title: Drug design, synthesis, in vitro and in silico evaluation of selective monoaminoxidase B inhibitors based on 3-acetyl-2-dichlorophenyl-5-aryl-2,3-dihydro-1,3,4-oxadiazole chemical scaffold.
abstract: With the aim to identify new, potent and selective monoamine oxidase B (MAO-B) inhibitors, molecular interaction field analysis has been applied to a MAO-B complex with 3-acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazole chemical structure, known as a privileged scaffold for this target. Several compounds displayed potent in vitro activity, exhibiting IC50 values in the medium to low nanomolar range. The enantiomers of most promising derivatives were separated by enantioselective HPLC and in vitro evaluated. Experimental results, according to theoretical drug design, clearly indicated a key role of the ligand stereochemistry in the target recognition/inhibition. In particular the (R)- enantiomers showed the best activity with respect to the (S)- stereoisomer. Finally, docking experiments coupled to molecular dynamics (MD) simulations, were applied for understanding the putative MAO -B binding modes of the new compounds providing detailed information for further structural optimization.
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Meleddu
authors.affiliation: Facultad de Farmacia, Departamento de Farmacología, Universidad de Santiago de Compostela, Campus Vida, La Coruña, 15782 Santiago de Compostela, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Yanez
authors.affiliation: Dipartimento del Farmaco, Istituto Superiore di Sanità, V.le Regina Elena 299, 00161 Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bianco
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Sanna
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Arridu
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Cossu
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Cottiglia
authors.affiliation: Dipartimento di Chimica "Ugo Schiff", Via della Lastruccia, 3-13 - 50019 Sesto Fiorentino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Faggi
authors.affiliation: Dipartimento di Scienze della Salute, Università; "Magna Græcia" di Catanzaro, Campus "S. Venuta", Viale Europa, 88100 Catanzaro, Italy. Electronic address: ortuso@unicz.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.affiliation: Dipartimento di Scienze della Salute, Università; "Magna Græcia" di Catanzaro, Campus "S. Venuta", Viale Europa, 88100 Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Elias
authors.initials: E
authors.lastname: Maccioni
mesh_terms: D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000611516:3-acetyl-2-dichlorophenyl-5-aryl-2,3-dihydro-1,3,4-oxadiazole; D008996:Monoamine Oxidase Inhibitors; D010069:Oxadiazoles; D008995:Monoamine Oxidase
keywords: 2,3-Dihydro-1,3,4-oxadiazoles; Docking; MAO-B; Molecular dynamics; Neurodegenerative disorders