Synthesis and biological evaluation of novel 2-phenylquinazoline-4-amine derivatives:identification of 6-phenyl-8H-benzo[g]quinazolino[4,3-b]quinazolin-8-one as a highly potent inducer of NAD(P)H quinone oxidoreductase 1

A novel series of quinazoline compounds (2-14) incorporating biologically active heterocyclic moieties were designed and synthesized. The structure of the newly synthesized compounds was recognized on the basis of elemental analyses, IR, (1)H-NMR, (13)C-NMR and mass spectral data. All compounds were evaluated for their ability to induce the cytoprotective enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) using a quantitative bioassay and a docking study was performed in the Kelch domain of Keap1 obtained from the Protein Data Bank (PDB ID: 4IQK) to explore the ability of the synthesized compounds to block the Nrf2-binding site of Keap1. All of the synthesized compounds showed concentration-dependent inducer activity with potencies in the low- or sub-micromolar range. Compound 12 was the most potent inducer in this new series, with a concentration that doubles the specific activity of NQO1 (CD value) of 70 nM. The identification of this compound offers a new chemical scaffold for future development of highly potent inducers.</p

Impact Factors in a Curriculum Vitae for Scholarship Application

Introduction: Scholarship applicants often receive different advice on what should be included in their Curriculum Vitae (CV). This study aims to investigate what the essential components of a CV being prepared for scholarships are, how to present them, and what their level of impact is. Materials and Methods: The authors sent an online structured questionnaire to 7512 corresponding authors of recent published papers in Scopus; 124 completed questionnaires were returned. Recommended elements for a CV were chosen according to the Delphi consensus technique with a threshold of 50%. Results: This survey revealed that headings, bullet points and careful error checking were essential parts of the layout. For the content of the CV, besides publications, education and training background, research experience and research interest were also necessary. Moreover, almost all respondents ranked publications as the most important qualification of an academic scholarship candidate. Publications also came first as the most impressive factor, followed by awards and honours. The number of publications, quality of journal, impact factor and total citation should be presented in publication section. The importance of publications in getting academic scholarships is significantly emphasized in this recent study. Conclusions: Having research experience and papers in peer review journals, are highly recommended for students seeking academic scholarships

Antimicrobial and antioxidant properties of methanol extract, fractions and compounds from the stem bark of Entada abyssinica Stend ex A. Satabie

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the antimicrobial and antioxidant activities of the methanol extract, fractions and isolated compounds from <it>Entada abyssinica </it>stem bark, plant used traditionally against gastrointestinal infections.</p> <p>Methods</p> <p>The methanol extract of <it>E. abyssinica </it>stem bark was pre-dissolved in a mixture of methanol and water, and then partitioned between <it>n</it>-hexane, ethyl acetate and <it>n</it>-butanol. The ethyl acetate portion was fractionated by column chromatography and the structures of isolated compounds elucidated by analysis of spectroscopic data and comparison with literature data. Antimicrobial activity was assayed by broth microdilution techniques on bacteria and yeasts. The antioxidant activity was determined by DPPH radical scavenging method.</p> <p>Results</p> <p>Four known compounds [(5<it>S</it>,6<it>R</it>,8a<it>R</it>)-5-(carboxymethyl)-3,4,4a,5,6,7,8,8a-octahydro-5,6,8a-trimethylnaphthalenecarboxylic acid (<b>1</b>), methyl 3,4,5-trihydroxybenzoate (<b>2</b>), benzene-1,2,3-triol (<b>3</b>) and 2,3-dihydroxypropyltriacontanoate (<b>4</b>)] were isolated. Compared to the methanol extract, fractionation increased the antibacterial activities of the <it>n</it>-hexane and ethyl acetate fractions, while the antifungal activities increased in ethyl acetate, <it>n</it>-butanol and aqueous residue fractions. The isolated compounds were generally more active on bacteria (9.7 to 156.2 μg/ml) than yeasts (78.1 to 312.5 μg/ml). Apart from compound <b>1</b>, the three others displayed DPPH^·scavenging activity (RSa), with RSa₅₀values of 1.45 and 1.60 μg/ml.</p> <p>Conclusion</p> <p>The results obtained from this study support the ethnomedicinal use of <it>E. abyssinica </it>in the treatment of gastrointestinal infections and the isolated compounds could be useful in the standardisation of antimicrobial phytomedicine from this plant.</p

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

NAD(P)H:quinone oxidoreductase 1 inducer activity of some novel anilinoquinazoline derivatives

Mostafa M Ghorab,1,2 Mansour S Alsaid,1 Maureen Higgins,3 Albena T Dinkova-Kostova,3&ndash;5 Abdelaaty A Shahat,1,6 Nehal H Elghazawy,7 Reem K Arafa7,8 1Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia; 2Department of Drug Radiation Research, National Center for Radiation Research &amp; Technology, Atomic Energy Authority, Cairo, Egypt; 3Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, UK; 4Department of Medicine, 5Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 6Phytochemistry Department, National Research Center, Dokki, Giza, 7Zewail City of Science and Technology, 8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo,&nbsp;Egypt Abstract: The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements pathway enables cells to survive oxidative stress conditions through regulating the expression of cytoprotective enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1). This work presents the design and synthesis of novel anilinoquinazoline derivatives (2&ndash;16a) and evaluation of their NQO1 inducer activity in murine cells. Molecular docking of the new compounds was performed to assess their ability to inhibit Keap1&ndash;Nrf2 protein&ndash;protein interaction through occupying the Keap1&ndash;Nrf2-binding domain, which leads to Nrf2 accumulation and enhanced gene expression of NQO1. Docking results showed that all compounds can potentially interact with Keap1; however, 1,5-dimethyl-2-phenyl-4-(2-phenylquinazolin-4-ylamino)-1,2-dihydropyrazol-3-one (9), the most potent inducer, showed the largest number of interactions with key amino acids in the binding pocket (Arg483, Tyr525, and Phe478) compared to the native ligand or any other compound in this series. Keywords: Kelch domain, molecular modeling, Keap1/Nrf2, cytoprotection, NQO1 inductio

Multicomponent chemistry in the synthesis of carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors (CAIs) are of growing interest since various isoforms of the enzyme are identified as promising drug targets for treatment of disease. The principal drawback of the clinically used CAIs is the lack of isoform selectivity, which may lead to observable side effects. Studies aiming at the design of isoform-selective CAIs entail generation and biological testing of arrays of compounds, which is a resource- and time-consuming process. Employment of multicomponent reactions is an efficient synthetic strategy in terms of gaining convenient and speedy access to a range of scaffolds with a high degree of molecular diversity. However, this powerful tool appears to be underutilized for the discovery of novel CAIs. A number of studies employing multicomponent reactions in CAI synthesis have been reported in literature. Some of these reports provide inspiring examples of successful use of multicomponent chemistry to construct novel potent and often isoform-selective inhibitors. On critical reading of several publications, however, it becomes apparent that for some chemical series designed as CAIs, the desired inhibitory properties are only assumed and never tested for. In these cases, the biological profile is reported based on the results of phenotypical cellular assays, with no correlation with the intended on-target activity. Present review aims at critically assessing the current literature on the multicomponent chemistry in the CAI design