title: Fragment-based design, docking, synthesis, biological evaluation and structure-activity relationships of 2-benzo/benzisothiazolimino-5-aryliden-4-thiazolidinones as cycloxygenase/lipoxygenase inhibitors.
abstract: Balanced modulation of several targets is one of the current strategies for the treatment of multi-factorial diseases. Based on the knowledge of inflammation mechanisms, it was inferred that the balanced inhibition of cyclooxygenase-1/cyclooxygenase-2/lipoxygenase might be a promising approach for treatment of such a multifactorial disease state as inflammation. Detection of fragments responsible for interaction with enzyme's binding site provides the basis for designing new molecules with increased affinity and selectivity. A new chemoinformatics approach was proposed and applied to create a fragment library that was used to design novel inhibitors of cycloxygenase-1/cycloxygenase-2/lipoxygenase enzymes. Potential binding sites were elucidated by docking. Synthesis of novel compounds, and the in vitro/in vivo biological testing confirmed the results of computational studies. The benzothiazolyl moiety was proved to be of great significance for developing more potent inhibitors.
authors: Department of Medical Laboratory Studies, School of Health and Medical Care, Alexander Technological Education Institute of Thessaloniki, Thessaloniki 57400, Greece.
authors: Phaedra
authors: P
authors: Eleftheriou
authors: Athina
authors: A
authors: Geronikaki
authors: Dimitra
authors: D
authors: Hadjipavlou-Litina
authors: Paola
authors: P
authors: Vicini
authors: Olga
authors: O
authors: Filz
authors: Dmitry
authors: D
authors: Filimonov
authors: Vladimir
authors: V
authors: Poroikov
authors: Shailendra S
authors: SS
authors: Chaudhaery
authors: Kuldeep K
authors: KK
authors: Roy
authors: Anil K
authors: AK
authors: Saxena
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D008084:Lipoxygenase / Q000737:chemistry / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D053778:Thiazolidines; D008084:Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2