Synthesis, stereochemical identification, and selective inhibitory activity against human monoamine oxidase-B of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones.
A series of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones have been investigated for their ability to inhibit selectively the activity of the human A and B isoforms of monoamine oxidase (MAO). The target compounds, which present a stereogenic center on the cyclohexane ring, were obtained as pure (R) and (S) enantiomers by enantioselective HPLC. The absolute configuration of homochiral forms isolated on a semipreparative scale was obtained by a combined strategy based on chemical correlation and single-crystal X-ray diffraction. All compounds showed higher activity against the human MAO-B isoform with IC50 values ranging between 26.81 +/- 2.74 microM and 14.20 +/- 0.26 nM, and the assays carried out on the pure enantiomers showed higher activity for the (R) form. A computational study was performed by molecular mechanics, DFT-based quantomechanics, and docking techniques on the most active and human MAO-B selective inhibitor 8.
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 Roma, Italy.
Maccioni
Elias
E
Secci
Daniela
D
Bolasco
Adriana
A
Chimenti
Paola
P
Granese
Arianna
A
Carradori
Simone
S
Alcaro
Stefano
S
Ortuso
Francesco
F
Yáñez
Matilde
M
Orallo
Francisco
F
Cirilli
Roberto
R
Ferretti
Rosella
R
La Torre
Francesco
F
D002851:Chromatography, High Pressure Liquid; D003512:Cyclohexanones / Q000737:chemistry; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013816:Thermodynamics; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013882:Thiosemicarbazones / Q000737:chemistry
C527963:2-methylcyclohexanone thiosemicarbazone; D003512:Cyclohexanones; D006835:Hydrazones; D008996:Monoamine Oxidase Inhibitors; D013844:Thiazoles; D013882:Thiosemicarbazones; D008995:Monoamine Oxidase