New 1,2,4-triazole/pyrazole hybrids linked to oxime moiety as nitric oxide donor celecoxib analogs: Synthesis, cyclooxygenase inhibition anti-inflammatory, ulcerogenicity, anti-proliferative activities, apoptosis, molecular modeling and nitric oxide release studies

• Published in: Bioorganic chemistry 2020-05, Vol.98, p.103752, Article 103752
• Main Authors: Fadaly, Wael A.A., Elshaier, Yaseen A.M.M., Hassanein, Emad H.M., Abdellatif, Khaled R.A.
• Format: Article
• Language: English
• Subjects: 1,2,4-Triazole; Animals; Anti-cancer; Anti-inflammatory; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Celecoxib - chemical synthesis; Celecoxib - chemistry; Celecoxib - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2 inhibitors; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Gene expression; Humans; Male; Models, Molecular; Molecular docking; Molecular Structure; Nitric Oxide - metabolism; Nitric oxide donor; Oximes - chemistry; Oximes - pharmacology; PC-3 Cells; Pyrazole; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rats; Rats, Wistar; Stomach Ulcer - drug therapy; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology; Ulcerogenicity
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103752

[Display omitted] •Two new series of hybrid structures 16a-f and 19a-f containing 1,2,4-triazole and pyrazole were synthesized.•16a-f and 19a-f showed good in vitro COX-2 selectivity and in vivo anti-inflammatory activities.•16a-f and 19a-f showed good activities against A-549, MCF-7, HCT-116 and PC-3 cell lines.•Compounds 19b and 19e arrested cell cycle and were good inhibitor for p38MAPK and VEGFR-2. Two new series of hybrid structures 16a-f and 19a-f containing 1,2,4-triazole moiety, pyrazole core with COX-2 pharmacophore and oxime as NO donor moiety were designed, synthesized and evaluated for anti-inflammatory, cytotoxic activities and NO release. All compounds were more selective for COX-2 isozyme especially the sulphamoyl derivatives (16b, 16e, 19b and 19e) had COX-2 selectivity indexes (S.I. = 9.78, 8.57, 10.78 and 10.47 respectively) in comparison to celecoxib (S.I. = 8.68). Similarly, 16b, 16e, 19b and 19e were the most potent anti-inflammatory derivatives with ED50 = 46.98–54.45 μmol/kg better than celecoxib (ED50 = 76.09 μmol/kg). Also, 16b, 16e, 19b and 19e were significantly less ulcerogenic (ulcer indexes = 2.79–3.95) upon comparison with ibuprofen (ulcer index = 20.25) and comparable with celecoxib (ulcer index = 2.93). Regarding anti-cancer activity, most of the target derivatives 16a-f and 19a-f showed good activities against A-549, MCF-7, HCT-116 and PC-3 cancer cell lines. Additionally, these derivatives examined against F180 fibroblasts to investigate their selectivity indexes. The sulphamoyl derivatives with internal oxime 19b and 19e were the most potent derivatives against all used cell lines especially PC-3 (IC50 = 1.48 and 0.33 µM respectively) with 11.75 and 39.4-fold respectively selectivity towards PC-3 than F180 fibroblasts. The mechanistic investigation of 19b and 19e revealed that both compounds arrested cell cycle at G2/M phase by 32.16 and 39.95 folds, up-regulated Bax expression by 6.83 and 14.52 folds and down-regulated the expression of the gene Bcl-2 by 0.57 and 0.36fold respectively. Also, 19b and 19e were good inhibitor for p38MAPK (0.65 for 19b and 0.58 for 19e) and VEGFR-2 (0.39 for 19b and 0.54 for 19e) in comparison with PC-3 control cell. All compounds 16a-f and 19a-f released NO in a slow rate (0.15–3.17%) and the four sulphamoyl derivatives 16b, 16e, 19b and 19e were the most NO releasers (3.06, 2.15, 3.17 and 2.54% respectively). Docking studies were carried out to explain the interaction of 16a-f and 19a-f w