simulations to evaluate their potential inhibition against Influenza A Neuraminidase and RNA-dependent RNA polymerase of human coronavirus 229E. Subsequently, the compounds were further tested in vitro using a cytopathic inhibition assay to assess their antiviral activity against both human Influenza (H1N1) and human coronavirus (HCoV-229E). Diphenyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (furan-2-yl) methyl) phosphonate (3f) and diethyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) methyl) phosphonate (4e) were demonstrated direct inhibition activity against Influenza A Neuraminidase and RNA-dependent RNA polymerase. This was supported by their highly favorable binding energies in-silico, with top-ranked values of -12.5 kcal/mol and -14.2 kcal/mol for compound (3f), and -13.5 kcal/mol and -9.89 kcal/mol for compound (4e). Moreover, they also displayed notable antiviral efficacy in vitro against both viruses. These compounds demonstrated significant antiviral activity, as evidenced by selectivity indices (SI) of 101.7 and 51.8, respectively against H1N1, and 24.5 and 5.1 against HCoV-229E, respectively.

Discovery of Pyrano[2,3-c]pyrazole Derivatives as Novel Potential Human Coronavirus Inhibitors: Design, Synthesis, In Silico, In Vitro, and ADME Studies.

The SARS-CoV-2 pandemic at the end of 2019 had major worldwide health and economic consequences. Until effective vaccination approaches were created, the healthcare sectors endured a shortage of operative treatments that might prevent the infection's spread. As a result, academia and the pharmaceutical industry prioritized the development of SARS-CoV2 antiviral medication. Pyranopyrazoles have been shown to play a prominent function in pharmaceutical chemistry and drug sighting because of their significant bioactive properties. We provide herein a novel sequence of pyranopyrazoles and their annulated systems whose antiviral efficacy and cytotoxicity were explored versus human coronavirus 229E (HCoV-229E) Vero-E6 cell lines as a model for the Coronaviridae family. Fifteen synthetic congeners pointed out miscellaneous antiviral efficacies against HCoV-229E with variable inhibition degrees. Compound 18 showed a high selectivity index (SI = 12.6) that established spectacular inhibitory capacity against human coronavirus 229E. Compounds 6, 7, and 14 exposed moderate efficacies. Compounds 6, 7, 14, and 18 exhibited substantial antiviral action through the replication phase with reduction percentages extending from 53.6%, 60.7%, and 55% to 82.2%, correspondingly. Likewise, when assessed to the positive control tipranavir (88.6%), the inhibitory efficiency of compounds 6, 7, 14, and 18 versus the SARS-CoV2 Mpro provided high percentages of 80.4%, 73.1%, 81.4% and up to 84.5%, respectively. In silico studies were performed to investigate further the biological activity and the target compounds' physical and chemical features, including molecular dynamic (MD) simulations, protein-ligand docking, ADME studies, and density functional theory (DFT) calculations. These inquiries demonstrated that this series of metabolically stable pyranopyrazoles and their annulated systems are effective human coronavirus inhibitors that inhibit the viral Mpro protein and may have emerged as a novel COVID-19 curative option.

Significant role of some miRNAs as biomarkers for the degree of obesity.

BACKGROUND: Obesity is one of the most serious problems over the world. MicroRNAs have developed as main mediators of metabolic processes, playing significant roles in physiological processes. Thus, the present study aimed to evaluate the expressions of (miR-15a, miR-Let7, miR-344, and miR-365) and its relationship with the different classes in obese patients. METHODS: A total of 125 individuals were enrolled in the study and classified into four groups: healthy non-obese controls (n = 50), obese class I (n = 24), obese class II (n = 17), and obese class III (n = 34) concerning body mass index (BMI < 30 kg/m2, BMI 30-34.9 kg/m2, BMI 35-39.9 kg/m2 and BMI ≥ 40 kg/m2, respectively). BMI and the biochemical measurements (fasting glucose, total cholesterol, triglycerides, HDL and LDL, urea, creatinine, AST, and ALT) were determined. The expressions of (miR-15a, miR-Let7, miR-344, and miR-365) were detected through quantitative real-time PCR (RT-qPCR). RESULTS: There was a significant difference between different obese classes and controls (P < 0.05) concerning (BMI, TC, TG, HDL, and LDL). In contrast, fasting glucose, kidney, and liver functions had no significant difference. Our data revealed that the expression of miR-15a and miR-365 were significantly associated with different obese classes. But the circulating miR-Let7 and miR-344 were not significantly related to obesity in different classes. CONCLUSION: Our study indicated that miR-15a and miR-365 might consider as biomarkers for the obesity development into different obese classes. Thus, the relationship between regulatory microRNAs and disease has been the object of intense investigation.

