Anti-inflammatory effect of 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole derivatives as p38α inhibitors.

In the present work, the anti-inflammatory effect of 30 compounds containing 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole was investigated. All final target compounds showed significant Inhibitory effect on p38α. P38α is considered one of the key kinases in the inflammatory process due to its regulatory effect on pro-inflammatory mediators. The final target compounds divided into four group based on the type of terminal moiety (amide and sulfonamide) and the linker between pyrimidine ring and terminal moiety (ethyl and propyl). Most compounds with terminal sulfonamide moiety and propyl linker between the sulfonamide and pyrimidine ring were the most potent among all synthesized final target compounds with sub-micromolar IC50s. Compound 24g (with p-Cl benzene sulfonamide and propyl linker) exhibited the highest activity over P38α with IC50 0.68 µM. All final target compounds were tested for their ability to inhibit nitric oxide release and prostaglandin E2 production. Compounds having amide terminal moiety with ethyl linker showed higher inhibitory activity for nitric oxide release and compound 21d exhibited the highest activity for nitric oxide release with IC50 1.21 µM. Compounds with terminal sulfonamide moiety and propyl linker showed the highest activity for inhibiting PGE2 production and compounds 24i and 24g had the lowest IC50s with value 0.87 and 0.89 µM, respectively. Compounds 21d, 22d and 24g were tested for their ability to inhibit over expression of iNOS, COX1, and COX2. In addition the ability of compounds 21d, 22d and 24g to inhibit inflammatory cytokines were determined. Finally molecular docking of the three compounds were performed on P38α crystal structure to expect their mode of binding.

Design, synthesis, and biological investigation of oxadiazolyl, thiadiazolyl, and pyrimidinyl linked antipyrine derivatives as potential non-acidic anti-inflammatory agents.

A novel series of 12 antipyrine derivatives containing 1,3,4-oxadiazoles (4a-d), 1,3,4-thiadiazoles (6a-d), and pyrimidines (8a-d), was preparedand assessed for its potential in vitro COX-2 inhibitors. Compared to Celecoxib, compounds 4b-d and 8d were the most potent derivatives c with a half-maximal inhibitory concentration range of 53-69 nM. Considering COX-2 selectivity index, compounds 4 b and 4c were chosen among these most potent derivatives for further investigation. The in vivo ability of compounds 4 b and 4c to counteract carrageenan-induced paw edoema has been assessed and their potential underlying mechanisms have been elucidated and the results have been further validated using molecular docking simulations.

Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights.

This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications.

New benzothiazole hybrids as potential VEGFR-2 inhibitors: design, synthesis, anticancer evaluation, and in silico study.

A new series of 2-aminobenzothiazole hybrids linked to thiazolidine-2,4-dione 4a-e, 1,3,4-thiadiazole aryl urea 6a-d, and cyanothiouracil moieties 8a-d was synthesised. The in vitro antitumor effect of the new hybrids was assessed against three cancer cell lines, namely, HCT-116, HEPG-2, and MCF-7 using Sorafenib (SOR) as a standard drug. Among the tested compounds, 4a was the most potent showing IC50 of 5.61, 7.92, and 3.84 µM, respectively. Furthermore, compounds 4e and 8a proved to have strong impact on breast cancer cell line with IC50 of 6.11 and 10.86 µM, respectively. The three compounds showed a good safety profile towards normal WI-38 cells. Flow cytometric analysis of the three compounds in MCF-7 cells revealed that compounds 4a and 4c inhibited cell population in the S phase, whereas 8a inhibited the population in the G1/S phase. The most promising compounds were subjected to a VEGFR-2 inhibitory assay where 4a emerged as the best active inhibitor of VEGFR-2 with IC50 91 nM, compared to 53 nM for SOR. In silico analysis showed that the three new hybrids succeeded to link to the active site like the co-crystallized inhibitor SOR.

X-ray Structures and Computational Studies of Two Bioactive 2-(Adamantane-1-carbonyl)-N-substituted Hydrazine-1-carbothioamides.

