Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)- pyrazole derivatives.
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.
Chimenti
Franco
F
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.
Maccioni
Elias
E
Secci
Daniela
D
Bolasco
Adriana
A
Chimenti
Paola
P
Granese
Arianna
A
Befani
Olivia
O
Turini
Paola
P
Alcaro
Stefano
S
Ortuso
Francesco
F
Cirilli
Roberto
R
La Torre
Francesco
F
Cardia
Maria C
MC
Distinto
Simona
S
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
D008996:Monoamine Oxidase Inhibitors; D011720:Pyrazoles; D013859:Thiocarbamates; D008995:Monoamine Oxidase