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.

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.

Translation and validation of the Arabic version of the General Medication Adherence Scale (GMAS) in Saudi patients with chronic illnesses.

PURPOSE: The study aimed to translate and validate the Arabic version of General Medication Adherence Scale (GMAS) in Saudi patients with chronic diseases. METHODS: A multi-center cross sectional study was conducted for a month in out-patient wards of hospitals in Khobar, Dammam, Makkah, and Madinah, Saudi Arabia. Patients were randomly selected from a registered patient pools at hospitals and the item-subject ratio was kept at 1:20. The tool was assessed for factorial, construct, convergent, known group and predictive validities as well as, reliability and internal consistency of scale were also evaluated. Sensitivity, specificity, and accuracy were also evaluated. Data were analyzed using SPSS v24 and MedCalc v19.2. The study was approved by concerned ethics committees (IRB-129-25/6/1439) and (IRB-2019-05-002). RESULTS: A total of 282 responses were received. The values for normed fit index (NFI), comparative fit index (CFI), Tucker Lewis index (TLI) and incremental fit index (IFI) were 0.960, 0.979, 0.954 and 0.980. All values were >0.95. The value for root mean square error of approximation (RMSEA) was 0.059, i.e., <0.06. Hence, factorial validity was established. The average factor loading of the scale was 0.725, i.e., >0.7, that established convergent validity. Known group validity was established by obtaining significant p-value <0.05, for the associations based on hypotheses. Cronbach's α was 0.865, i.e., >0.7. Predictive validity was established by evaluating odds ratios (OR) of demographic factors with adherence score using logistic regression. Sensitivity was 78.16%, specificity was 76.85% and, accuracy of the tool was 77.66%, i.e., >70%. CONCLUSION: The Arabic version of GMAS achieved all required statistical parameters and was validated in Saudi patients with chronic diseases.

The rational design, synthesis, and antimicrobial investigation of 2-Amino-4-Methylthiazole analogues inhibitors of GlcN-6-P synthase.

A series of novel 2-Amino-4-Methylthiazole analogs were developed via three-step reaction encompassing hydrazine-1-carboximidamide motif to combat Gram-positive and Gram-negative bacterial and fungal infections. Noticeably, the thiazole-carboximidamide derivatives 4a-d displayed excellent antimicrobial activity and the most efficacious analogue 4d with MIC/MBC values of 0.5 and 4 µg/mL, compared to reference drugs with very low toxicity to mammalian cells, resulting in a prominent selectivity more than 100 folds. Microscopic investigation of 4d biphenyl analogue showed cell wall lysis and promote rapid bactericidal activity though disrupting the bacterial membrane. In addition, an interesting in vitro investigation against GlcN-6-P Synthase Inhibition was done which showed potency in the nanomolar range. Meanwhile, this is the first study deploying a biomimicking strategy to design potent thiazole-carboximidamides that targeting GlcN-6-P Synthase as antimicrobial agents. Importantly, Molecular modeling simulation was done for the most active 4d analogue to study the interaction of this analogue which showed good binding propensity to glucosamine binding site which support the in vitro data.

Introducing of acyclonucleoside analogues tethered 1,2,4-triazole as anticancer agents with dual epidermal growth factor receptor kinase and microtubule inhibitors.

This study reports an efficient and convenient regioselective synthesis of a novel series of S- and S,N-bis(acyclonucleoside) analogues carrying 5-(2-chlorophenyl)-2,4-dihydro-1,2,4-triazole-3-thione. A facile and straightforward synthesis of thiazolotriazole and triazolothiazines has also been reported. Structures of all newly synthesized compounds were well characterized by infrared IR, 1H and 13C nuclear magnetic resonance (NMR) and mass (MS) spectra analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using staurosporine as a reference drug against three different types: human liver cancer cell line (Hep G2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the S-acyclonucleoside analogues and S,N-bis(acyclonucleoside) analogues showed excellent activity with micromolar (µM) half maximal inhibitory concentration (IC50) values against tumor cells. EGFR assay and tubulin inhibition assay analysis were performed for the most active compounds to get more details about their mechanism of action. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. Extensive structure activity relationship (SAR) analyses were also carried out.

First example of Azo-Sulfa conjugated chromene moieties: Synthesis, characterization, antimicrobial assessment, docking simulation as potent class I histone deacetylase inhibitors and antitumor agents.

This report presents the development of a novel and primary model of sulfonamide compounds encompassing a chromene azo motif with the intent of becoming applicable for drug candidates in the cases of drug-resistant pathogens. The novel molecules (7a-n) have been synthesized via a two-step reaction. First, 4-((2, 4-dihydroxyphenyl)diazenyl)benzenesulfonamide (3a-e) were obtained through the reaction of their corresponding diazotized 4-aminobenzenesulfonamides (1a-e) with resorcinol, followed by the heterocyclization of 3a-e with arylidenemalononitriles (6a-d). Upon structural identification, the newly synthesized compounds were evaluated for their antibacterial and antifungal activities. Moreover, their cytotoxic screening was performed against three cancer cell lines: HCT-116, HepG-2, and MCF-7. Further examinations were comprised of the inhibitory effect analyses of the novel sulfonamide/chromene derivatives against the HDAC classes and the Tubulin polymerization in order to discern the prime antitumor drug candidates.

Predictors of Health-Related Quality of Life Among Patients with Type II Diabetes Mellitus Who Are Insulin Users: A Multidimensional Model.

