Abstract

Multitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer’s disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD’s complex pathophysiology. A preliminary series of 3,7-substituted coumarin derivatives were synthesised and evaluated for enzyme inhibitory activity, cytotoxicity as well as neuroprotective ability. The results indicated that the compounds are weak cholinesterase inhibitors with five compounds demonstrating relatively potent inhibition and selectivity towards MAO-B with IC₅₀ values between 0.014 and 0.498 hx00B5;µM. Significant neuroprotective effects towards MPP⁺-compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 µM for all compounds. The overall results demonstrated that substitution of the phenylethyloxy moiety at the 7-position imparted superior general activity to the derivatives, with the propargylamine substitution at the 3-position, in particular, displaying the best MAO-B selectivity and neuroprotection.

摘要

多靶点定向配体 (MTDL) 正在成为阿尔茨海默病 (AD) 的有希望的治疗选择。香豆素衍生物可作为设计 MTDL 的良好起点，因为它们固有地抑制单胺氧化酶 (MAO) 和胆碱酯酶，它们是 AD 复杂病理生理学的共谋。合成了一系列初步的 3,7-取代香豆素衍生物，并评估了酶抑制活性、细胞毒性和神经保护能力。结果表明，这些化合物是弱胆碱酯酶抑制剂，其中五种化合物对 MAO-B 表现出相对有效的抑制作用和选择性，IC ₅₀值在 0.014 和 0.498 hx00B5 之间；μM。对 MPP 的显着神经保护作用⁺还观察到受损的 SH-SY5Y 神经母细胞瘤细胞，所有化合物在 10 µM 下均无固有细胞毒性。总体结果表明，在 7 位取代苯乙氧基部分赋予衍生物优异的一般活性，尤其是在 3 位取代炔丙胺，显示出最佳的 MAO-B 选择性和神经保护作用。