Two biologically active adamantane-linked hydrazine-1-carbothioamide derivatives, namely 2-(adamantane-1-carbonyl)-N-(tert-butyl)hydrazine-1-carbothioamide) 1 and 2-(adamantane-1-carbonyl)-N-cyclohexylhydrazine-1-carbothioamide 2, have been synthesized. X-ray analysis was conducted to study the effect of the t-butyl and cyclohexyl moieties on the intermolecular interactions and conformation of the molecules in the solid state. X-ray analysis reveals that compound 1 exhibits folded conformation, whereas compound 2 adopts extended conformation. The Hirshfeld surface analysis indicates that the contributions of the major intercontacts involved in the stabilization of the crystal structures do not change much as a result of the t-butyl and cyclohexyl moieties. However, the presence and absence of these contacts is revealed by the 2D-fingerprint plots. The CLP-Pixel method was used to identify the energetically significant molecular dimers. These dimers are stabilized by different types of intermolecular interactions such as N-H···S, N-H···O, C-H···S, C-H···O, H-H bonding and C-H···π interactions. The strength of these interactions was quantified by using the QTAIM approach. The results suggest that N-H···O interaction is found to be stronger among other interactions. The in vitro assay suggests that both compounds 1 and 2 exhibit urease inhibition potential, and these compounds also display moderate antiproliferative activities. Molecular docking analysis shows the key interaction between urease enzyme and title compounds.

Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11ß-HSD1 Molecular Docking and ADMET Prediction.

Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N-Mannich bases (1-3) are presented. Compounds 1, 2 and 3 crystallized in the monoclinic P21/c, P21 and P21/n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H⋯O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-H⋯N, C-H⋯S and C-H⋯π interactions. The energy frameworks for crystal structures of 1-3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1-3 were determined using in silico techniques. Molecular docking of the compounds into the 11ß-HSD1 active site showed comparable binding affinity scores (-7.50 to -8.92 kcal/mol) to the 11ß-HSD1 co-crystallized ligand 4YQ (-8.48 kcal/mol, 11ß-HSD1 IC50 = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential.

Design, Synthesis and Anticancer Profile of New 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine-Linked Sulfonamide Derivatives with V600EBRAF Inhibitory Effect.

A new series of 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine linked sulfonamide derivatives 12a-n was designed and synthesized according to the structure of well-established V600EBRAF inhibitors. The terminal sulfonamide moiety was linked to the pyrimidine ring via either ethylamine or propylamine bridge. The designed series was tested at fixed concentration (1 µM) against V600EBRAF, finding that 12e, 12i and 12l exhibited the strongest inhibitory activity among all target compounds and 12l had the lowest IC50 of 0.49 µM. They were further screened on NCI 60 cancer cell lines to reveal that 12e showed the most significant growth inhibition against multiple cancer cell lines. Therefore, cell cycle analysis of 12e was conducted to investigate the effect on cell cycle progression. Finally, virtual docking studies was performed to gain insights for the plausible binding modes of vemurafenib, 12i, 12e and 12l.

1,3,4-Oxadiazole N-Mannich Bases: Synthesis, Antimicrobial, and Anti-Proliferative Activities.

The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a-l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a-d, respectively. The in vitro inhibitory activity of compounds 4a-l and 5a-d was assessed against pathogenic Gram-positive, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. The piperazinomethyl derivatives 5c and 5d displayed broad-spectrum antibacterial activities the minimal inhibitory concentration (MIC) 0.5-8 µg/mL) and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. In addition, the anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. The optimum anti-proliferative activity was attained by compounds 4l, 5a, 5c, and 5d.

A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation.

