title: Synthesis, docking simulation, biological evaluations and 3D-QSAR study of 5-Aryl-6-(4-methylsulfonyl)-3-(metylthio)-1,2,4-triazine as selective cyclooxygenase-2 inhibitors.
abstract: A series of 5-Aryl-6-(4-methylsulfonyl)-3-(metylthio)-1,2,4-triazine derivatives were synthesized and their COX-1/COX-2 inhibitory activity as well as in vivo anti-inflammatory and analgesic effects were evaluated. All of compounds showed strong inhibition of COX-2 with IC50 values in the range of 0.1-0.2μM and in most cases had stronger anti-inflammatory and analgesic effects than indomethacin at doses 3 and 6mg/kg. Among them, 5-(4-chlorophenyl)-6-(4-(methylsulfonyl) phenyl)-3-(methylthio)-1,2,4-triazine (9c) was the most potent and selective COX-2 compound; its selectivity index of 395 was comparable to celecoxib (SI=405). Evaluation of anti-inflammatory and analgesic effects of 9c showed its higher potency than indomethacin and hence could be considered as a promising lead candidate for further drug development. Furthermore, the affinity data of these compounds were rationalized through enzyme docking simulation and 3D-QSAR study by k-Nearest Neighbour Molecular Field Analysis.
authors.affiliation: Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Irannejad
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Abbas
authors.initials: A
authors.lastname: Kebriaieezadeh
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Afshin
authors.initials: A
authors.lastname: Zarghi
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Farhad
authors.initials: F
authors.lastname: Montazer-Sadegh
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
authors.forename: Abbas
authors.initials: A
authors.lastname: Shafiee
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
authors.forename: Amir
authors.initials: A
authors.lastname: Assadieskandar
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran. Electronic address: moamini@sina.tums.ac.ir.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Amini
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002351:Carrageenan; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D014227:Triazines; C093444:1,2,4-triazine; D002351:Carrageenan; D051546:Cyclooxygenase 2
keywords: 1,2,4-Triazine; 3D-QSAR; Cyclooxygenase; Docking; Inflammatory and analgesic properties