Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University) Varanasi, Varanasi, 221005, Uttar Pradesh, India.
ChemMedChem. 2019 Jul 17;14(14):1359-1376. doi: 10.1002/cmdc.201900277. Epub 2019 Jul 8.
A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A/B). The results of in vitro studies revealed IC values in the micromolar range, with the majority of the compounds showing selectivity for the MAO-B isoform. N-[2-Oxo-1-(prop-2-ynyl)indolin-3-ylidene]benzo[d][1,3]dioxole-5-carbohydrazide (3) was identified as a lead AChE inhibitor with IC =0.052±0.006 μm. N-[(3E)-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-2H-1,3-benzodioxole-5-carbohydrazide (2) was the lead MAO-B inhibitor with IC =0.034±0.007 μm, and showed 50 times greater selectivity for MAO-B over MAO-A. The kinetic studies revealed that compounds 2 and 3 displayed competitive and reversible inhibition of AChE and MAO-B, respectively. The molecular docking studies revealed the significance of hydrophobic interactions in the active site pocket of the enzymes under investigation. Further optimization studies might lead to the development of potential neurotherapeutic agents.
一组哌啶酸衍生的腙与不同的色胺部分被合成，并评估其对乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BChE）和单胺氧化酶 A 和 B（MAO-A/B）的抑制活性。体外研究的结果显示出在微摩尔范围内的 IC 值，大多数化合物对 MAO-B 同工型表现出选择性。N-[2-氧代-1-（丙-2-炔基）吲哚啉-3-亚基]苯并[d][1,3]二氧杂环戊烯-5-甲酰肼（3）被鉴定为 AChE 抑制剂的先导化合物，IC =0.052±0.006μm。N-[(3E)-5-氯-2-氧代-2,3-二氢-1H-吲哚-3-亚基]-2H-1,3-苯并二氧杂环戊烯-5-甲酰肼（2）是 MAO-B 抑制剂的先导化合物，IC =0.034±0.007μm，对 MAO-B 的选择性比 MAO-A 高 50 倍。动力学研究表明，化合物 2 和 3 分别对 AChE 和 MAO-B 显示出竞争性和可逆抑制作用。分子对接研究表明，在研究的酶的活性口袋中，疏水相互作用的重要性。进一步的优化研究可能导致潜在的神经治疗药物的开发。
