Synthesis, semipreparative HPLC separation, biological evaluation, and 3D-QSAR of hydrazothiazole derivatives as human monoamine oxidase B inhibitors.
The present study reports on synthesis in high yields (70-99%), HPLC enantioseparation, inhibitory activity against human monoamino oxidases, and molecular modeling including 3D-QSAR studies, of a large series of (4-aryl-thiazol-2-yl)hydrazones (1-45). Most of the synthesized compounds proved to be potent and selective inhibitors of hMAO-B isoform in the micromolar or nanomolar range, thus demonstrating that hydrazothiazole could be considered a good pharmacophore to design new hMAO-B inhibitors. Due to the presence in some derivatives of a chiral center, we also performed a semipreparative chromatographic enantioseparation of these compounds obtained by a stereoconservative pattern. The separated enantiomers were submitted to in vitro biological evaluation to point out the stereorecognition of the active site of the enzyme towards these structures. Finally, a 3D-QSAR study was carried out using Comparative Molecular Field Analysis (CoMFA), aiming to deduce rational guidelines for the further structural modification of these lead compounds.
Chimenti
Franco
F
Dipartimento di Chimica e Tecnologie del Farmaco Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy.
Secci
Daniela
D
Bolasco
Adriana
A
Chimenti
Paola
P
Granese
Arianna
A
Carradori
Simone
S
Maccioni
Elias
E
Cardia
M Cristina
MC
Yáñez
Matilde
M
Orallo
Francisco
F
Alcaro
Stefano
S
Ortuso
Francesco
F
Cirilli
Roberto
R
Ferretti
Rosella
R
Distinto
Simona
S
Kirchmair
Johannes
J
Langer
Thierry
T
D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
D006835:Hydrazones; D008996:Monoamine Oxidase Inhibitors; D013844:Thiazoles; D008995:Monoamine Oxidase