Gökhan-Kelekçi Nesrin, Simşek O Ozgün, Ercan Ayşe, Yelekçi Kemal, Sahin Z Sibel, Işik Samil, Uçar Gülberk, Bilgin A Altan
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Hacettepe University, 06100 Sihhiye, Ankara, Turkey.
Bioorg Med Chem. 2009 Sep 15;17(18):6761-72. doi: 10.1016/j.bmc.2009.07.033. Epub 2009 Jul 23.
A novel series of 2-thiocarbamoyl-2,3,4,5,6,7-hexahydro-1H-indazole and 2-substituted thiocarbamoyl-3,3a,4,5,6,7-hexahydro-2H-indazoles derivatives were synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The target molecules were identified on the basis of satisfactory analytical and spectra data (IR, (1)H NMR, (13)C NMR, (2)D NMR, DEPT, EI-MASS techniques and elemental analysis). Synthesized compounds showed high activity against both the MAO-A (compounds 1d, 1e, 2c, 2d, 2e) and the MAO-B (compounds 1a, 1b, 1c, 2a, 2b) isoforms. In the discussion of the results, the influence of the structure on the biological activity of the prepared compounds was delineated. It was suggested that non-substituted and N-methyl/ethyl bearing compounds (except 2c) increased the inhibitory effect and selectivity toward MAO-B. The rest of the compounds, carrying N-allyl and N-phenyl, appeared to select the MAO-A isoform. The inhibition profile was found to be competitive and reversible for all compounds. A series of experimentally tested (1a-2e) compounds was docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The autodock 4.01 program was employed to perform automated molecular docking. In order to see the detailed interactions of the docked poses of the model inhibitors compounds 1a, 1d, 1e and 2e were chosen because of their ability to reversibly inhibit the MAO-B and MAO-A and the availability of experimental inhibition data. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Excellent to good correlations between the calculated and experimental K(i) values were obtained. In the docking of the MAO-A complex, the trans configuration of compound 1e made various very close interactions with the residues lining the active site cavity these interactions were much better than those of the other compounds tested in this study. This tight binding observation may be responsible for the nanomolar inhibition of form of MAOA. However, it binds slightly weaker (experimental K(i)=1.23 microM) to MAO-B than to MAO-A (experimental K(i)=4.22 nM).
合成了一系列新型的2-硫代氨基甲酰基-2,3,4,5,6,7-六氢-1H-吲唑和2-取代硫代氨基甲酰基-3,3a,4,5,6,7-六氢-2H-吲唑衍生物，并研究了它们抑制单胺氧化酶（MAO）A和B同工型活性的能力。根据令人满意的分析和光谱数据（红外光谱、¹H核磁共振、¹³C核磁共振、²D核磁共振、无畸变极化转移增强法、电子轰击质谱技术和元素分析）确定了目标分子。合成的化合物对MAO-A（化合物1d、1e、2c、2d、2e）和MAO-B（化合物1a、1b、1c、2a、2b）同工型均表现出高活性。在结果讨论中，阐述了结构对所制备化合物生物活性的影响。结果表明，未取代的以及带有N-甲基/乙基的化合物（2c除外）增强了对MAO-B的抑制作用和选择性。其余带有N-烯丙基和N-苯基的化合物似乎对MAO-A同工型具有选择性。发现所有化合物的抑制模式均为竞争性且可逆的。对一系列经过实验测试的（1a - 2e）化合物进行了MAO-A和MAO-B同工酶活性位点的计算机对接。使用自动对接4.01程序进行自动分子对接。为了观察模型抑制剂化合物1a、1d、1e和2e对接姿势的详细相互作用，选择它们是因为它们能够可逆地抑制MAO-B和MAO-A以及有可用的实验抑制数据。配体与每种MAO同工型活性位点之间分子间疏水和氢键作用的差异与它们的生物学数据相关。观察这些配体的对接位置发现它们与许多先前报道对酶抑制有影响的残基相互作用。计算得到的和实验得到的K(i)值之间具有良好到优异的相关性。在MAO-A复合物的对接中，化合物1e的反式构型与活性位点腔内衬的残基形成了各种非常紧密的相互作用，这些相互作用比本研究中测试的其他化合物要好得多。这种紧密结合的现象可能是MAO-A纳米摩尔级抑制形式的原因。然而，它与MAO-B的结合（实验K(i)=1.23微摩尔）比与MAO-A的结合（实验K(i)=4.22纳摩尔）稍弱。
