QSAR Modeling of COX-2 Inhibitory Activity of Thiazinan, Benzthiazinan and Benzdiazinan Derivatives

COX-2 inhibitory activities of some thiazinan, benzdiazinan and benzthiazinan derivatives were modeled by quantitative structure–activity relationship (QSAR) with stepwise-multiple linear regression (SW-MLR) method. The built model was robust and predictive with correlation coefficient (R2) of 0.840 for training and 0.522 for test groups. The quality of the model was evaluated by leave-one out (LOO) cross validation and LOO correlation coefficient (Q2) was 0.639. We also investigated a leverage approach for defining of applicability domain of model. According to QSAR model results, COX-2 inhibitory activity of selected data set had correlation with VE3_Dzm (Logarithmic coefficient sum of the last eigenvector from Barysz matrix weighted by mass), GATS6c (geometrical structure of the considered molecules in a complex way) and GATS5i (Geary autocorrelation of lag 5 weighted by ionization potential) descriptors which derived from their structures

Design, synthesis and docking studies of novel anti-HIV agents

Introduction: AIDS therapeutic targets principally consists of three enzymes: reverse transcriptase (RT), protease (PR) and integrase (IN). Integrase strand transfer inhibitors among the HIV inhibitors has the advantage of suitable safety profile and high potency. The chelating motif and coplanar hydrophobic aryl group are the common pharmacophores of an integrase strand transfer inhibitor (INSTI). According to the cyclic chelating group of dolutegravir, we incorporated the chelating group into a cyclic motif and novel 2-mercaptooxazoloxocumarin tricyclic scaffold was designed. Hydrophobic part of the ligand was attached through s-arylation to occupy the same position as the halobenzyl pharmacophoric group of INSTIs. Methods and Results: 4-Hydroxy-3-nitro coumarin was prepared in a nitration procedure of 4-hydroxy coumarin with the aid of concentrated nitric acid and sulfuric acid. Reduction of the 4-hydroxy-3-nitro coumarin in the presence of sodium dithionite and sodium acetate in water gave the 3-amino-4-hydroxy coumarin. 2-Mercaptooxazolocoumarin was prepared by the reaction of carbon disulfide with 3-amino-4-hydroxy coumarin in methanolic potassium hydroxide. Then, this intermediate was treated with substituted benzyl halides in the presence of potassium carbonate and acetone. Final derivatives were recrystallized from ethanol and confirmed by IR, LC-MS (ESI), 1HNMR & 13CNMR. According to the docking results, the tricyclic scaffold could п-stack the 3’-end reactive adenosine in the IN active site just same as the co-crystallized ligand dolutegravir and the ligand heteroatoms complexes the magnesium cofactors in the IN. Conclusions: Here, we introduced a novel scaffold for anti-HIV activity. The superimposed structure with co-crystallized ligand dolutegravir confirmed the potential for integrase inhibitory activity just same as the second generation integrase inhibitor dolutegravir

Design and Synthesis of Novel cyclopeptide Derivatives as New Cytotoxic Agents

A new series of anti-cancer agents based on cyclopeptide scaffold containing methyl sulfonyl group at the para position of the C-4 phenyl ring were synthesized and their cytotoxic activities were determined against several human cancer cell lines. compounds, c Glu-Ser-Pro-Lys-PhSO2Me (1v), c Gly-Pro-Ala-Lys-PhSO2Me (2v) c Ser-Glu-Gly-Pro-Lys-PhSO2Me (3v) c Lys-Gly-Pro-Asp-PhSO2Me (4v)   c Asp-Gly-Pro-Lys-PhSO2Me (5v) were synthesized and characterized by lc-mass spectroscopy and NMR .based on the results  the most potent cytotoxic cyclicpeptide against A549 cell line was (1v) with IC50 values 3.18 µM  and the most potent cytotoxic cyclicpeptide against MCF-7 cell line was (5v) with IC50 values 2.46 µM   respectively, while most of the compounds had sufficient activity against MCF-7, HEPG-2 , HT-29 and A-549 cell lines are with mean IC50 values ranging from 2.46 to 31.44 µM. Introduction: The logical design of this study was based on the use of pharmacophoric moiety of COX-2 inhibitors with aromatic or cyclic amino acids and acidic amino acids to simulate the structure of COX-2 inhibitors. As a result, it would be appealing to COX-2 inhibitors with peptide structure which show antitumor and anti-inflammatory effects. Methods and Results: The results clearly indicated that modified cyclopeptides (1v - 5v), showed significant cytotoxic activity against all chosen cell lines. Compound (5v) showed a great anti-cancer activity against MCF-7 cell line and Compound (3v) showed a great anti-cancer activity against A549 cell line. Conclusions: In this study we synthesized 5 modified cyclopeptides by solid phase peptide synthesis approach and examined the cytotoxicity of them on 4 different cell lines. This study indicates that all synthesized compounds showed significant cytotoxicity against different cell lines specially against MCF-7 and A549 cell lines. In addition, modifications on the sequence of modified cyclopeptides had a significant influence on the cell cytotoxicity