4-Phenylcoumarin derivatives as new HIV-1 NNRTIs: Design, synthesis, biological activities, and computational studies.

A series of 4-phenylcoumarin derivatives was synthesized and evaluated for their cellular anti-HIV-1 and HIV-2 activities as well as their inhibitory effects against HIV-1 reverse transcriptase (RT). The hydrazone compound 8b and the ethylthiosemicarbazide derivative 4c showed the best inhibition activity against wild-type (WT) HIV-1. The promising compounds were further evaluated against HIV-1 RT and exhibited significant inhibitory activity with compound 8b showing comparable effect to the reference NNRTI Efavirenz (IC50 = 9.01 nM). Structure activity relationship study revealed the importance of 6-chloro and 4-phenyl substituents for optimum activity, as well as the 5-atoms linker (=N-NH-CO-CH2-O-) at position 7 of coumarin scaffold that can support the rotation and flexibility of compound 8b to fit well in the binding pocket. The molecular docking of compound 8b demonstrated a typical seahorse binding mode with better binding interactions that covered more residues when compared to Efavirenz.

Maillard reaction for nucleation of polymer quantum dots from chitosan-glucose conjugate: Antagonistic for cancer and viral diseases.

Polymer dots (PDs) ingrained from biopolymers are characterized by their biocompatibility & non-toxicity to be superiorly applicable for biomedicines. The point of novelty in the current study is to focus on the effect of Maillard reaction for conjugation of chitosan with glucose to enhance the affinity of chitosan as a biological resource of PDs. Chitosan-glucose conjugate was firstly prepared by Maillard reaction. PDs were nucleated from chitosan (C1 acidic, 10.6 nm & C2 basic, 11.4 nm) and chitosan-glucose conjugate (C3 acidic, 6.8 nm & C4 basic, 5.7 nm). The affinity of chitosan versus chitosan-glucose conjugate as molecular precursors for PDs as antiviral and anticancer laborers was studied. The synthesized PDs were tested against lung cancer (NSCLC, A549) and the estimated IC50 was 282.4 & 165.4 µg/mL for PDs (C3 & C4) ingrained from chitosan-glucose conjugate. The antiviral action of PDs against Coronavirus (229E) was estimated and the obtained IC50 for C3 & C4 was 43.6 and 19.3 mg/mL, respectively. PDs ingrained from chitosan-glucose conjugate showed higher anticancer and antiviral activities compared to that clustered from chitosan. Consequently, the modification of chitosan via Maillard reaction enhanced the biological affinity of the obtained PDs to be effectively applicable as antitumor and antiviral laborers.

Design, Synthesis, Antiviral Evaluation, and Molecular Dynamics Simulation Studies of New Spirocyclic Thiopyrimidinones as Anti HCoV-229E.

The current pandemic threat presented by viral pathogens like SARS-CoV-2 (COVID-19) suggests that virus emergence and dissemination are not geographically confined. As a result, the quest for antiviral agents has become critical to control this pandemic. In the current study, we provide a novel family of spirocyclic thiopyrimidinone derivatives whose cytotoxicity and antiviral efficacy were investigated against human coronavirus 229E (HCoV-229E) as a model for the Coronaviridae family. We utilized MTT and cytopathic effect (CPE) inhibitory tests on green monkey kidney (vero-E6) cell lines. The new molecules showed varied degrees of antiviral activity against the vero-E6 cell lines with minimal cytotoxicity. With a high level of a selective index (SI=14.8), compound 9 showed outstanding inhibitory ability and could effectively suppress the human coronavirus 229E. Molecular dynamics simulation (MD) studies were performed to measure the interaction and stability of the protein-ligand complex in motion. The MD results for the most active compound 9 explored remarkable interactions with the binding pockets of the main protease (Mpro) of SARS-CoV-2 enzyme confirming the results gained from in vitro experiments. ADMET properties were also predicted for all the tested compounds. All these results demonstrated that the novel spirocyclic thiopyrimidinone derivatives would have the potential to be safe, low-cost chemical compounds that might be used as a novel therapeutic option for Coronaviridae viruses like COVID-19.

