Novel quinoline incorporating 1,2,4-triazole/oxime hybrids: Synthesis, molecular docking, anti-inflammatory, COX inhibition, ulceroginicity and histopathological investigations

• Published in: Bioorganic chemistry Vol. 75; pp. 242 - 259
• Main Authors: Mohassab, Aliaa M., Hassan, Heba A., Abdelhamid, Dalia, Abdel-Aziz, Mohamed, Dalby, Kevin N., Kaoud, Tamer S.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.12.2017; Elsevier
• Subjects: Animals; Anti-inflammatory; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - therapeutic use; Anti-Inflammatory Agents - toxicity; Binding Sites; Biochemistry & Molecular Biology; Catalytic Domain; Chemistry; Chemistry, Organic; COX inhibition; Cyclooxygenase 1 - chemistry; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - pharmacology; Edema - chemically induced; Edema - drug therapy; Enzyme Activation - drug effects; Gastric Mucosa - drug effects; Gastric Mucosa - pathology; Histopathology; Inhibitory Concentration 50; Kinetics; Life Sciences & Biomedicine; Liver - drug effects; Liver - pathology; Molecular Docking Simulation; Nitric Oxide - metabolism; Oxime; Oximes - chemistry; Oximes - pharmacology; Physical Sciences; Quinoline; Quinolines - chemistry; Rats; Science & Technology; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology; Ulceroginicity; Quinoline; Oxime; Histopathology; Ulceroginicity; Anti-inflammatory; COX inhibition; SELECTIVE-INHIBITION; MYCOBACTERIUM-TUBERCULOSIS; DESIGN; IN-VITRO; DRUGS; NITRIC-OXIDE; BIOLOGICAL EVALUATION; ANTIFUNGAL AGENTS; ANTIMALARIAL ACTIVITY; DERIVATIVES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2017.09.018

Compound 7c exhibited the best binding with COX-1 active site with energy score −12.20 and least biding with COX-2 active site and emphasize the idea of being more selective towards COX-1. Compound 7c showed IC50 of 1.0 on COX-1 and no inhibition on COX-2 enzyme. [Display omitted] •Synthesis of new 1,2,4-triazole/quinoline nitric oxide hybrids.•Investigation of nitric oxide release.•Biological evaluation including anti-inflammatory activity, histopathological investigation, and ulcerogenic liability.•Investigating possible mechanism of action through in vitro COX inhibition assays and enzyme kinetic studies.•Docking studies on the empty active site of COX-1 and COX-2 enzymes. A series of novel quinolines incorporating 1,2,4-triazole/oxime hybrids were prepared. They showed remarkable anti-inflammatory activity and exhibited very low incidence of gastric ulceration, compared to indomethacin. Most of the compounds tested showed remarkable inhibition of the COX-1 isozyme, with IC50’s ranging from 0.48 to 28µM. Compounds 7c and 9g showed high safety profiles with normal stomach tissue integrity. Docking studies supported the observed in vitro inhibitory activity towards the COX enzymes that may explain their promising anti-inflammatory activity relative to indomethacin. Moreover, differences between the COX-1 and COX-2 isozymes in observed energy scores, as well as in the number of interactions with some of the compounds tested, might predict their higher selectivity towards COX-1 rather than COX-2. Compound 9e was found to inhibit both COXs non-competitively with Ki values of 81µM and 94.6µM.