title: Analogue-based design, synthesis and docking of non-steroidal anti-inflammatory agents. Part 2: methyl sulfanyl/methyl sulfonyl substituted 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones.
abstract: A series of methyl sulfanyl/methyl sufonyl substituted 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-one were designed using analogue-based design, scaffold hopping and shape similarity matching. The designed compounds were synthesized in 2-3 steps with simple chemistry and screened by ovine cyclooxygenases (COXs) inhibitory assay and carrageenan-induced rat paw edema assay. Among the screened compounds, two compounds exhibited 100% cyclooxygenase-2 (COX-2) inhibitory potency without showing cycloxygenase-1 (COX-1) inhibition at 20 μM. The compounds also showed promising in vivo anti-inflammatory potential. A structure-activity relationship within the dataset was established by correlating the effect of aromatic ring substituent constants, structural variables and physico-chemical descriptors with in vivo anti-inflammatory activity. Molecular docking studies were also performed on the title compounds to study the binding interactions to COX-2 active site residues. The experimentally determined COX-2 inhibitory activity was found moderately correlating with binding modes predicted for compounds by Glide XP dock scoring function. The 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-one pharmacophore reported herein should be a new lead for further development of novel non-steroidal anti-inflammatory agents.
authors.affiliation: School of Pharmacy, Devi Ahilya Vishwavidyalaya, Ring Road, Indore 452017, (M.P.), India. drmanislab@gmail.com
authors.forename: E
authors.initials: E
authors.lastname: Manivannan
authors.forename: S C
authors.initials: SC
authors.lastname: Chaturvedi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004487:Edema / Q000188:drug therapy; D062105:Molecular Docking Simulation; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D052999:Quinazolinones; D051546:Cyclooxygenase 2