Structural and Energetic Properties of Weak Noncovalent Interactions in Two Closely Related 3,6-Disubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole Derivatives: In Vitro Cyclooxygenase Activity, Crystallography, and Computational Investigations

Two 3,6-disubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives, namely, 3-(adamantan-1-yl)-6-(2-chloro-6-fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 1 and 6-(2-chloro-6-fluorophenyl)-3-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 2, were prepared, and the detailed analysis of the weak intermolecular interactions responsible for the supramolecular self-assembly was performed using X-ray diffraction and theoretical tools. Analyses of Hirshfeld surface and 2D fingerprint plot demonstrated the effect of adamant-1-yl/phenyl moieties on intermolecular interactions in solid-state structures. The effect of these substituents on H···H/Cl/N contacts was more specific. The CLP-PIXEL and density functional theory methods provide information on the energetics of molecular dimers observed in these compounds. The crystal structure of compound 1 stabilizes with a variety of weak intermolecular interactions, including C–H···N, C–H···π, and C–H···Cl hydrogen bonds, a directional C–S···π chalcogen bond, and unconventional short F···C/N contacts. The crystal structure of compound 2 is stabilized by π-stacking interactions, C–H···N, C–H···π, and C–H···Cl hydrogen bonds, and highly directional attractive σ–hole interactions such as the C–Cl···N halogen bond and the C–S···N chalcogen bond. In addition, S(lp)···C(π) and short N···N contacts play a supportive role in the stabilization of certain molecular dimers. The final supramolecular architectures resulting from the combination of different intermolecular interactions are observed in both the crystal packing. The molecular electrostatic potential map reveals complementary electrostatic potentials of the interacting atoms. The quantum theory of atoms in molecules approach was used to delineate the nature and strength of different intermolecular interactions present in different dimers of compounds 1 and 2. The in vitro experiments suggest that both compounds showed selectivity against COX-2 targets rather than COX-1. Molecular docking analysis showed the binding pose of the compounds at the active sites of COX-1/2 enzymes

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Acriflavine: an efficient green fluorescent probe for sensitive analysis of aceclofenac in pharmaceutical formulations

Abstract Acriflavine is a multipurpose drug that shows antibacterial, antiviral, antimalarial, and antifungal activities. The remarkable native fluorescence of acriflavine is exploited in analytical chemistry field as an efficient probe for analysis of pharmaceutical and biological compounds. The fluorescent probe action of acriflavine is based on the remarkable fluorescence turning-off via formation of ion-pair complexes with acidic drugs at a specific pH. Herein, the acidic drug aceclofenac is analysed for the first time using acriflavine as a fluorescent probe. Aceclofenac can form an ion-pair complex with acriflavine at pH 8.5, and hence it partially turns off the fluorescence intensity of acriflavine over a concentration range of 1–20 µg/mL. The fluorescence quenching was monitored at 502 nm following an excitation at 265 or 451 nm. The reaction stoichiometry between acriflavine and aceclofenac was found to be 1:1 using limiting logarithmic method. The type of quenching was confirmed to be static using Stern–Volmer plot. The method showed low values of quantitation limit (0.89 µg/mL) and detection limit (0.29 µg/mL). Moreover, the method was linear (r = 0.9999), accurate, precise (RSD < 1.7%), robust, and specific. The proposed method was successfully employed to analyse aceclofenac in its dosage forms with high %recovery (98–101%). Additionally, GAPI and AGREE approaches were used to guarantee the suggested techniques' greenness, and the findings showed an excellent level of greenness

Naringenin suppresses NLRP3 inflammasome activation via the mRNA-208a signaling pathway in isoproterenol-induced myocardial infarction

Objective: To investigate the cardioprotective effect of naringenin against isoproterenol (ISO)-induced cardiotoxicity in rats. Methods: Rats were divided into five groups: the normal group, the ISO group (85 mg/kg b.w.); the ISO+naringenin (50 mg/kg b.w.) group, the ISO+naringenin (100 mg/kg b.w.) group and the ISO+propranolol (10 mg/kg b.w.) group. Plasma creatine kinase-MB (CK-MB), cardiac troponin T, lactate dehydrogenase, brain natriuretic peptide (BNP), and IL-10, as well as cardiac transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF) and malondialdehyde (MDA) were examined. In addition, NLRP3 and mRNA-208a expressions were evaluated by RT-PCR analysis. Histopathological examination was also performed to assess cardiac damages. Results: Naringenin treatment significantly decreased plasma lactate dehydrogenase, CK-MB, cardiac troponin T, BNP, and IL-10, as well as cardiac TGF-β1, VEGF, and MDA while increasing p-Akt and superoxide dismutase in ISO-administered rats. It also reduced NLRP3 and mRNA-208a gene expression levels. Furthermore, naringenin improved ISO-induced cardiac damage. Conclusions: Naringenin attenuates myocardial dysfunction in ISO-treated rats by decreasing oxidative stress and increasing cardiac endogenous antioxidant system, which may be modulated partly by improvement of NLRP3 and mRNA-208a gene expression

Structural and Energetic Properties of Weak Noncovalent Interactions in Two Closely Related 3,6-Disubstituted-[1,2,4]triazolo[3,4‑<i>b</i>][1,3,4]thiadiazole Derivatives: In Vitro Cyclooxygenase Activity, Crystallography, and Computational Investigations

Two 3,6-disubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives, namely, 3-(adamantan-1-yl)-6-(2-chloro-6-fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 1 and 6-(2-chloro-6-fluorophenyl)-3-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 2, were prepared, and the detailed analysis of the weak intermolecular interactions responsible for the supramolecular self-assembly was performed using X-ray diffraction and theoretical tools. Analyses of Hirshfeld surface and 2D fingerprint plot demonstrated the effect of adamant-1-yl/phenyl moieties on intermolecular interactions in solid-state structures. The effect of these substituents on H···H/Cl/N contacts was more specific. The CLP-PIXEL and density functional theory methods provide information on the energetics of molecular dimers observed in these compounds. The crystal structure of compound 1 stabilizes with a variety of weak intermolecular interactions, including C–H···N, C–H···π, and C–H···Cl hydrogen bonds, a directional C–S···π chalcogen bond, and unconventional short F···C/N contacts. The crystal structure of compound 2 is stabilized by π-stacking interactions, C–H···N, C–H···π, and C–H···Cl hydrogen bonds, and highly directional attractive σ–hole interactions such as the C–Cl···N halogen bond and the C–S···N chalcogen bond. In addition, S(lp)···C(π) and short N···N contacts play a supportive role in the stabilization of certain molecular dimers. The final supramolecular architectures resulting from the combination of different intermolecular interactions are observed in both the crystal packing. The molecular electrostatic potential map reveals complementary electrostatic potentials of the interacting atoms. The quantum theory of atoms in molecules approach was used to delineate the nature and strength of different intermolecular interactions present in different dimers of compounds 1 and 2. The in vitro experiments suggest that both compounds showed selectivity against COX-2 targets rather than COX-1. Molecular docking analysis showed the binding pose of the compounds at the active sites of COX-1/2 enzymes

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