4-(4-Fluoro­benzene­sulfonamido)­phenyl 4-fluoro­benzene­sulfonate

In the title compound, C18H13F2NO5S2, the complete mol­ecule is generated by a crystallographic inversion centre, and the O atom and the N—H group attached to the central ring are statistically disordered. The dihedral angle between the central and terminal benzene rings is 64.03 (6)°. In the crystal, N—H⋯O, C—H⋯F and C—H⋯O inter­actions link the mol­ecules into a three-dimensional network

4-(3-Methyl­benzene­sulfonamido)­phenyl 3-methyl­benzene­sulfonate

The complete mol­ecule of the title compound, C20H19NO5S2, is generated by a crystallographic twofold axis and the O atom and N—H group attached to the central benzene ring are statistically disordered. The dihedral angle between the central and terminal benzene rings is 56.91 (5)° and that between the terminal benzene rings is 29.80 (5)°. In the crystal, N—H⋯O hydrogen bonding links the mol­ecules into sheets lying parallel to the ab plane

Analgesic effect of neohesperidin is mediated by TRPV1 antagonism

Context: Transient receptor potential vanilloid type 1 (TRPV1) is a non-specific cation channel. It is one of the most important targets in pain research. Aims: To evaluate new TRPV1 antagonists without altering body temperature. Methods: Docking simulation was performed, and one of the candidate compounds, neohesperidin, was tested using thermal and chemical pain models in BALB/c mice. Rectal body temperature was measured using a temperature meter with a thermocouple probe detector, and the capsaicin-evoked calcium response was determined in dorsal root ganglia (DRG) neurons. Results: Docking resulted in the identification of 30 compounds able to interact with the essential amino acids required for the antagonistic activity of TRPV1. Neohesperidin was chosen for further investigations because of its good binding energy (-6.63 kcal/mol) and because its TRPV1 antagonistic activity was not tested before. This study reported for the first time that neohesperidin exerted analgesic activity through TRPV1 antagonism without altering body temperature. Its activity was comparable to the known TRPV1 antagonist N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). In the writhing test, acetic acid-induced abdominal cramps decreased by 66% using 30 mg/kg of neohesperidin. All tested doses of neohesperidin significantly decreased paw-licking time in the capsaicin-induced paw-licking test. A significant increase in the latency time in hot plate and tail flick tests was observed using 30 and 60 mg/kg of neohesperidin. In DRG neurons, neohesperidin reduced capsaicin-evoked calcium responses. Conclusions: Neohesperidin exerts a significant analgesic activity without altering body temperature, which could be due, at least partially, to its antagonistic activity against TRPV1

Qur’anic Ethics for Environmental Responsibility: Implications for Business Practice

Despite the growing interest in examining the role of religious beliefs as a guide towards environmental conscious actions, there is still a lack of research informed by an analysis of divine messages. This deficiency includes the extent to which ethics for environmental responsibility are promoted within textual divine messages; types of environmental themes promoted within the text of divine messages; and implications of such religious environmental ethics for business practice. The present study attempts to fill this gap by conducting a thorough content analysis of environmental themes within the divine message of Muslims (the Qur’an) focusing on their related ethical aspects and business implications. The analysis has revealed 675 verses in 84 chapters throughout all 30 parts of the Qur’an, with environmental content relating to the core components of the natural world, i.e. human beings, water, air, land, plants, animals, and other natural resources. This environmental content and its related ethics are grounded on the belief that humans are vicegerents of God on the earth and their behaviours and actions are motivated by earthly and heavenly rewards. Implications of these findings for different sectors/businesses are also highlighted

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Unlocking the Conformational Changes of P2Y₁₂: Exploring an Acridinone Compound’s Effect on Receptor Activity and Conformation

The P2Y12 receptor is an important member of the purinergic receptor family, known for its critical role in platelet activation and thrombosis. In our previously published study, the acridinone analogue NSC618159 was identified as a potent antagonist of P2Y12. In this work, we investigate the conformational changes in P2Y12 when bound to NSC618159 using molecular dynamics simulations on the receptor’s active and inactive forms (4PXZ and 4NTJ, respectively). It was observed that it took the systems about 7 ns and 12 ns to stabilise when NSC618159 was in complex with the active and inactive forms of P2Y12, respectively. Additionally, the binding pocket of the crystal structure 4PXZ expanded from 172.34 Å3 to an average of 661.55 Å3 when bound to NSC618159, with a maximum pocket volume of 820.49 Å3. This expansion was attributed to the pulled away transmembrane (TM) helices and the adoption of a more open conformation by extracellular loop 2 (EL2). In contrast, 4NTJ’s pocket volume was mostly consistent and had an average of 1203.82 Å3. Moreover, the RMSF profile of the NSC618159-4PXZ complex showed that residues of TM-I and TM-VII had similar fluctuations to the 4NTJ crystal structure, representing the inactive form of P2Y12. Finally, the energy components and binding affinities of NSC618159 towards the active and inactive forms of P2Y12 were predicted using the MM-PBSA approach. According to the results, the binding affinity of NSC618159 towards both active (4PXZ) and inactive (4NTJ) forms of P2Y12 was found to be almost identical, with values of −43.52 and −41.68 kcal/mol, respectively. In conclusion, our findings provide new insights into the conformational changes of P2Y12 upon binding to NSC618159 and may have implications for the development of new P2Y12 antagonists with enhanced potency and specificity