BACKGROUND: Diabetes Mellitus is a progressive, chronic and multifactorial endocrine disorder characterized by elevated serum glucose levels. It has a direct effect to social and health related quality of life. OBJECTIVE: This study aimed to determine the health-related quality of life among patients with type II diabetes mellitus (T2DM) using insulin therapy. METHODS: Cross-sectional observational study design was used to collect data from Malaysian patients with T2DM. Subjective and objective assessments were made either by using several questionnaires or each patient's specific medication profile registered to care sites. Study participants were recruited from both public hospitals and community health clinics located in Kuala Lumpur, Malaysia. RESULTS: A total of 430 patients with T2DM were recruited in this study with a response rate of 94.7%. The oral antidiabetic medication (OAM) group consisted of 63.0% of the study population and the rest (37.0%) were Insulin users. The body mass index and glycosylated hemoglobin patterns were significantly different between groups (P < 0.011 and P < 0.001). Insulin users showed high percentages of healthy body mass index index (44.7%) compared with OAM users (35.8%) and controlled glycemic index (glycosylated hemoglobin ≤7.5%) was significantly (P = 0.001) better among the insulin-user group compared with the OAM group. The Euro Quality of Life-5 dimension domain analysis indicated significant differences with domains of usual work (P < 0.047), pain and discomfort (P < 0.041), and anxiety and depression (P < 0.001) among insulin users versus OAM users. We also observed a significant difference between the groups regarding diet, monitoring, and disease-specific knowledge. The mean (SD) adherence score showed that insulin users were significantly (P < 0.001) more adherent (6.09 [2.98]) than OAM were nonadherent (4.19 [4.68]). CONCLUSIONS: This study suggests the valuable effect of insulin therapy among patients with T2DM compared with OAMs on health-related quality of life, medication adherence, and health state. Insulin users reported they had better diabetes-related knowledge and treatment adherence characteristics than noninsulin users.

Sulforaphane treatment reverses corticosteroid resistance in a mixed granulocytic mouse model of asthma by upregulation of antioxidants and attenuation of Th17 immune responses in the airways.

Sulforaphane has received considerable attention in recent years due to its antioxidant and anti-inflammatory properties. Its preventive effect in the inhibition of airway inflammation is known; however, whether it affects mixed granulocyte asthma (corticosteroid resistance phenotype) is largely undiscovered. Therefore, we assessed the effect of pharmacological activation of Nrf2, a redox-sensitive transcription factor, using sulforaphane in a mouse model of mixed granulocyte airway inflammation. Mice were sensitized and challenged with cockroach allergen extract (CE), and airway inflammatory parameters and markers of steroid resistance [Nrf2 activity, oxidant-antioxidant balance in airway epithelial cells (AECs)/lung, and IL-17A-related pathway in Th17 cells and dendritic cells (DCs)] were investigated. Our results show that sulforaphane administration reduced neutrophilic airway inflammation, myeloperoxidase (MPO) activity, and Th17 immune responses in a mixed granulocyte mouse model of asthma through Nrf2 activation. On the other hand, corticosteroid treatment decreased Th2/eosinophilic immune responses but had little on Th17/neutrophilic immune responses. However, combined treatment with both almost completely blocked both neutrophilic/eosinophilic and Th17/Th2 immune responses in the lung. Sulforaphane treatment led to induction of antioxidant enzymes (SOD, GPx) in AECs and pulmonary non-enzymatic antioxidants. Further, it led to reduction in inflammatory cytokines (IL-6/IL-23/IL-17A) in Th17 cells/CD11c + DCs during mixed granulocytic inflammation. Collectively, our study presents the evidence that activation of Nrf2 by sulforaphane reduces neutrophilic airway inflammation by upregulation of antioxidants and downregulation of inflammatory cytokines in airways. This is possibly the basis for reversal of corticosteroid resistance in this model. This shows the therapeutic potential of sulforaphane in mixed granulocyte asthma.

Eugenol, a potential schistosomicidal agent with anti-inflammatory and antifibrotic effects against Schistosoma mansoni, induced liver pathology.

INTRODUCTION: Schistosomiasis is one of the most prevalent parasitic infections in developing countries. Although chemotherapy is one of the main strategies in controlling the disease, it is less effective in reversal of schistosome-induced pathology especially in the chronic and advanced stages of schistosomiasis. New strategies and prospective therapeutic agents with antifibrotic effects are needed. Eugenol has a wide anti-inflammatory effect. In the present study, we investigated the possible antischistosomal effect of eugenol on Schistosoma mansoni. MATERIALS AND METHODS: The murine model of S. mansoni was established in three groups of adult male Balb-c mice; group I (infected non-treated group) and groups II and III (infected groups) treated orally with eugenol and praziquantel (PZQ), respectively. The expression of the sensitive immunohistochemical marker α-smooth muscle actin (α-SMA) in schistosome-infected tissues was determined. In addition, parasitological, biochemical, and histological parameters that reflect disease severity and morbidity were examined. RESULTS: Eugenol treatment showed significant reduction in total worm burden by 19.2%; however, the oogram pattern showed no marked difference compared to that of the PZQ group. Yet, eugenol significantly reduced the serum levels of hepatic enzymes: aspartate aminotransferase and alanine aminotransferase. Histopathological examination revealed a significant reduction in both numbers and diameters of hepatic granulomata, which was consistent with reduction in collagen fiber deposition. Additionally, the antifibrotic effect of eugenol was validated by its considerable reduction in the expression of the sensitive marker α-SMA in both eugenol- and PZQ-treated groups. CONCLUSION: Although eugenol could not totally eradicate adults of S. mansoni, the significant amelioration of liver enzymes and hepatic fibrosis potentiate eugenol's role as a promising antifibrotic and a complementary antischistosomal agent.