title: Structure-activity relationships and molecular modelling of new 5-arylidene-4-thiazolidinone derivatives as aldose reductase inhibitors and potential anti-inflammatory agents.
abstract: A series of 5-(carbamoylmethoxy)benzylidene-2-oxo/thioxo-4-thiazolidinone derivatives (6-9) were synthesized as inhibitors of aldose reductase (AR), enzyme which plays a crucial role in the development of diabetes complications as well as in the inflammatory processes associated both to diabetes mellitus and to other pathologies. In vitro inhibitory activity indicated that compounds 6-9a-d were generally good AR inhibitors. Acetic acid derivatives 8a-d and 9a-d were shown to be the best enzyme inhibitors among the tested compounds endowed with significant inhibitory ability levels reaching submicromolar IC50 values. Moreover, some representative AR inhibitors (7a, 7c, 9a, 9c, 9d) were assayed in cultures of human keratinocytes in order to evaluate their capability to reduce NF-kB activation and iNOS expression. Compound 9c proved to be the best derivative endowed with both interesting AR inhibitory effectiveness and ability to reduce NF-kB activation and iNOS expression. Molecular docking and molecular dynamics simulations were undertaken to investigate the binding modes of selected compounds into the active site of AR in order to rationalize the inhibitory effectiveness of these derivatives.
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, University of Messina, Polo Universitario dell'Annunziata, 98168 Messina, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Maccari
authors.affiliation: Istituto di Chimica Biomolecolare (ICB) - CNR, Comprensorio Olivetti, Ed. 70, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Vitale
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, University of Messina, Polo Universitario dell'Annunziata, 98168 Messina, Italy. Electronic address: rottana@unime.it.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Ottanà
authors.affiliation: Dipartimento di Biologia, Unità di Biochimica, University of Pisa, Via S. Zeno 51, 56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rocchiccioli
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Marrazzo
authors.affiliation: Department of Bio-medical Sciences, Section of Physiology, University of Catania, V.le A. Doria 6, 95125 Catania, Italy.
authors.forename: Venera
authors.initials: V
authors.lastname: Cardile
authors.affiliation: Department of Bio-medical Sciences, Section of Physiology, University of Catania, V.le A. Doria 6, 95125 Catania, Italy.
authors.forename: Adriana Carol Eleonora
authors.initials: AC
authors.lastname: Graziano
authors.affiliation: Istituto di Chimica Biomolecolare (ICB) - CNR, Comprensorio Olivetti, Ed. 70, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Amodeo
authors.affiliation: Dipartimento di Biologia, Unità di Biochimica, University of Pisa, Via S. Zeno 51, 56126 Pisa, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Mura
authors.affiliation: Dipartimento di Biologia, Unità di Biochimica, University of Pisa, Via S. Zeno 51, 56126 Pisa, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Del Corso
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007908:Lens, Crystalline / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D053778:Thiazolidines; D000449:Aldehyde Reductase; D052247:Nitric Oxide Synthase Type II
keywords: 5-(carbamoylmethoxy)benzylidene-2-oxo/thioxo-4-thiazolidinone derivatives; 5-Arylidene-4-thiazolidinone derivatives; Aldose reductase; Anti-inflammatory agents; Enzyme inhibitors; Molecular modelling