Synthesis, Biological Evaluation, and In Silico Studies of Novel Coumarin-Based 4H,5H-pyrano[3,2-c]chromenes as Potent ß-Glucuronidase and Carbonic Anhydrase Inhibitors.

The search for novel heterocyclic compounds with a natural product skeleton as potent enzyme inhibitors against clinical hits is our prime concern in this study. Here, a simple and facile two-step strategy has been designed to synthesize a series of novel coumarin-based dihydropyranochromenes (12a-12m) in a basic moiety. The synthesized compounds were thus characterized through spectroscopic techniques and screened for inhibition potency against the cytosolic hCA II isoform and ß-glucuronidase. Few of these compounds were potent inhibitors of hCA II and ß-glucuronidase with varying IC50 values ranging from 4.55 ± 0.22 to 21.77 ± 3.32 µM and 440.1 ± 1.17 to 971.3 ± 0.05 µM, respectively. Among the stream of synthesized compounds, 12e and 12i were the most potent inhibitors of ß-glucuronidase, while 12h, 12i, and 12j showed greater potency against hCA II. In silico docking studies illustrated the significance of substituted groups on the pyranochromene skeleton and binding pattern of these highly potent compounds inside enzyme pockets.

Synthesis, spectroscopic, SC-XRD/DFT and non-linear optical (NLO) properties of chromene derivatives.

In the present study, we reported the efficient synthesis of novel, heterocyclic, coumarin-based pyrano-chromene derivatives, 2-amino-8-methyl-5-oxo-4-[2-(2-oxo-2H-chromen-3-ylmethoxy)-phenyl]-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (4a) and 2-amino-8-methyl-5-oxo-4-[2-(2-oxo-2H-chromen-3-ylmethoxy)-phenyl]-4H,5H-pyrano[3,2-c]chromene-3-carboxylic acid methyl ester (4b). The chemical structures of synthesized compounds were resolved by employing various spectroscopic techniques like UV-Vis, FT-IR, 1H & 13C NMR, and single crystal X-ray diffraction (SC-XRD) analysis. The compounds; 4a and 4b, with appealing π-bonded skeleton were further analyzed in terms of their electronic and structural aspects using an integral approach of density functional theory (DFT) and time-dependent DFT (TD/DFT). The methodology: M06-2X/6-31G(d,p) level of theory was applied to compare their experimental data with theoretical outcomes using quantum chemical analysis. The frontier molecular orbitals (FMOs) study revealed that, 4a possesses a low band gap (5.168 eV) as compared to 4b (6.308 eV). Global reactivity parameters were associated with E gap values as 4a, with the lowest band gap showed the smaller value of hardness (0.094 eV) and a larger value of softness (5.266 eV). The non-linear optical (NLO) insight exhibited that, the average polarizability 〈α〉 and second hyperpolarizability (γ tot) were observed in 4a as 6.77005 × 10-23 and 0.145 × 104 esu, respectively. Overall, the computational studies suggest that the investigated compounds have distinct NLO properties.

In Silico Inhibition of BACE-1 by Selective Phytochemicals as Novel Potential Inhibitors: Molecular Docking and DFT Studies.

BACKGROUND: Alzheimer's Disease (AD) has become the most common age-dependent disease of dementia. The trademark pathologies of AD are the presence of amyloid aggregates in neurofibrils. Recently phytochemicals being considered as potential inhibitors against various neurodegenerative, antifungal, antibacterial and antiviral diseases in human beings. OBJECTIVE: This study targets the inhibition of BACE-1 by phytochemicals using in silico drug discovery analysis. METHODS: A total of 3150 phytochemicals were collected from almost 25 different plants through literature assessment. The ADMET studies, molecular docking and density functional theory (DFT) based analysis were performed to analyze the potential inhibitory properties of these phytochemicals. RESULTS: The ADMET and docking results exposed seven compounds that have high potential as an inhibitory agent against BACE-1 and show binding affinity >8.0 kcal/mol against BACE-1. They show binding affinity greater than those of various previously reported inhibitors of BACE-1. Furthermore, DFT based analysis has shown high reactivity for these seven phytochemicals in the binding pocket of BACE- 1, based on ELUMO, EHOMO and Kohn-Sham energy gap. All seven phytochemicals were testified (as compared to experimental ones) as novel inhibitors against BACE-1. CONCLUSION: Out of seven phytochemicals, four were obtained from plant Glycyrrhiza glabra i.e. Shinflavanone, Glabrolide, Glabrol and PrenyllicoflavoneA, one from Huperzia serrate i.e. Macleanine, one from Uncaria rhynchophylla i.e. 3a-dihydro-cadambine and another one was from VolvalerelactoneB from plant Valeriana-officinalis. It is concluded that these phytochemicals are suitable candidates for drug/inhibitor against BACE-1, and can be administered to humans after experimental validation through in vitro and in vivo trials.

