title: Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)- pyrazole derivatives.
abstract: A novel series of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)-pyrazole derivatives have been synthesized and investigated for the ability to inhibit selectively the activity of the A and B isoforms of monoamine oxidase (MAO). All the synthesized compounds show high activity against both the MAO-A and the MAO-B isoforms with Ki values between 27 and 4 nM and between 50 and 1.5 nM, respectively, except for a few derivatives whose inhibitory activity against MAO-B was in the micromolar range. Knowing that stereochemistry may be an important modulator of biological activity, we performed the semipreparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation. The selectivity of the (-)-(S)-1 enantiomer against MAO-B increases twice and a half, while the selectivity of the (-)-(S)-4 enantiomer against MAO-A triples. Both the MAO-A and MAO-B isoforms respectively of the 1O5W and 1GOS models deposited in the Protein Data Bank were considered in the computational study. The docking study was carried out using several computational approaches with the aim of proposing possible binding modes of the MAO enantioselective compounds 1 and 4.
authors.affiliation: Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Chimenti
authors.forename: Elias
authors.initials: E
authors.lastname: Maccioni
authors.forename: Daniela
authors.initials: D
authors.lastname: Secci
authors.forename: Adriana
authors.initials: A
authors.lastname: Bolasco
authors.forename: Paola
authors.initials: P
authors.lastname: Chimenti
authors.forename: Arianna
authors.initials: A
authors.lastname: Granese
authors.forename: Olivia
authors.initials: O
authors.lastname: Befani
authors.forename: Paola
authors.initials: P
authors.lastname: Turini
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.forename: Francesco
authors.initials: F
authors.lastname: La Torre
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cardia
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
mesh_terms: D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D009010:Monte Carlo Method; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D008996:Monoamine Oxidase Inhibitors; D011720:Pyrazoles; D013859:Thiocarbamates; D008995:Monoamine Oxidase