Synthesis of new quinoline scaffolds via a solvent-free fusion method and their anti-microbial properties

Purpose: To develop a robust and simple fusion-based methodology for the synthesis of various 5-(-3- nitrophenyl) pyrimido[5,4-c] quinoline-2,4(1H,3H)-diones (5 – 9).Method: The synthesis involved formation of a Knoevenagel product using barbituric acid and 3- nitrobenzaldehyde which cyclized on fusing with various sulfanilamides in a sealed tube at 170 – 212°C. This resulted in the synthesis of the target quinolines (5 – 9). To evaluate their antibacterial and antiviral properties, the synthesized quinolines were tested against four gram-negative bacterial strains and four poultry viruses. The MIC and IC50 of each active compound were calculated.Results: Data from NMR, mass spectrometry and elemental analysis confirmed the formation of quinoline scaffolds. Antibacterial screening revealed that all the compounds had antibacterial activities. However, the minimum inhibitory concentration (MIC) of compounds 6 – 8 and 9 against Proteus vulgaris and Klebsiella pneumoniae showed that these compounds were more active than the standard drug ampicillin. Antiviral studies and IC50 values showed that compounds 5 – 9 were effective against Newcastle disease virus (NDV) and infectious bursal disease virus (IBDV), while compounds 5, 6 and 8 were active against avian influenza virus subtype H9N2 (AIV); compounds 7 and 8 were active against infectious bronchitis virus (IBV).Conclusion: A simple strategy of fusion of Knoevenagel product with aromatic amines can be used to synthesize highly functionalized quinoline scaffolds which are potential drug candidates for development of new antibacterial and antiviral agents.Keywords: Quinoline scaffolds, Barbituric acid, Knoevenagel condensation, Antiviral, Antibacteria

Synthesis, biological evaluation and molecular docking studies of Mannich bases derived from 1, 3, 4-oxadiazole- 2-thiones as potential urease inhibitors

Purpose: To design and synthesize a series of new structural motifs of urease inhibitors, 3-[{(substituted phenyl) amino} methyl]-5-(3, 4, 5-trimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones and 3- {[(pyridin-2-yl)amino]methyl}-5-(3,4,5-trimethoxy phenyl)-1,3,4-oxadiazole-2(3H)-thiones from 1, 3, 4- oxadiazole-2-thione.Methods: Targeted Mannich base derivatives were synthesized by the reaction of 1, 3, 4-oxadiazole-2- thione with formaldehyde and respective aromatic amines. These structural motifs were subjected to 1H–NMR, 13C–NMR and mass spectrometric analysis. Compound 4, i.e., 1,3,4-oxadiazole-2-thione and its corresponding Mannich bases (5-17) were subjected to in silico screening as urease inhibitors, using crystal structure of urease (Protein Data Bank ID: 5FSE) as a model enzyme. Furthermore, the targeted compounds were evaluated for their in vitro urease inhibition and anti-oxidant activities using thiourea and propyl gallate as standards, respectively.Results: The docking score of targeted compounds predicted that they are promising urease inhibitors. Subsequently, in vitro studies on Jack bean urease supported the results from virtual screening, and found compounds 4, 5, 9,10,12, 13, 14 and 15 very potent urease inhibitors with half-maximal inhibitory concentration (IC50) values in the range of 5.93 ± 0.13 to 9.76 ± 0.11, relative to thiourea (IC50 = 21.25 ± 0.15). Compounds 4 – 6, and compounds 12 - 17 also exhibited higher antioxidant activities than propyl gallate.Conclusion: In view of their potent urease inhibition and antioxidant activities, these structural motifs have potentials as new candidates for the development of anti-ulcer drugs.Keywords: 1, 3, 4-Oxadiazole-2-thiones, Antioxidant, Molecular docking, Urease inhibition, Anti-ulce

Preliminary Phytochemical Screening, Proximate Analysis, Antioxidant and Antibacterial Activities of an Algal Species of Hydrodictyon Reticulatum

The freshwater algae grow in a wide range of aquatic habitats across the globe and are rich in secondary metabolites. The present study was designed to conduct the phytochemical screening, proximate analysis, antioxidant and antibacterial activities of water net (Hydrodictyon reticulatum), an algal weed from Pakistan. The pure and dried algal mass was crushed into a fine powder and four solvent-based extracts were used for phytochemical screening. The results of preliminary qualitative screening indicated the presence of flavonoids, phenols, quinones, steroids, resins, anthraquinones, glycosides, lignin, proteins, saponins, tannins, reducing sugars, alkaloids, terpenoids, fats, and oils, whereas the quantification results revealed the high quantities of total ash, crude proteins, crude fiber, alkaloids, carotenoids, flavonoids, and chlorophyll a. The studied methanolic extracts with maximum concentration (150 μg/ml) showed significantly (p-value ≤ 0.05) higher antioxidant and antibacterial activities. The IC50 values of the crude methanolic extract of water net were found very close to streptomycin (positive control) against both bacterial pathogenic species of Klebsiella pneumoniae and Staphylococcus aureus. This study concluded that the crude extracts of water net possessed antibacterial activity at par to streptomycin drug, and requires further detailed study for the separation, identification, and testing of the pure phytochemical compound to be used by the nutraceutical and or pharmaceutical industry