Design and Synthesis of Novel Tetrapeptide Analogues as New Cytotoxic Agents

New series of compounds based on a tetrapeptide scaffold containing methyl sulfonyl group at the para position of a phenyl ring were synthesized and their cytotoxic activities were examined against several human cancer cell lines including MCF-7 (breast cancer Cell Line), HepG2 (human liver cancer Cell Line), HT-29 (Human Colorectal Adenocarcinoma Cell Line) and A549 (adenocarcinomic human alveolar basal epithelial cells) using MTT assay. Based on the results, among the synthesized peptides, 5e, 5f, 1g, and 3g were the most potent cytotoxic compounds that were more toxic than the reference compound, Celecoxib, against the tested cell lines. These compounds could be candidate for finding cytotoxic agents with new peptide scaffolds which show COX-2 inhibitory activity as well. HIGHLIGHTS•A group of tetrapeptides was reported as COX-2 inhibitors with antiproliferative activity.•New tetrapeptides containing methyl sulfonyl group at the para position of a phenyl ring were synthesized.•Some of novel compounds exhibited more potent cytotoxic effect than Celecoxib as the reference

Design, Synthesis and Biological Evaluation of New 5,5-Diarylhydantoin Derivatives as Selective Cyclooxygenase-2 Inhibitors

A new group of 5,5-diarylhydantoin derivatives bearing a methylsulfonyl COX-2 pharmacophore at the para position of the C-5 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 inhibition structure-activity relationships identified 5-[4-(methylsulfonyl)phenyl]-5-phenyl-hydantoin (4) as a highly potent and selective COX-2 inhibitor (COX-2 IC50 = 0.077 μM; selectivity index > 1298). It was more selective than the reference drug celecoxib (COX-2 IC50 = 0.060 μM; selectivity index = 405). A molecular modeling study where 4 was docked in the binding site of COX-2 indicated that the p-MeSO2 COX-2 pharmacophore group on the C-5 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket. The results of this study showed that the type of substituent on the N-3 hydantoin ring substituent is important for COX-2 inhibitory activity

Evaluating the Effects of Umifenovir Compared to Lopinavir/Ritonavir in the Management of Patients with COVID-19: A Randomized Controlled Trial

Background. Due to the lack of specific safe medications for the treatment of COVID-19, medications used for other similar conditions are being tested to alleviate the condition of COVID-19 patients, resulting in acceptable outcomes in some cases. Umifenovir (Arbidol®) is used to treat influenza viruses by inhibiting the fusion of the virus with the host cell. According to previous findings, umifenovir may inhibit SARS-CoV-2 infection by interfering with the release of SARS-CoV-2 from inside the cell. This study aimed to determine the effects of umifenovir, a fusion inhibitor, versus lopinavir/ritonavir in treating patients with COVID-19. Methods. This study was a randomized controlled trial consisting of 90 confirmed COVID-19 patients divided into the lopinavir/ritonavir group and the umifenovir group. The lopinavir/ritonavir group received 100/25 mg twice, while the umifenovir group was given 200 mg thrice a day, in both groups, for seven days. Outcomes included mortality rate and the need for mechanical ventilation or intensive care unit admission. Length of stay in the hospital and ICU and the lab tests trend were also assessed. Results. The mortality rate and the need for admission to the ICU were significantly lower in the umifenovir group (8% vs. 27.5%; P-value = 0.02). Moreover, The levels of white blood cells were also lower in the umifenovir group than in the control group by day 10 (6.2 (5.3-7.4) vs. 10.8 (9.9-13); P-value <0.001). Conclusions. Umifenovir may reduce the need for admission to the ICU and mortality rate in patients with COVID-19 compared with lopinavir/ritonavir. The lab test trends were also in favor of umifenovir use.

Global, regional, and national burden of chronic kidney disease, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI

Quantifying risks and interventions that have affected the burden of diarrhoea among children younger than 5 years : an analysis of the Global Burden of Disease Study 2017

Background Many countries have shown marked declines in diarrhoea! disease mortality among children younger than 5 years. With this analysis, we provide updated results on diarrhoeal disease mortality among children younger than 5 years from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) and use the study's comparative risk assessment to quantify trends and effects of risk factors, interventions, and broader sociodemographic development on mortality changes in 195 countries and territories from 1990 to 2017. Methods This analysis for GBD 2017 had three main components. Diarrhoea mortality was modelled using vital registration data, demographic surveillance data, and verbal autopsy data in a predictive, Bayesian, ensemble modelling tool; and the attribution of risk factors and interventions for diarrhoea were modelled in a counterfactual framework that combines modelled population-level prevalence of the exposure to each risk or intervention with the relative risk of diarrhoea given exposure to that factor. We assessed the relative and absolute change in diarrhoea mortality rate between 1990 and 2017, and used the change in risk factor exposure and sociodemographic status to explain differences in the trends of diarrhoea mortality among children younger than 5 years. Findings Diarrhoea was responsible for an estimated 533 768 deaths (95% uncertainty interval 477 162-593 145) among children younger than 5 years globally in 2017, a rate of 78.4 deaths (70.1-87.1) per 100 000 children. The diarrhoea mortality rate ranged between countries by over 685 deaths per 100 000 children. Diarrhoea mortality per 100 000 globally decreased by 69.6% (63.1-74.6) between 1990 and 2017. Among the risk factors considered in this study, those responsible for the largest declines in the diarrhoea mortality rate were reduction in exposure to unsafe sanitation (13.3% decrease, 11.2-15.5), childhood wasting (9.9% decrease, 9.6-10.2), and low use of oral rehydration solution (6.9% decrease, 4-8-8-4). Interpretation Diarrhoea mortality has declined substantially since 1990, although there are variations by country. Improvements in sociodemographic indicators might explain some of these trends, but changes in exposure to risk factors-particularly unsafe sanitation, childhood growth failure, and low use of oral rehydration solution-appear to be related to the relative and absolute rates of decline in diarrhoea mortality. Although the most effective interventions might vary by country or region, identifying and scaling up the interventions aimed at preventing and protecting against diarrhoea that have already reduced diarrhoea mortality could further avert many thousands of deaths due to this illness. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.Peer reviewe