Interleukin (IL)-6 is an important regulator of immunity and inflammation in many diseases. Single nucleotide polymorphisms (SNPs) in the IL-6 gene influence outcome after allogeneic stem cell transplantation (ASCT), but the possible importance of SNPs in the IL-6 receptor has not been examined. We therefore investigated whether SNPs in the IL-6R gene influenced biochemical characteristics and clinical outcomes after ASCT. We examined the IL-6 promoter variant rs1800975 and the IL-6R SNPs rs4453032, rs2228145, rs4129267, rs4845374, rs4329505, rs4845617, rs12083537, rs4845618, rs6698040 and rs4379670 in a 101 population-based cohort of allotransplant recipients and their family donors. Patients being homozygous for the major alleles of the IL-6R SNPs rs2228145 and rs4845618 showed high pretransplant CRP serum levels together with decreased sIL-6R levels; the decreased IL-6R levels persisted 6 months post-transplant. In contrast, patients being homozygous for the minor allele of the IL-6R SNP rs4379670 showed decreased pretransplant CRP levels. Furthermore, the IL-6R rs4845618 donor genotype showed an association with severe acute graft-versus-host disease (GVHD), whereas the donor genotype of the IL-6 SNP rs1800795 was associated with decreased survival 100 days post-transplant. Finally, the recipient genotype of the IL-6R SNP rs4329505 showed a strong association with 2-years non-relapse mortality, and this effect was also highly significant in multivariate analysis. IL-6 and IL-6R SNPs influence the clinical outcome after allogeneic stem cell transplantation.

PREVALENCE OF FOVEOLAR LUCENCY WITH DIFFERENT GAS TAMPONADES IN SURGICALLY CLOSED MACULAR HOLES ASSESSED BY SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To evaluate the prevalence of foveolar lucency (FL) in surgically closed macular holes by spectral domain optical coherence tomography. METHODS: One hundred forty-two eyes of 132 patients underwent pars plana vitrectomy, internal limiting membrane peeling, and gas tamponade in a 60-month time frame. Anatomical success and FL rates assessed by spectral domain optical coherence tomography, mean preoperative, and postoperative best-measured visual acuity and surgical details were retrospectively analyzed. RESULTS: Spectral domain optical coherence tomography confirmed closed holes with FL in 33.7% (34/101) of eyes at 1 month, 7.3% (9/123) at 3 months, 4.6% (6/129) at 6 months, and 3% (4/133) at 12 months. Prevalence of FL in closed holes at Month 1 was lower in C3F8-treated eyes (9.5%, 2/21) compared with C2F6 (40.9%, 18/44, P = 0.03) and SF6-treated eyes (38.9%, 14/36, P = 0.05). No differences were observed at Month 3. No differences in best-measured visual acuity change were observed between closed holes with or without FL at Month 1 (-0.14 ± 0.19 vs. -0.11 ± 0.23, P = 0.48) or any of the other time points. CONCLUSION: Temporary FL is a highly prevalent feature in successfully closed macular holes. Eyes treated with C3F8 gas had lower rates of FL at Month 1 than C2F6 and SF6-treated eyes. The presence of FL in closed holes does not seem to have any effect on the visual outcomes.

International consensus statement on the peri-operative management of direct oral anticoagulants in cardiac surgery.

Despite current recommendations on the management of severe peri-operative bleeding, there is no pragmatic guidance for the peri-operative monitoring and management of cardiac surgical patients taking direct oral anticoagulants. Members of the Transfusion and Haemostasis Subcommittee of the European Association of Cardiothoracic Anaesthesiology, of their own volition, performed an independent systematic review of peer-reviewed original research, review articles and case reports and developed the following consensus statement. This has been endorsed by the European Association of Cardiothoracic Anaesthesiology. In our opinion, most patients on direct oral anticoagulant therapy presenting for elective cardiac surgery can be safely managed in the peri-operative period if the following conditions are fulfilled: direct oral anticoagulants have been discontinued two days before cardiac surgery, corresponding to five elimination half-live periods; in patients with renal or hepatic impairment or a high risk of bleeding, a pre-operative plasma level of direct oral anticoagulants has been determined and found to be below 30 ng.ml-1 (currently only valid for dabigatran, rivaroxaban and apixaban). In cases where plasma level monitoring is not possible (e.g. assay was not available), discontinuation for 10 elimination half-live periods (four days) is required. For FXa inhibitors, a standard heparin-calibrated anti-Xa level of < 0.1 IU.ml-1 should be measured, indicating sufficient reduction in the anticoagulant effect. Finally, short-term bridging with heparin is not required in the pre-operative period.