Does academic assessment system type affect levels of academic stress in medical students? A cross-sectional study from Pakistan

Introduction Stress among medical students induced by academic pressures is on the rise among the student population in Pakistan and other parts of the world. Our study examined the relationship between two different systems employed to assess academic performance and the levels of stress among students at two different medical schools in Karachi, Pakistan. Methods A sample consisting of 387 medical students enrolled in pre-clinical years was taken from two universities, one employing the semester examination system with grade point average (GPA) scores (a tiered system) and the other employing an annual examination system with only pass/fail grading. A pre-designed, self-administered questionnaire was distributed. Test anxiety levels were assessed by The Westside Test Anxiety Scale (WTAS). Overall stress was evaluated using the Perceived Stress Scale (PSS). Results There were 82 males and 301 females while four did not respond to the gender question. The mean age of the entire cohort was 19.7±1.0 years. A total of 98 participants were from the pass/fail assessment system while 289 were from the GPA system. There was a higher proportion of females in the GPA system (85% vs. 59%; p \u3c 0.01). Students in the pass/fail assessment system had a lower score on the WTAS (2.4±0.8 vs. 2.8±0.7; p=0.01) and the PSS (17.0±6.7 vs. 20.3±6.8; p \u3c 0.01), indicating lower levels of test anxiety and overall stress than in students enrolled in the GPA assessment system. More students in the pass/fail system were satisfied with their performance than those in the GPA system. Conclusion Based on the present study, we suggest governing bodies to revise and employ a uniform assessment system for all the medical colleges to improve student academic performance and at the same time reduce stress levels. Our results indicate that the pass/fail assessment system accomplishes these objectives

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Preliminary Phytochemical Screening, Proximate Analysis, Antioxidant and Antibacterial Activities of an Algal Species of Hydrodictyon Reticulatum

The freshwater algae grow in a wide range of aquatic habitats across the globe and are rich in secondary metabolites. The present study was designed to conduct the phytochemical screening, proximate analysis, antioxidant and antibacterial activities of water net (Hydrodictyon reticulatum), an algal weed from Pakistan. The pure and dried algal mass was crushed into a fine powder and four solvent-based extracts were used for phytochemical screening. The results of preliminary qualitative screening indicated the presence of flavonoids, phenols, quinones, steroids, resins, anthraquinones, glycosides, lignin, proteins, saponins, tannins, reducing sugars, alkaloids, terpenoids, fats, and oils, whereas the quantification results revealed the high quantities of total ash, crude proteins, crude fiber, alkaloids, carotenoids, flavonoids, and chlorophyll a. The studied methanolic extracts with maximum concentration (150 μg/ml) showed significantly (p-value ≤ 0.05) higher antioxidant and antibacterial activities. The IC50 values of the crude methanolic extract of water net were found very close to streptomycin (positive control) against both bacterial pathogenic species of Klebsiella pneumoniae and Staphylococcus aureus. This study concluded that the crude extracts of water net possessed antibacterial activity at par to streptomycin drug, and requires further detailed study for the separation, identification, and testing of the pure phytochemical compound to be used by the nutraceutical and or pharmaceutical industry

Effect of Diabetes Mellitus and Anti-Diabetic Drugs on Bone Health-A Review

Osteoporosis and diabetes mellitus (DM) are widespread diseases and have a significant health burden. Type-1 diabetes mellitus (T1DM) and Type-2 diabetes mellitus (T2DM) are associated with an increased bone fracture. In T1DM, the increased risk of bone fracture is associated with low bone mass. In patients with T2DM, the risk of fracture of the bone is increased due to low quality of bone, despite increased bone mineral density (BMD). In type 2 diabetic patients, bone fragility depends on the quality of bone instead of a reduction in bone mass. Thiazolidinediones (TZD) cause differentiation of adipocytes and inhibit differentiation of osteoblast and bone marrow stromal stem cells (BMSC). In this review, we have described the effect of anti-diabetic drugs and diabetes mellitus on bone health and our finding shows that sulfonylureas and metformin have no negative effect on bone health and protect bones against fractures