The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Cirrhosis and other chronic liver diseases (collectively referred to as cirrhosis in this paper) are a major cause of morbidity and mortality globally, although the burden and underlying causes differ across locations and demographic groups. We report on results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 on the burden of cirrhosis and its trends since 1990, by cause, sex, and age, for 195 countries and territories. Methods We used data from vital registrations, vital registration samples, and verbal autopsies to estimate mortality. We modelled prevalence of total, compensated, and decompensated cirrhosis on the basis of hospital and claims data. Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost due to premature death and years lived with disability. Estimates are presented as numbers and age-standardised or age-specific rates per 100 000 population, with 95% uncertainty intervals (UIs). All estimates are presented for five causes of cirrhosis: hepatitis B, hepatitis C, alcohol-related liver disease, non-alcoholic steatohepatitis (NASH), and other causes. We compared mortality, prevalence, and DALY estimates with those expected according to the Socio-demographic Index (SDI) as a proxy for the development status of regions and countries. Findings In 2017, cirrhosis caused more than 1.32 million (95% UI 1.27-1.45) deaths (440000 [416 000-518 000; 33.3%] in females and 883 000 [838 000-967 000; 66.7%] in males) globally, compared with less than 899 000 (829 000-948 000) deaths in 1990. Deaths due to cirrhosis constituted 2.4% (2.3-2.6) of total deaths globally in 2017 compared with 1.9% (1.8-2.0) in 1990. Despite an increase in the number of deaths, the age-standardised death rate decreased from 21.0 (19.2-22.3) per 100 000 population in 1990 to 16.5 (15.8-18-1) per 100 000 population in 2017. Sub-Saharan Africa had the highest age-standardised death rate among GBD super-regions for all years of the study period (32.2 [25.8-38.6] deaths per 100 000 population in 2017), and the high-income super-region had the lowest (10.1 [9.8-10-5] deaths per 100 000 population in 2017). The age-standardised death rate decreased or remained constant from 1990 to 2017 in all GBD regions except eastern Europe and central Asia, where the age-standardised death rate increased, primarily due to increases in alcohol-related liver disease prevalence. At the national level, the age-standardised death rate of cirrhosis was lowest in Singapore in 2017 (3.7 [3.3-4.0] per 100 000 in 2017) and highest in Egypt in all years since 1990 (103.3 [64.4-133.4] per 100 000 in 2017). There were 10.6 million (10.3-10.9) prevalent cases of decompensated cirrhosis and 112 million (107-119) prevalent cases of compensated cirrhosis globally in 2017. There was a significant increase in age-standardised prevalence rate of decompensated cirrhosis between 1990 and 2017. Cirrhosis caused by NASH had a steady age-standardised death rate throughout the study period, whereas the other four causes showed declines in age-standardised death rate. The age-standardised prevalence of compensated and decompensated cirrhosis due to NASH increased more than for any other cause of cirrhosis (by 33.2% for compensated cirrhosis and 54.8% for decompensated cirrhosis) over the study period. From 1990 to 2017, the number of prevalent cases snore than doubled for compensated cirrhosis due to NASH and more than tripled for decompensated cirrhosis due to NASH. In 2017, age-standardised death and DALY rates were lower among countries and territories with higher SDI. Interpretation Cirrhosis imposes a substantial health burden on many countries and this burden has increased at the global level since 1990, partly due to population growth and ageing. Although the age-standardised death and DALY rates of cirrhosis decreased from 1990 to 2017, numbers of deaths and DALYs and the proportion of all global deaths due to cirrhosis increased. Despite the availability of effective interventions for the prevention and treatment of hepatitis B and C, they were still the main causes of cirrhosis burden worldwide, particularly in low-income countries. The impact of hepatitis B and C is expected to be attenuated and overtaken by that of NASH in the near future. Cost-effective interventions are required to continue the prevention and treatment of viral hepatitis, and to achieve early diagnosis and prevention of cirrhosis due to alcohol-related liver disease and NASH. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.Peer reviewe