Toxicological and hematological effect of Terminalia arjuna bark extract on a freshwater catfish, Heteropneustes fossilis.

Increasing demand for eco-friendly botanical piscicides and pesticides as replacements for harmful synthetic chemicals has led to investigation of new sources of plant materials. Stem bark of Terminalia arjuna, which has been used as a popular folk medicine since ancient time, was examined for its piscicidal activity. This study aims to determine toxicity of ethanol extract of T. arjuna bark on fresh water stinging catfish (Heteropneustes fossilis), along with evaluation of changes in hematological parameters of the fishes exposed to a lethal concentration. The percent mortality of fishes varied significantly in response to concentrations of the extract and exposure times (between exposure time F = 36.57, p < 0.001; between concentrations F = 39.93, p < 0.001). The lethal concentrations (LC50) of ethanol extract were found to be 12.7, 8.94, 5.63 and 4.71 mg/l for 24, 48, 72 and 96 h, respectively. During acute toxicity test, blood samples of treatment fishes showed significant decreases in the red blood cells count, hematocrit content, hemoglobin concentration, mean corpuscular hemoglobin concentration and plasma protein level when compared to those of the control group, while there were significant increases in the mean corpuscular volume, mean corpuscular hemoglobin, white blood cells count and plasma glucose concentration. These results suggest that T. arjuna bark extract could be considered as a potent piscicide due to its toxic effect on fish, particularly fish hematology.

Development of Olive Oil Containing Phytosomal Nanocomplex for Improving Skin Delivery of Quercetin: Formulation Design Optimization, In Vitro and Ex Vivo Appraisals.

The objective of the current work was to fabricate, optimize and assess olive oil/phytosomal nanocarriers to improve quercetin skin delivery. Olive oil/phytosomal nanocarriers, prepared by a solvent evaporation/anti-solvent precipitation technique, were optimized using a Box-Behnken design, and the optimized formulation was appraised for in vitro physicochemical characteristics and stability. The optimized formulation was assessed for skin permeation and histological alterations. The optimized formulation (with an olive oil/PC ratio of 0.166, a QC/PC ratio of 1.95 and a surfactant concentration of 1.6%), and with a particle diameter of 206.7 nm, a zeta potential of -26.3 and an encapsulation efficiency of 85.3%, was selected using a Box-Behnken design. The optimized formulation showed better stability at ambient temperature when compared to refrigerating temperature (4 °C). The optimized formulation showed significantly higher skin permeation of quercetin when compared to an olive-oil/surfactant-free formulation and the control (~1.3-fold and 1.9-fold, respectively). It also showed alteration to skin barriers without remarkable toxicity aspects. Conclusively, this study demonstrated the use of olive oil/phytosomal nanocarriers as potential carriers for quercetin-a natural bioactive agent-to improve its skin delivery.

Rome III subgroups of functional dyspepsia exhibit different characteristics of antral contractions measured by strain rate imaging - a pilot study.

