Can Nafiz Öncü, Osmaniye Derya, Levent Serkan, Sağlık Begüm Nurpelin, Korkut Büşra, Atlı Özlem, Özkay Yusuf, Kaplancıklı Zafer Asım
Department of Analytical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey; Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey; Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.
Eur J Med Chem. 2018 Jan 20;144:68-81. doi: 10.1016/j.ejmech.2017.12.013. Epub 2017 Dec 6.
In the recent works, it was shown that numerous thiazolylhydrazine derivatives display hMAO inhibitory activity in the range of micromolar concentration. Hence, in the present study a new series of new thiazole-hydrazines (3a-3n) were designed, synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro flurometric method. The enzyme inhibition assay revealed that most of the synthesized compounds have selective inhibition potency against hMAO-A. The compounds 3f and 3h showed promising hMAO-A inhibition with an IC values of 0.012 μM and 0.011 μM and significant selectivity indexes of 1214 and 1601 towards hMAO-A, respectively. The mechanism of hMAO-A inhibition of compounds 3f and 3h was investigated by Lineweaver-Burk graphics and reversible-competitive inhibition of hMAO-A was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 3h was found as non-cytotoxic and non-genotoxic. Theoretical calculation of ADME properties suggested that synthesized compounds may have a good pharmacokinetic profile. The docking study of compound 3f and 3h revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound.
在最近的研究中发现，许多噻唑基肼衍生物在微摩尔浓度范围内显示出对人单胺氧化酶（hMAO）的抑制活性。因此，在本研究中，设计、合成、表征了一系列新的噻唑 - 肼类化合物（3a - 3n），并通过体外荧光法筛选它们对hMAO - A和hMAO - B的抑制活性。酶抑制试验表明，大多数合成化合物对hMAO - A具有选择性抑制效力。化合物3f和3h对hMAO - A显示出有前景的抑制作用，IC值分别为0.012 μM和0.011 μM，对hMAO - A的选择性指数分别为1214和1601。通过Lineweaver - Burk图研究了化合物3f和3h对hMAO - A的抑制机制，并确定为对hMAO - A的可逆竞争性抑制。进行了细胞毒性和遗传毒性研究，发现化合物3h无细胞毒性和遗传毒性。ADME性质的理论计算表明，合成化合物可能具有良好的药代动力学特征。化合物3f和3h的对接研究表明，hMAO - A的活性位点与分析的化合物之间存在强相互作用。