Corrigendum: Fake News or Weak Science? Visibility and Characterization of Antivaccine Webpages Returned by Google in Different Languages and Countries.

[This corrects the article DOI: 10.3389/fimmu.2018.01215.].

Fake News or Weak Science? Visibility and Characterization of Antivaccine Webpages Returned by Google in Different Languages and Countries.

The 1998 Lancet paper by Wakefield et al., despite subsequent retraction and evidence indicating no causal link between vaccinations and autism, triggered significant parental concern. The aim of this study was to analyze the online information available on this topic. Using localized versions of Google, we searched "autism vaccine" in English, French, Italian, Portuguese, Mandarin, and Arabic and analyzed 200 websites for each search engine result page (SERP). A common feature was the newsworthiness of the topic, with news outlets representing 25-50% of the SERP, followed by unaffiliated websites (blogs, social media) that represented 27-41% and included most of the vaccine-negative websites. Between 12 and 24% of websites had a negative stance on vaccines, while most websites were pro-vaccine (43-70%). However, their ranking by Google varied. While in Google.com, the first vaccine-negative website was the 43rd in the SERP, there was one vaccine-negative webpage in the top 10 websites in both the British and Australian localized versions and in French and two in Italian, Portuguese, and Mandarin, suggesting that the information quality algorithm used by Google may work better in English. Many webpages mentioned celebrities in the context of the link between vaccines and autism, with Donald Trump most frequently. Few websites (1-5%) promoted complementary and alternative medicine (CAM) but 50-100% of these were also vaccine-negative suggesting that CAM users are more exposed to vaccine-negative information. This analysis highlights the need for monitoring the web for information impacting on vaccine uptake.

Early laparoscopic cholecystectomy is more cost-effective than delayed laparoscopic cholecystectomy in the treatment of acute cholecystitis.

BACKGROUND: This economic evaluation quantifies the cost-effectiveness of early laparoscopic cholecystectomy (ELC) versus delayed laparoscopic cholecystectomy (DLC) in the management of acute cholecystitis. The two interventions were assessed in terms of outcome measures, including utilities, to derive quality-adjusted life years (QALYs) as a unit of effectiveness. This study hypothesizes that ELC is more cost-effective than DLC. MATERIALS AND METHODS: In this economic evaluation, existing literature was compiled and analyzed to estimate the incremental cost-effectiveness of ELC versus DLC. Six randomized controlled trials were used to schematically represent the probabilities of each decision tree branch. To calculate health outcomes, quality of life scores were sourced from three articles and multiplied by the expected length of life postintervention to give QALYs. From an National Health Service (NHS) perspective, one QALY may be sacrificed if the incremental cost-effectiveness ratio is above £20,000-£30,0000 in cost savings. RESULTS: This economic evaluation calculated the average net present values of ELC to be £3920 and DLC to be £4565, demonstrating that ELC is the less-expensive intervention, with potential cost savings of £645 per operation. When scaling these savings up to a population approximately comparable to the size of the UK, full-scale implementation of ELC rather than DLC will potentially save the NHS £30,000,000 per annum. CONCLUSION: ELCs are cost-effective from the perspective of the NHS. As such, policy should review existing guidelines and consider the merits of ELC versus DLC, improving resource allocation. The findings of this article advocate that ELC should become a standard practice.

Quality of online information on breast cancer treatment options.

Offering breast cancer patients treatment choice has become a priority as the involvement of patients in the decision-making process is associated with improved physical and psychological outcomes. As the Internet is increasingly being used by patients as a source of medical information, it is important to evaluate the quality of information relating to breast cancer on the Internet. We analysed 200 websites returned by google.co.uk searching "breast cancer treatment options" in terms of their typology and treatment options described. These were related to standard measures of health information quality such as the JAMA score and the presence of quality certifications, as well as readability. We found that health portals were of higher quality whilst commercial and professional websites were of poorer quality in terms of JAMA criteria. Overall, readability was higher than previously reported for other conditions, and Google ranked websites with better readability higher. Most websites discussed surgical and medical treatments. Few websites, with a large proportion being of commercial typology, discussed complementary and alternative medicine. Google ranked professional websites low whilst websites from non-profit organizations were promoted in the ranking.