PURPOSE: Rome III defines two distinct entities of functional dyspepsia (FD), namely epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). We aimed at studying these subgroups of FD by simultaneously assessing antral strain, gastric accommodation and emptying and visceral hypersensitivity. MATERIALS AND METHODS: Strain during antral contractions was assessed by ultrasound strain rate imaging in 15 controls and 19 FD patients (8 EPS patients and 11 PDS patients). Gastric accommodation and emptying were assessed using B-mode ultrasonography. Symptoms were assessed by visual analogue scale (VAS). RESULTS: During fasting, antral strain in EPS patients (mean±SEM) was 61.4 ±â€Š6.4 %, significantly higher than in controls (47.5 ±â€Š3.3 %; p = 0.042) and in PDS patients (28.6 ±â€Š1.7 %; p = 0.001). PDS patients had lower strain than controls (p < 0.001). Postprandially, EPS patients had higher strain than both controls and PDS patients (p < 0.01) but no difference was found between controls and PDS patients. Compared with controls, PDS patients had significantly larger fasting proximal area than controls (14.9 ±â€Š1.6 cm2 vs. 7.8 ±â€Š0.2 cm2; p < 0.001), whereas EPS patients did not differ (12.1 ±â€Š1.9 cm2; p = 0.057). Gastric emptying fraction (1 - proximal area at 40 min postprandially/area at 1 min postprandial × 100) at 40 min postprandially in EPS patients 46.4 ±â€Š6.6 % was lower than in controls (62.9 ±â€Š1.3 %; p = 0.032), but higher than PDS patients (27.4 ±â€Š5.3 %; p = 0.018). CONCLUSION: Anterior radial strain measured by ultrasound strain rate imaging may discriminate between subgroups of FD and healthy controls. This study supports the Rome III classification of FD into EPS and PDS groups.

Polycystic Ovary Syndrome: An Updated Overview Foregrounding Impacts of Ethnicities and Geographic Variations.

Polycystic ovary syndrome (PCOS) is one of the most common heterogeneous conditions of the endocrine reproductive system in women of childbearing age. Hyperandrogenism and oligomenorrhea are the two core characteristics of PCOS, a complicated and multifaceted illness. The condition is also linked to several major side effects, which include type 2 diabetes, early atherosclerosis, infertility, and endometrial cancer. There are few facts and statistics available on PCOS prevalence internationally due to the significant degree of geographic and ethnic variance and inconsistency caused by different diagnosis standards. Limited (n = 179) explorations have been made in the context of the prevalence of this complicated illness so far, and out of these, only 55 studies have discussed its association with race and/or ethnicity. However, those studies remain restricted due to the small sample size, biased selection, and the lack of comparative studies. Variations in PCOS prevalence frequency also arise due to different diagnostic criteria, as well as racial and ethnic differences, associated lifestyle factors, and subsequent illnesses that affect the accuracy of the diagnosis. The main objective behind this systematic review is to provide comprehensive epidemiological data on PCOS that is organized geographically. This evidence-based study also provides an overview of the clinical management of PCOS to instigate further research on this complex endocrinological condition and the subsequent development of preventive treatment strategies.

Combination of ligand and structure based virtual screening approaches for the discovery of potential PARP1 inhibitors.

Poly (ADP-ribose) polymerase 1 (PARP1) has high therapeutic value as biomolecular target for research and development of small molecules with antineoplastic activity, since it is upregulated in many cancers, especially in ovarian and BRCA 1/2 mutated breast cancers. Decades of investigation of PARP inhibitors (PARPi) have led to the approval of several drug compounds, however clinical application of PARPi in cancer therapy is limited due to a number of factors, including low selectivity, weak affinity and undesired side effects. Thus, identification of novel drug-like chemical compounds with alternatives to the known PARPi chemical scaffolds, binding modes and interaction patterns with amino acid residues in the active site is of high therapeutic importance. In this study we applied a combination of ligand- and structure-based virtual screening approaches with the goal of identification of novel potential PARPi.

Phenylboronic Acid-Grafted Chitosan Nanocapsules for Effective Delivery and Controllable Release of Natural Antioxidants: Olive Oil and Hydroxytyrosol.

