No abstract

In the designed compounds, a new linker was inserted in the form of fragments with verified VEGFR‐2 inhibitory potential, including an α,β‐unsaturated ketonic fragment, pyrazole, and pyrimidine. Also, new distal hydrophobic moieties were attached to these linkers that are expected to increase the hydrophobic interaction with VEGFR‐2 and, consequently, the affinity. These structural optimizations have led us to identify the novel dihydropyrazole derivative 6e as a promising hit molecule. All the new derivatives were evaluated to assess their anticancer activity against three human cancer cell lines, including HepG2, HCT‐116, and MCF‐7. The results of the in vitro anticancer evaluation study revealed the moderate to excellent cytotoxicity of 6c, 6e, 6g, and 7b, with IC50 values in the low micromolar range. The inhibitory activity of VEGFR‐2 was investigated for 16 of the designed compounds. The enzyme assay results of the new compounds were compared with those of sorafenib as a reference VEGFR‐2 inhibitor. The obtained results demonstrated that our derivatives are potent VEGFR‐2 inhibitors. The most potent derivatives 6c, 6e, 6g, and 7b showed IC50 values in the range of 0.11–0.22 µM. Molecular docking and pharmacokinetic studies were also conducted to rationalize the VEGFR‐2 inhibitory activity and to evaluate the ability of the most potent derivatives to be developed as good drug candidates.

The COVID-19 pandemic continues to be a global health crisis. The gut microbiome critically affects the immune system and some respiratory infections are associated with changes in the gut microbiome, here we evaluated the role of nutritional and lifestyle habits that modulate gut microbiota on COVID-19 outcomes in a longitudinal cohort study that included 200 consecutive patients infected with COVID-19. Of these, 122 cases were mild and 78 were moderate, according to WHO classification. After detailed explanation by a consultant in clinical nutrition, participants responded to a written questionnaire on daily sugar, probiotic and prebiotic intake in food, sleeping hours, exercise duration, and antibiotic prescription, during the past one year before infection. daily consumption of prebiotic-containing foods, less sugar, regular exercise, adequate sleep, and fewer antibiotic prescriptions, led to a milder disease and rapid virus clearance. Additionally, data on these factors were compiled into a single score, the ESSAP score (Exercise, Sugar consumption, Sleeping hours, Antibiotics taken, and Probiotics and Prebiotics administration; 0–11 points), median ESSAP score was 5 for both mild and moderate cases; however, the range was 4–8 in mild cases but 1–6 in moderate (p = 0.001, OR:4.2, 95%CI:1.9-9.1), our results showed a negative correlation between regular consumption of yogurt containing probiotics and disease severity (p = 0.007, OR:1.6, 95%CI:1.1-2.1). Mild COVID-19 disease was associated with 10-20 minutes of daily exercise (p = 0.016), sleeping at least 8 hours daily prescribed antibiotics less than 5 times per year (p = 0.077), ate plenty of prebiotic-containing food.

A new series of 6-iodo-2-phenyl-3-substituted-quinazolin-4(3H)-one (5-12 a-b ) derivatives were synthesized, evaluated for their anticonvulsant activity against pentylenetetrazole (PTZ)-induced seizures and maximal electroshock test and compared with the reference drugs phenobarbital sodium and methaqualone. The neurotoxicity was assessed using rotarod test. The molecular docking was performed for all the synthesized compounds to assess their binding affinities to GABA-A receptor in order to rationalize their anticonvulsant activities in a qualitative way. The data obtained from the molecular modeling were correlated with those obtained from the biological screening. Compounds 9 a , 9 b , 12 a and 7 a showed the highest anticonvulsant activities of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test when compared with the reference drugs. The obtained results proved that the most active compounds could be a useful model for future design, adaptation and investigation to construct more active analogs.ª 2015 Production and hosting by Elsevier B.V. on behalf

In accordance with the significant impetus of the discovery of potent vascular endothelial growth factor receptor 2 (VEGFR‐2) inhibitors, herein, we report the design, synthesis, and anticancer evaluation of 12 new N‐substituted‐4‐phenylphthalazin‐1‐amine derivatives against HepG2, HCT‐116, and MCF‐7 cells as VEGFR‐2 inhibitors. The results of the cytotoxicity investigation indicated that HCT‐116 and MCF‐7 were the most sensitive cell lines to the influence of the newly synthesized derivatives. In particular, compound 7a was found to be the most potent derivative among all the tested compounds against the three cancer cell lines, HepG2, HCT116, and MCF‐7, with IC50 = 13.67 ± 1.2, 5.48 ± 0.4, and 7.34 ± 0.6 µM, respectively, which is nearly equipotent to that of sorafenib (IC50 = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively). All synthesized derivatives, 4a,b−8a−c, were evaluated for their inhibitory activities against VEGFR‐2. The tested compounds displayed high to low inhibitory activity, with IC50 values ranging from 0.14 ± 0.02 to 9.54 ± 0.85 µM. Among them, compound 7a was found to be the most potent derivative that inhibited VEGFR‐2 at an IC50 value of 0.14 ± 0.02 µM, which is nearly 72% of that of the sorafenib IC50 value (0.10 ± 0.02 µM). Compounds 7b, 8c, 8b, and 8a exhibited very good activity with IC50 values of 0.18 ± 0.02, 0.21 ± 0.03, 0.24 ± 0.02, and 0.35 ± 0.04 µM, respectively. Molecular modeling studies were carried out for all compounds against the VEGFR‐2 active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling studies. However, these modifications led to new phthalazine derivatives with higher VEGFR‐2 inhibitory activities than vatalanib and which are nearly equipotent to sorafenib.

No abstract

No abstract

Background COVID-19 is the largest outbreak to strike humanity. The wide scale of fatalities and morbidities lead to a concurrent pandemic of uncertainty in scientific evidence. Conflicting evidences are released on daily basis about the neonatal outcomes of COVID-19-positive mothers. The aim of this study was to use the relevant case reports and series to determine the percentage of newborns who test positive for COVID-19 who are born to COVID-19-positive mothers. Secondary outcomes included examining laboratory abnormalities among COVID-19-positive neonates, and any depicted placental abnormalities in COVID-19-positive mothers. For this purpose, systematic review was performed on all studies reporting primary data on fetus-mother pairs with COVID-19. Data bases were searched for studies that met our inclusion and exclusion criteria. Results Final screening revealed 67 studies, from which the primary data of 1787 COVID-19 mothers were identified and had their pregnancy outcome analyzed. Only 2.8% of infants born to COVID-19-positive mothers tested positive, and this finding is identical to percentages reported in former Coronaviridae outbreaks, whereas 20% manifested with intrauterine hypoxia alongside placental abnormalities suggestive of heavy placental vaso-occlusive involvement. Conclusions These findings suggest that while vertical transmission is unlikely, there appears to be an underlying risk of placental insufficiency due to the prothrombotic tendency observed in COVID-19 infection. Guidelines for proper prophylactic anticoagulation in COVID-positive mothers need to be established.