Cigarette smoking and medical students at King Edward Medical University, Lahore (Pakistan).

OBJECTIVES: To observe the frequency of cigarette smoking in medical students of King Edward Medical University and to determine associated variables. METHOD: A cross-sectional survey was conducted and data was collected through a self administered questionnaire from students at King Edward Medical University. Information about demographic characteristics, smoking status in family, number of cigarettes smoked/day, influence for starting it and use of nicotine replacement therapy was obtained. Duration of study was from April 1 to May 30, 2009. Smoker was defined as a person who, at the time of survey smoked cigarettes either daily or occasionally. RESULTS: Response rate was 65.4%, of these 396 (60.55%) were male and 88 (13.45%) were smokers. Smoking was more among the male students than females (p-value < 0.001). The greatest percentage of smokers was in 3rd Year (n = 29, 26.85%), majority were of 21-30 years age (n = 59, 19.53%), started smoking between 11-20 years (n = 48, 54.54%), smoked < 10 cigarettes/day (n = 37, 42.04%) and started smoking due to influence of friends (n = 53, 60.23%). Majority (n = 69, 78.4%) had no intention to quit in the next 6 months. Lack of Incentive (n = 32, 36.36%) and Addiction (n = 24, 27.27%) were the main reasons for not quitting. CONCLUSION: Our results showed a substantial trend of cigarette smoking in medical students in Pakistan. Prevalence is more in higher classes. Majority have a smoker in their family and had started smoking under influence of peers and media. They find it relaxing and addictive, hence difficult to quit. Nicotine use was found to be uncommon.

Cigarette smoking and health care professionals at Mayo Hospital, Lahore, Pakistan.

OBJECTIVES: To observe the frequency of cigarette smoking in doctors and paramedics and study various variables associated with it. METHODS: An anonymous questionnaire was given to randomly selected 250 Doctors and 250 Paramedics at Mayo Hospital in 2009. Information about demographic characteristics, smoking status in family, number of cigarettes smoked per day, influence for starting smoking, reason for continuation of smoking and use of nicotine replacement therapy was obtained. RESULTS: A total of 234 questionnaires from doctors and 207 from paramedics were received back (88.2% response rate). There were 280 males (163 Doctors; 117 Paramedics) and 161 females (71 Doctors; 90 Paramedics). Eightyseven (37.18%) Doctors and 74 (35.74%) Paramedics were smokers with 82 (50.31%) male doctors and 5 (7.04%) females. Similar results were obtained in Paramedics 72 (61.53%) males and 2 (2.22%) females. Of the smokers, majority started smoking between 11-20 years age with 39 (44.83%) Doctors and 48 (64.86%) Paramedics. Twenty three (26.44%) Doctors and 31 (41.89%) Paramedics smoked 11-20 cigarettes per day. Smoking was initiated due to the influence of friends by 48 (55.17%) Doctors and 56 (75.68%) Paramedics. Most smokers, 29 (33.33%) Doctors and 33 (44.59%) Paramedics found use of cigarette smoking as "Relaxing". Addiction was the main reason for difficulty in quitting cigarette smoking as reported by 33 (37.93%) Doctors and 31 (41.89%) Paramedics. Of the smokers, 61 (70.11%) doctors and 50 (32.43%) paramedics had no intention to quit smoking in the next 6 months. CONCLUSION: A significant number of doctors and paramedics, especially males, in Pakistan smoke cigarettes, which requires proper attention.

1-[1-(4-Bromo-phen-yl)ethyl-idene]-4-(2,4-dimeth-oxy-phen-yl)thio-semicarbazide.

In the title compound, C(17)H(18)BrN(3)O(2)S, the dihedral angle between the aromatic rings is 9.15 (17)°. A bifurcated intra-molecular N-H⋯(N,O) hydrogen bond generates two S(5) rings and a weak intra-molecular C-H⋯S inter-action completes an S(6) ring motif. In the crystal, inversion dimers linked by pairs of N-H⋯S hydrogen bonds generate R(2) (2)(8) loops and weak C-H⋯S and C-H⋯π inter-actions are also present.