Design, Synthesis and Biological Evaluation of New 5,5-Diarylhydantoin Derivatives as Selective Cyclooxygenase-2 Inhibitors

A new group of 5,5-diarylhydantoin derivatives bearing a methylsulfonyl COX-2 pharmacophore at the para position of the C-5 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 inhibition structure-activity relationships identified 5-[4-(methylsulfonyl)phenyl]-5-phenyl-hydantoin (4) as a highly potent and selective COX-2 inhibitor (COX-2 IC50 = 0.077 μM; selectivity index > 1298). It was more selective than the reference drug celecoxib (COX-2 IC50 = 0.060 μM; selectivity index = 405). A molecular modeling study where 4 was docked in the binding site of COX-2 indicated that the p-MeSO2 COX-2 pharmacophore group on the C-5 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket. The results of this study showed that the type of substituent on the N-3 hydantoin ring substituent is important for COX-2 inhibitory activity

Design, synthesis and biological evaluation of novel coumarin-based benzamides as potent histone deacetylase inhibitors and anticancer agents

Histone deacetylases (HDACs) are attractive therapeutic targets for the treatment of cancer and other diseases. It has four classes (I-IV), among them especially class I isozyme are involved in promoting tumor cells proliferation, angiogenesis, differentiation, invasion and metastasis and also viable targets for cancer therapeutics. A novel series of coumarin-based benzamides was designed and synthesized as HDAC inhibitors. The cytotoxic activity of the synthesized compounds (8a-u) was evaluated against six human cancer cell lines including HCT116, A2780, MCF7, PC3, HL60 and A549 and a single normal cell line (Huvec). We evaluated their inhibitory activities against pan HDAC and HDAC1 isoform. Four compounds (8f, 8q, 8r and 8u) showed significant cytotoxicity with IC50 in the range of 0.53–57.59 μM on cancer cells and potent pan-HDAC inhibitory activity (consists of HDAC isoenzymes) (IC50 = 0.80–14.81 μM) and HDAC1 inhibitory activity (IC50 = 0.47–0.87 μM and also, had no effect on Huvec (human normal cell line) viability (IC50 > 100 μM). Among them, 8u displayed a higher potency for HDAC1 inhibition with IC50 value of 0.47 ± 0.02 μM near equal to the reference drug Entinostat (IC50 = 0.41 ± 0.06 μM). Molecular docking studies and Molecular dynamics simulation of compound 8a displayed possible mode of interaction between this compound and HDAC1enzym

Pharmacological effects of a synthetic quinoline, a hybrid of tomoxiprole and naproxen, against acute pain and inflammation in mice: a behavioral and docking study

Objective(s): In the present study, we investigated the potential anti-nociceptive activity and acute anti-inflammatory effect of a synthetic quinoline compound (2-(4-Methoxyphenyl)benzo[h]quinoline-4-carboxylic acid, QC), possessing structural elements of both naproxen and tomoxiprole drugs. Materials and Methods: The anti-nociceptive activity of QC was evaluated using chemical- and thermal-induced nociception models and its acute anti-inflammatory effect was evaluated by xylene-induced ear edema test in mice. Results: QC displayed a dose dependent effect in both acute anti-nociceptive tests (writhing and hot plate). This compound at dose of 6.562 mg/kg showed a high anti-nociceptive effect near equal to  diclofenac 5 mg/kg. It also showed high anti-inflammatory effects (less than 6.562 mg/kg) comparable to those of reference drugs diclofenac (5 mg/kg) and celecoxib (100 mg/kg). Docking study showed that this quinoline derivative could inhibit COX-2 enzyme strongly. Conclusion: QC showed high anti-nociceptive and anti-inflammatory effects comparable to reference drugs and can exert its anti-nociceptive and anti-inflammatory activities through COX-2 inhibition

Exploring the Challenges of Prehospital Emergency Personnel in COVID-19 Pandemic: A qualitative study

Objectives: To explore the challenges and experiences of Prehospital Emergency Personnel in the context of the COVID-19 pandemic in Iran. Design: Qualitative study Setting: Prehospital Emergency Medical Services (EMS), Iran. Participants: 15 Prehospital Emergency personnel were invited to participate. Semi-structured in-depth interviews were conducted between Januarys to March 2021. Results: Themes relating to challenges of Prehospital Emergency Personnel in COVID – 19 were: Lack of preparedness of EMS for the pandemic, shortage of Personal Protective Equipment (PPE), psychological distress and negative emotions, shortage of staff and challenges associated with delivering care for patients using PPE. Conclusions: The current study found that Health Care Workers (HCWs) in the prehospital emergency field had multiple challenges in caring for their patients during COVID-19. Therefore, they are vulnerable in this situation. These challenges must be addressed in order to protect them in pandemics

Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitors

Objective(s): In the present study,a new series of 6-methoxy-2-arylquinoline analogues was designed and synthesized as P-glycoprotein (P-gp) inhibitors using quinine and flavones as the lead compounds. Materials and Methods: The cytotoxic activity of the synthesized compounds was evaluated against two human cancer cell lines including EPG85-257RDB, multidrug-resistant gastric carcinoma cells (P-gp-positive gastric carcinoma cell line), and EPG85-257P, drug-sensitive gastric carcinoma cells. Compounds showing low to moderate toxicity in the MTT test were selected to investigate their P-gp inhibition activity. Moreover, trying to explain the results of biological experiments, docking studies of the selected compounds into the homology-modeled human P-gp, were carried out. The physicochemical and ADME properties of the compounds as drug candidate were also predicted. Results: Most of our compounds exhibited negligible or much lower cytotoxic effect in both cancer cells. Among the series, 5a and 5b, alcoholic quinoline derivatives were found to inhibit the efflux of rhodamine 123 at the concentration of 10 μM significantly. Conclusion: Among the tested quinolines, 5a and 5b showed the most potent P-gp inhibitory activity in the series and were 1.3-fold and 2.1-fold stronger than verapamil, respectively. SAR data revealed that hydroxyl methyl in position 4 of quinolines has a key role in P-gp efflux inhibition of our compounds. ADME studies suggested that all of the compounds included in this study may have a good human intestinal absorption

Anticancer activity of two novel quinoline compounds on human gastric cancer cells

Background and Objective: Increasing interest has been devoted to the design and discovery of more effective anticancer agents in current medicinal chemistry because of the high prevalence of cancer in different societies and resistance occurrence to existing anticancer drugs. The aim of this study was to evaluate the anticancer activity of two novel quinoline compounds (RQ1 and RQ2) on human gastric cancer cells. Methods: In this descriptive - analytic study, the anticancer effects of the compounds were evaluated by MTT assay. This test was performed on two categories of gastric cancer cells sensitive to Danorubicin (EPG85-257P) and resistant to Danorubicin (EPG85-257RDB). The arresting mechanism in the G2 / M phase of the cell cycle and the induction of apoptosis by the compounds was investigated using the PI test and flow cytometric analysis. Results: Novel quinoline derivatives RQ1 and RQ2 showed good anticancer effects on both sensitive and resistant human gastric cancer cells (IC50=25-38mM). Compound RQ2 showed the most cytotoxic activity on the Danorubicin-sensitive cancer cell line with IC50=25mM. The percentage of Danorubicin resistant gastric cancer cells (EPG85-257RDB) in the G2 / M phase at 25mm concentration of RQ1 and RQ2 was 35.95 and 34.88, respectively, and 41.1% and 42.89% of these cells, after treatment with 50mm concentration of RQ1 and RQ2 arrested at the G2 / M phase respectively. Conclusion: The two novel quinoline compounds, RQ1 and RQ2 showed strong anticancer effect on both sensitive and resistant human gastric cancer cell lines

SYNTHESIS AND BIOLOGICAL EVALUATION OF SPIRO[INDOLINE-3,4'-PYRANO[2,3- C

Sulfonic acid functionalized SBA-15 nanoporous material (SBA-Pr-SO3H) with a large pore size of 6 nm, a high surface area, high selectivity, and excellent chemical and thermal stability was applied as an efficient heterogeneous nanoporous acid catalyst in the reaction of isatin with pyrazolones under mild reaction conditions. A novel class of symmetrical spiro[indoline-3,4'-pyrano[2,3-c:6,5-c']dipyrazol]-2-one derivatives was successfully obtained in high yields. Comparison of these results with those reported in the literature shows that the current method is efficient, and results in better reaction times and yields of the desired products. Other advantages of this new method are its operational simplicity, easy work-up procedure, and the use of SBA-Pr-SO3H as a reusable and environmentally benign nanoreactor, such that the reaction proceeds easily in its nanopores. We also tested the antimicrobial activity of the prepared compounds using the disc diffusion method, and some of the synthesized compounds exhibited the best results against B. subtilis and S. aureus