Olives and virgin olive oil (VOO) are a staple of Mediterranean diets and are rich in several beneficial phenolic compounds, including hydroxytyrosol (HT). Therefore, VOO was extracted from Koroneiki olive fruits, and its volatile as well as phenolic components were identified. Meanwhile, in order to upgrade the pharmaceutical capabilities of VOO and HT, a new conjugate phenylboronic acid-chitosan nanoparticles (PBA-CSNPs, NF-1) was fabricated and applied as nanocapsules for implanting high loading and efficient delivery of VOO and HT nanoformulations (NF-2 and NF-3). Due to the H-bonding interactions and boronate ester formation between the hydroxyl groups of the phenolic content of VOO or HT and the PBA groups in the nanocapsules (NF-1), VOO and HT were successfully loaded into the PBA-CSNPs nanocapsules with high loading contents and encapsulation efficacies. The NF-2 and NF-3 nanoformulations demonstrated physicochemical stability, as revealed by their respective zeta potential values, and pH-triggered drug release characteristics. The in vitro studies demonstrated that the nascent nanocapsules were almost completely nontoxic to both healthy and cancer cells, whereas VOO-loaded (NF-2) and HT-loaded nanocapsules (NF-3) showed efficient anti-breast cancer efficiencies. In addition, the antimicrobial and antioxidant potentials of VOO and HT were significantly improved after nanoencapsulation.

Identification of Novel Potential VEGFR-2 Inhibitors Using a Combination of Computational Methods for Drug Discovery.

The vascular endothelial growth factor receptor 2 (VEGFR-2) is largely recognized as a potent therapeutic molecular target for the development of angiogenesis-related tumor treatment. Tumor growth, metastasis and multidrug resistance highly depends on the angiogenesis and drug discovery of the potential small molecules targeting VEGFR-2, with the potential anti-angiogenic activity being of high interest to anti-cancer research. Multiple small molecule inhibitors of the VEGFR-2 are approved for the treatment of different type of cancers, with one of the most recent, tivozanib, being approved by the FDA for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC). However, the endogenous and acquired resistance of the protein, toxicity of compounds and wide range of side effects still remain critical issues, which lead to the short-term clinical effects and failure of antiangiogenic drugs. We applied a combination of computational methods and approaches for drug design and discovery with the goal of finding novel, potential and small molecule inhibitors of VEGFR2, as alternatives to the known inhibitors' chemical scaffolds and components. From studying several of these compounds, the derivatives of pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione in particular were identified.

Supramolecular Self-Assembly Built by Weak Hydrogen, Chalcogen, and Unorthodox Nonbonded Motifs in 4-(4-Chlorophenyl)-3-[(4-fluorobenzyl)sulfanyl]-5-(thiophen-2-yl)-4H-1,2,4-triazole, a Selective COX-2 Inhibitor: Insights from X-ray and Theoretical Studies.

A selective triazole-based COX-2 inhibitor, 4-(4-chlorophenyl)-3-[(4-fluorobenzyl)sulfanyl]-5-(thiophen-2-yl)-4H-1,2,4-triazole, C19H13ClFN3S2, has been synthesized, and its crystal structure was determined at 150 K. Single-crystal X-ray diffraction analysis revealed that the thiophene ring was disordered over two orientations. The crystal structure is stabilized by weak hydrogen and chalcogen bonds and unorthodox F···π and S···C(π) contacts. These noncovalent interactions cooperatively generate the supramolecular self-assembly in the crystalline state. The Hirshfeld surface and its associated two-dimensional (2D)-fingerprint plots were obtained to analyze the role of different noncovalent interactions in the crystal packing. Further, the enrichment ratio was obtained from different atom···atom pairs to calculate the propensity of these pairs to form noncovalent interactions. The strength of different dimeric motifs formed in the crystal structure and lattice energies was calculated by the PIXEL method. Furthermore, the topological analysis of the charge density of intermolecular interactions was described. A CSD survey of C-H···F hydrogen bond, C-S···Cl chalcogen bond, and unorthodox nonbonded contacts (F···π and S···C(π)) is presented. The title compound possesses selective inhibitory activity against human COX-2 enzyme rather than COX-1. The quantum mechanics (QM) polarized ligand docking analysis was used to predict the binding pose and study the title compound's selectivity against COX-1/2 enzymes.