Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Bioorg Med Chem Lett. 2013 Mar 1;23(5):1269-73. doi: 10.1016/j.bmcl.2013.01.003. Epub 2013 Jan 11.
Based on recent reports that the small molecules, isatin and phthalimide, are suitable scaffolds for the design of high potency monoamine oxidase (MAO) inhibitors, the present study examines the MAO inhibitory properties of a series of phthalide [2-benzofuran-1(3H)-one] analogues. Phthalide is structurally related to isatin and phthalimide and it is demonstrated here that substitution at C6 of the phthalide moiety yields compounds endowed with high binding affinities to both human MAO isoforms. Among the nineteen homologues evaluated, the lowest IC(50) values recorded for the inhibition of MAO-A and -B were 0.096 and 0.0014 μM, respectively. In most instances, C6-substituted phthalides exhibit MAO-B specific inhibition. Among a series of 6-benzyloxyphthalides bearing substituents on the para position of the phenyl ring the general order of potency was CF(3) > I > Br > Cl > F > CH(3) > H. The results also show that the binding modes of representative phthalides are reversible and competitive at both MAO isoforms. Based on these data, C6-substituted phthalides may serve as leads for the development of therapies for neurodegenerative disorders such as Parkinson's disease.
基于最近的报道，小分子靛红和邻苯二甲酰亚胺是设计高活性单胺氧化酶（MAO）抑制剂的合适支架，本研究检查了一系列苯酞[2-苯并呋喃-1（3H）-酮]类似物的 MAO 抑制特性。苯酞与靛红和邻苯二甲酰亚胺在结构上有关，这里证明苯酞部分的 C6 取代可产生对两种人 MAO 同工酶均具有高结合亲和力的化合物。在所评估的十九个同系物中，对 MAO-A 和 -B 的抑制的最低 IC50 值分别为 0.096 和 0.0014 μM。在大多数情况下，C6-取代的苯酞表现出 MAO-B 特异性抑制。在一系列带有苯环对位取代基的 6-苄氧基苯酞中，效力的一般顺序为 CF3 > I > Br > Cl > F > CH3 > H。结果还表明，代表性苯酞的结合模式在两种 MAO 同工酶上均为可逆和竞争性的。基于这些数据，C6-取代的苯酞可作为治疗帕金森病等神经退行性疾病的治疗方法的先导。