Incidence of acute kidney injury among COVID-19 patients in Egypt.

BACKGROUND: Despite the fact that the fundamental characteristics of coronavirus disease-2019 (COVID-19) are respiratory manifestations, multi-organ failure including the kidney has been documented. There are no clear comparisons of COVID-19 cases with and without acute kidney injury (AKI) to show whether there are aspects of acute kidney injury progression path or outcome that are unique to this disease. METHODS: In this work, we analyzed the data of 734 COVID-19 cases admitted to the Ahmad Maher Teaching Hospital in Cairo, Egypt, between June 6 and July 25, 2020. Data on demographics, comorbidities, laboratory results, and outcomes were assessed. To assess the incidence rate of AKI in Egyptian COVID-19 patients, comparisons were carried out between home-isolated COVID-19 patients, hospitalized COVID-19 patients, and ICU COVID-19-patients with or without AKI. RESULTS: AKI was more common in hospitalized mild COVID-19 patients than in home-isolated and ICU COVID-19 patients (15.0% versus 10.8% and 14.2%, respectively). The overall occurrence rate of AKI was significantly higher in COVID-19 patients (n=91, 14%). Hemodialysis, on the other hand, was required in 76% of the extreme ICU COVID-19 patients who developed AKI (22/29). The absolute number of patients with AKI COVID-19 who required hemodialysis was 34 (37%). This accounted for 5.2% of all COVID-19 patients and 37% of those with AKI. The mortality rate in COVID-19 patients with or without AKI was 15.4% and 4.8%, respectively. CONCLUSION: AKI in our COVID-19 patients is associated with a high mortality rate in ICU-COVID-19 patients. Our findings suggest that COVID-19 patients, particularly ICU COVID-19 patients, should be closely monitored for the development of AKI. Early identification of AKI, as well as prompt intervention, can improve COVID-19 patient outcomes.

Folic acid-conjugated mesoporous silica particles as nanocarriers of natural prodrugs for cancer targeting and antioxidant action.

Naturally derived prodrugs have a wide range of pharmacological activities, including anticancer, antioxidant, and antiviral effects. However, significant barriers inhibit their use in medicine, e.g. their hydrophobicity. In this comprehensive study, we investigated simple and effective nanoformulations consisting of amine-functionalized and conjugated with folic acid (FA) mesoporous silica nanoparticles (MSNs). Two types of MSNs were studied: KCC- 1, with mean size 324 nm and mean pore diameter 3.4 nm, and MCM - 41, with mean size 197 and pore diameter 2 nm. Both types of MSNs were loaded with three anticancer prodrugs: curcumin, quercetin, and colchicine. The nanoformulations were tested to target in vitro human hepatocellular carcinoma cells (HepG2) and HeLa cancer cells. The amine-functionalized and FA-conjugated curcumin-loaded, especially KCC-1 MSNs penetrated all cells organs and steadily released curcumin. The FA-conjugated MSNs displayed higher cellular uptake, sustained intracellular release, and cytotoxicity effects in comparison to non-conjugated MSNs. The KCC-1 type MSNs carrying curcumin displayed the highest anticancer activity. Apoptosis was induced through specific signaling molecular pathways (caspase-3, H2O2, c-MET, and MCL-1). The nanoformulations displayed also an enhanced antioxidant activity compared to the pure forms of the prodrugs, and the effect depended on the time of release, type of MSN, prodrug, and assay used. FA-conjugated MSNs carrying curcumin and other safe natural prodrugs offer new possibilities for targeted cancer therapy.