D'Ascenzio Melissa, Carradori Simone, Secci Daniela, Mannina Luisa, Sobolev Anatoly P, De Monte Celeste, Cirilli Roberto, Yáñez Matilde, Alcaro Stefano, Ortuso Francesco
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Bioorg Med Chem. 2014 May 15;22(10):2887-95. doi: 10.1016/j.bmc.2014.03.042. Epub 2014 Apr 5.
Exploring the effect that substituents on the cycloaliphatic ring had on the inhibitory activity against human monoamine oxidase B of a series of 4-aryl-2-cycloalkylidenhydrazinylthiazoles led to the synthesis of a new series of 2-methylcyclopentyl and 3-methylcyclopentyl derivatives which were tested in vitro as mixtures of diastereoisomers. In fact, due to the presence of a chiral center on the cycloaliphatic ring and a trisubstituted CN bond, they exist as four diastereoisomers ((E)-(R), (E)-(S), (Z)-(R), (Z)-(S)). 4-(2,4-Difluorophenyl)-2-(2-(3-methylcyclopentylidene)hydrazinyl)thiazole was chosen as a model to investigate the influence of stereochemical requirements on the inhibitory activity against hMAO-B of these derivatives after a stereoconservative synthesis and semi-preparative HPLC diastereoseparation. (R)-(Z) isomer of this compound was endowed with a potent and selective hMAO-B inhibition higher than that of reference drugs as also corroborated by molecular modeling studies.
探索脂环族环上的取代基对一系列4-芳基-2-环亚烷基肼基噻唑对人单胺氧化酶B抑制活性的影响，从而合成了一系列新的2-甲基环戊基和3-甲基环戊基衍生物，并将其作为非对映异构体混合物进行体外测试。事实上，由于脂环族环上存在一个手性中心和一个三取代的碳氮键，它们以四种非对映异构体（（E）-（R）、（E）-（S）、（Z）-（R）、（Z）-（S））的形式存在。在进行立体保守合成和半制备型高效液相色谱非对映体分离后，选择4-（2,4-二氟苯基）-2-（2-（3-甲基环亚烷基）肼基）噻唑作为模型，研究立体化学要求对这些衍生物对hMAO-B抑制活性的影响。该化合物的（R）-（Z）异构体具有比参考药物更强的选择性hMAO-B抑制活性，分子模拟研究也证实了这一点。
