Abstract

The inhibition of monoamine oxidase B (MAO-B) could be an effective approach for the treatment of various neurological disorders. In this study, a series of 1, 4-benzodioxan-substituted chalcone derivatives were designed, synthesised and evaluated for their inhibitory activity against human MAO-B (hMAO-B). The majority of these compounds showed inhibitory activity and high selectivity. The most potent compound, (E)-1-(3-bromo-4-fluorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)prop-2-en-1-one (22), exhibited an IC₅₀ of 0.026 µM with a selectivity index greater than 1538. Kinetics and reversibility studies confirmed that the representative active compounds acted as competitive and reversible inhibitors of hMAO-B. The enzyme-inhibitor interactions were investigated by molecular docking studies and the rationale was provided. As these potent hMAO-B inhibitors exhibited low neurotoxicity and possessed promising drug-like properties, we believe that these active compounds could be further investigated as potential drug candidates for future in vivo studies.

摘要

抑制单胺氧化酶B（MAO-B）可能是治疗各种神经系统疾病的有效方法。在这项研究中，设计，合成和评估了一系列1，1,4-苯并二恶烷取代的查耳酮衍生物对人MAO-B（hMAO-B）的抑制活性。这些化合物大多数显示出抑制活性和高选择性。最有效的化合物（E）-1-（3-溴-4-氟苯基）-3-（2,3-二氢苯并[ b ] [1,4]二恶英-6-基）丙-2-en-1 -一个（22），展示了IC ₅₀选择性为0.026 µM，选择性指数大于1538。动力学和可逆性研究证实，代表性的活性化合物是hMAO-B的竞争性和可逆性抑制剂。通过分子对接研究了酶-抑制剂的相互作用，并提供了理论依据。由于这些有效的hMAO-B抑制剂表现出较低的神经毒性并具有有希望的药物样特性，因此我们认为这些活性化合物可以作为潜在的候选药物进行进一步的体内研究。