Structure-Based Drug Design Studies Toward the Discovery of Novel Chalcone Derivatives as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors

Human Epidermal Growth Factor Receptor-1 (EGFR), a transmembrane tyrosine kinase receptor (RTK), has been associated with several types of cancer, including breast, lung, ovarian, and anal cancers. Thus, the receptor was targeted by a variety of therapeutic approaches for cancer treatments. A series of chalcone derivatives are among the most highly potent and selective inhibitors of EGFR described to date. A series of chalcone derivatives were proposed in this study to investigate the intermolecular interactions in the active site utilizing molecular docking and molecular dynamics simulations. After a careful analysis of docking results, compounds 1a and 1d were chosen for molecular dynamics simulation study. Extensive hydrogen bond analysis throughout 7 ns molecular dynamics simulation revealed the ability of compounds 1a and 1d to retain the essential interactions needed for the inhibition, especially MET 93. Finally, MM-GBSA calculations highlight on the capability of the ligands to bind strongly within the active site with binding energies of −44.04 and −56.6 kcal/mol for compounds 1a and 1d, respectively. Compound 1d showed to have a close binding energy with TAK-285 (−66.17 kcal/mol), which indicates a high chance for compound 1d to exhibit inhibitory activity, thus recommending to synthesis it to test its biological activity. It is anticipated that the findings reported here may provide very useful information for designing effective drugs for the treatment of EGFR-related cancer disease

Molecular modeling, synthesis, characterization and pharmacological evaluation of benzo[d]oxazole derivatives as non-steroidal anti-inflammatory agents

A series of N-(2-(4-chlorobenzyl)benzo[d]oxazol-5-yl)-3-substituted-propanamide (3a–3n) were synthesized and evaluated for their acute and chronic anti-inflammatory potential. The structure of the compounds was elucidated by elemental and spectral (IR, 1H NMR and MS) analysis. The synthesized compounds (at a dose of 20 mg/kg b.wt. p.o.) have shown their ability to provide 45.1–81.7% protection against carrageenan-induced paw edema, in comparison with diclofenac sodium (69.5%) and ibuprofen (64.7%). The most active compounds 3a, 3l and 3n were screened for chronic anti-inflammatory activity (cotton-pellet-induced granuloma) and to study their ulcerogenic activity. Compounds 3a, 3l and 3n showed 48.4%, 39.3% and 44.0% protection against cotton pellets-induced granuloma compared to diclofenac sodium (60.2%). The tested compounds were less ulcerogenic than the ibuprofen. Molecular modeling studies suggest that these compounds have strong interaction with the COX-2 enzyme, which is responsible for the activity

Pharmacophore modeling and 3D-QSAR studies of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors

1200-120615-Hydroxyprostaglandin dehydrogenase (15-PGDH) plays an important role in gastric ulcer healing, bone formation and dermal wound healing, encouraging several efforts to discover and optimize new inhibitors. We explored possible pharmacophoric space of 15-PGDH using four diverse sets of inhibitors. After that, GA and MLR methods have been employed to identify the optimal pharmacophore model(s) and physicochemical descriptors able to access Quantitative structure-activity relationship equation (r2=0.711, r2(adj)=0.6927, r2(LOO)= 0.6598). One pharmcophore model has emerged in the Quantitative structure-activity relationship equation and has been validated by ROC curve analysis and molecular docking

Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling

The M2 channel protein on the influenza A virus membrane has become the main target of the anti-flu drugs amantadine and rimantadine. The structure of the M2 channel proteins of the H3N2 (PDB code 2RLF) and 2009-H1N1 (Genbank accession number GQ385383) viruses may help researchers to solve the drug-resistant problem of these two adamantane-based drugs and develop more powerful new drugs against influenza A virus. In the present study, we searched for new M2 channel inhibitors through a combination of different computational methodologies, including virtual screening with docking and pharmacophore modeling. Virtual screening was performed to calculate the free energies of binding between receptor M2 channel proteins and 200 new designed ligands. After that, pharmacophore analysis was used to identify the important M2 protein-inhibitor interactions and common features of top binding compounds with M2 channel proteins. Finally, the two most potential compounds were determined as novel leads to inhibit M2 channel proteins in both H3N2 and 2009-H1N1 influenza A virus