Shankar Gauri, Kumar Prabhat, Rai Sanskriti, Ghosh Aparajita, Varma Tanmaykumar, Wani Mushtaq Ahmad, Kumar Sunil, Mandloi Upesh, Singh Gireesh Kumar, Garg Prabha, Kulkarni Onkar, Srikrishna Saripella, Kumar Saroj, Modi Gyan
Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi, U.P, 221005, India.
Cell and Neurobiology Laboratory, Department of Biochemistry, Institute of Science, BHU, Varanasi, 221005, India.
Eur J Med Chem. 2025 Feb 5;283:117066. doi: 10.1016/j.ejmech.2024.117066. Epub 2024 Nov 27.
Contemporary research evidence has corroborated a gradual loss of central cholinergic neurons in Alzheimer's Disease (AD). This progressive deterioration leads to cognitive dysfunction and impaired motor activity, culminating in the brain cell's death in the disease. The approved drugs for AD treatment can only offer relief from symptoms without addressing the underlying pathological hallmarks of the disease. To address the limitations associated with rivastigmine (RIV), a marketed drug for AD, a series of tryptamine derivatives was designed, synthesized, and evaluated in various in-vitro and in-vivo AD models. Enzyme inhibition studies identified compounds 6d and 6e as the lead molecules with potent inhibitors against AChE (6d, IC: 0.99 ± 0.009 nM and 6e IC: 7.97 ± 0.016 nM and BChE (6d, IC: 27.79 ± 0.21 nM and 6e, IC: 0.79 ± 0.005 nM), compared to the marketed drug Riv (AChE, IC: 6630 ± 0.76 nM, BChE IC = 91 ± 0.40 nM). The molecular docking and dynamics studies corroborated the enzyme inhibition studies. The PAMPA assay strongly suggested the BBB crossing ability of the lead molecules. Further, 6d and 6e demonstrated the capability to counteract oxidative stress and Aβ in various in-vitro studies. Compound 6e exhibited remarkable radical scavenging activity in the DPPH assay (IC: 22.91 ± 1.73 μM) compared to rivastigmine (% radical scavenging activity: 3.71 ± 0.09 at 200 μM). Interestingly, 6d and 6e exhibited promising activity in the AD Drosophila model by protecting eye phenotypes from degeneration induced by Aβ toxicity and reduced mitochondrial and cellular oxidative stress in this model. Furthermore, upon oral administration, 6d and 6e could reverse scopolamine-induced amnesia by improving spatial and cognitive memory in mice at 0.3 and 0.5 mg/kg compared to rivastigmine at 3 mg/kg and were found to have potent ex-vivo anti-ChEs properties, which are correlated with the observed pro-cognitive effects in the Morris Water Maze, likely mediated through the inhibition of both cholinesterases. The expression of various neuroprotection markers, such as BDNF and TRKB, was significantly overexpressed compared to the disease control group.
当代研究证据证实，阿尔茨海默病（AD）患者中枢胆碱能神经元会逐渐丧失。这种渐进性恶化会导致认知功能障碍和运动活动受损，最终导致疾病中脑细胞死亡。已获批用于AD治疗的药物只能缓解症状，而无法解决该疾病潜在的病理特征。为了解决与已上市的AD药物卡巴拉汀（RIV）相关的局限性，设计、合成了一系列色胺衍生物，并在各种体外和体内AD模型中进行了评估。酶抑制研究确定化合物6d和6e为先导分子，它们是乙酰胆碱酯酶（AChE）（6d，IC：0.99±0.009 nM和6e IC：7.97±0.016 nM）和丁酰胆碱酯酶（6d，IC：27.79±0.21 nM和6e，IC：0.79±0.005 nM）的强效抑制剂，与已上市药物Riv（AChE，IC：6630±0.76 nM，BChE IC = 91±0.40 nM）相比。分子对接和动力学研究证实了酶抑制研究结果。PAMPA试验有力地表明了先导分子的血脑屏障穿越能力。此外，在各种体外研究中，6d和6e表现出对抗氧化应激和Aβ的能力。与卡巴拉汀相比（在200 μM时自由基清除活性百分比：3.71±0.09），化合物6e在DPPH试验中表现出显著的自由基清除活性（IC：22.91±1.73 μM）。有趣的是，6d和6e在AD果蝇模型中表现出有前景的活性，可保护眼睛表型免受Aβ毒性诱导的退化，并降低该模型中的线粒体和细胞氧化应激。此外，口服给药后，与3 mg/kg的卡巴拉汀相比，6d和6e在0.3和0.5 mg/kg时可通过改善小鼠的空间和认知记忆来逆转东莨菪碱诱导的失忆，并且发现它们具有强大的体外抗胆碱酯酶特性，这与在莫里斯水迷宫中观察到的促认知作用相关，可能是通过抑制两种胆碱酯酶介导的。与疾病对照组相比，各种神经保护标志物如脑源性神经营养因子（BDNF）和酪氨酸激酶受体B（TRKB）的表达显著上调。
