title: Computer-aided discovery of anti-inflammatory thiazolidinones with dual cyclooxygenase/lipoxygenase inhibition.
abstract: New anti-inflammatory agents possessing dual cyclooxygenase/lipoxygenase (COX/LOX) inhibition were discovered by computer-aided prediction of biological activity for 573 virtually designed chemical compounds. Prediction of biological activity was performed by PASS, and prediction results were analyzed with PharmaExpert software. Nine 2-(thiazole-2-ylamino)-5-phenylidene-4-thiazolidinone derivatives differing by the phenyl group substitution were selected for synthesis and experimental testing as potential COX/LOX inhibitors. Eight tested compounds exhibited anti-inflammatory activity in the carrageenin-induced paw edema. It was shown that seven tested compounds (77.8%) were LOX inhibitors, seven compounds were COX inhibitors (77.8%), and six tested compounds (66.7%) were dual COX/LOX inhibitors. Analysis of lipophilicity of the compounds showed a negative correlation with inhibition of edema formation. The binding modes of the most active compounds of this series (2-(thiazole-2-ylamino)-5-( m-chlorophenylidene)-4-thiazolidinone for COX-1 and COX-2, and 2-(thiazole-2-ylamino)-5-( m-nitrophenylidene)-4-thiazolidinone for 15-LOX) were proposed on the basis of docking studies.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University, Thessaloniki, Greece.
authors.forename: Athina A
authors.initials: AA
authors.lastname: Geronikaki
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Lagunin
authors.forename: Dimitra I
authors.initials: DI
authors.lastname: Hadjipavlou-Litina
authors.forename: Phaedra T
authors.initials: PT
authors.lastname: Eleftheriou
authors.forename: Dmitrii A
authors.initials: DA
authors.lastname: Filimonov
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Poroikov
authors.forename: Intekhab
authors.initials: I
authors.lastname: Alam
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002351:Carrageenan; D003198:Computer Simulation; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D008084:Lipoxygenase / Q000187:drug effects*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011237:Predictive Value of Tests; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D053778:Thiazolidines; D002351:Carrageenan; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases