Investigations on the 2-thiazolylhydrazyne scaffold: synthesis and molecular modeling of selective human monoamine oxidase inhibitors.
A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71-99%) and characterized by elemental analysis and (1)H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) inhibitory activity and selectivity and most of them showed IC(50) values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the CN, displayed IC(50)=3.81+/-0.12 nM and selectivity ratio=119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the enzyme-inhibitor interaction toward hMAO isoforms and to explain the structure-activity relationship of this kind of inhibitors.
Chimenti
Franco
F
Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma La Sapienza, Ple A Moro 5, 00185 Rome, Italy.
Bolasco
Adriana
A
Secci
Daniela
D
Chimenti
Paola
P
Granese
Arianna
A
Carradori
Simone
S
Yáñez
Matilde
M
Orallo
Francisco
F
Ortuso
Francesco
F
Alcaro
Stefano
S
D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D006834:Hydrazines; D008996:Monoamine Oxidase Inhibitors; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase