Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, 281406, India.
Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, 281406, India.
Comput Biol Chem. 2019 Apr;79:63-72. doi: 10.1016/j.compbiolchem.2019.01.012. Epub 2019 Jan 29.
Monoamine oxidase (MAO) enzymes are one of the most promising targets for the treatment of neurological disorders. A series of phenylisoxazole carbohydrazides was designed, synthesized and screened for both MAO-A and MAO-B inhibition using Amplex Red assays. None of the compounds inhibited the MAO-A activity while most of them significantly inhibited MAO-B in the micromolar to nanomolar range. Among them, the compound N'-(4-methylbenzylidene)-5-phenylisoxazole-3-carbohydrazide (6c) exhibited the most potent inhibitory activity towards MAO-B. Enzyme kinetic studies revealed the reversible and competitive nature of compound 6c towards MAO-B inhibition. The results of the enzyme inhibition assay were in agreement with molecular docking study, in which compound 6c displayed a strong binding affinity for MAO-B with a docking score of -10.98 Kcal/mol. In order to explore the neuroprotective effect of compound 6c, MPTP-induced mouse model for Parkinson's disease was used, and motor behavioural assessment of experimental animals was carried out. The compound 6c was able to significantly prevent the MPTP-induced neurotoxicity as revealed by improvement in gait behaviour in footprint test and increase in grip strength score in horizontal wire test. Thus, phenylisoxazole carbohydrazides can be promising leads in the development of potent, selective and reversible MAO-B inhibitors for the treatment of Parkinson's disease.
单胺氧化酶（MAO）酶是治疗神经紊乱最有希望的靶点之一。我们设计、合成了一系列苯并异恶唑甲脒，并采用 Amplex Red 测定法对其 MAO-A 和 MAO-B 的抑制作用进行了筛选。没有一种化合物能抑制 MAO-A 的活性，但大多数化合物在微摩尔到纳摩尔范围内能显著抑制 MAO-B。其中，化合物 N'-(4-甲基苄叉基)-5-苯并异恶唑-3-甲脒（6c）对 MAO-B 的抑制活性最强。酶动力学研究表明，化合物 6c 对 MAO-B 的抑制作用具有可逆和竞争的性质。酶抑制测定的结果与分子对接研究一致，其中化合物 6c 对 MAO-B 表现出很强的结合亲和力，对接得分为-10.98 Kcal/mol。为了探索化合物 6c 的神经保护作用，我们使用了 MPTP 诱导的帕金森病小鼠模型，并对实验动物的运动行为进行了评估。结果表明，化合物 6c 能够显著预防 MPTP 诱导的神经毒性，表现在足迹试验中步态行为的改善和水平丝试验中握力评分的增加。因此，苯并异恶唑甲脒类化合物可能是开发高效、选择性和可逆 MAO-B 抑制剂治疗帕金森病的有前途的先导化合物。
