Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India.
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India.
Eur J Med Chem. 2023 Mar 5;249:115145. doi: 10.1016/j.ejmech.2023.115145. Epub 2023 Jan 23.
Vasicine is a pyrroloquinazoline alkaloid, which has been isolated from the plant Adhatoda vasica. Naturally inspired semi-synthetic transformations were prepared using vasicine as a synthetic precursor to overcome Alzheimer's disease (AD). These semi-synthetic analogs exhibited stable interactions and were well resided at AChE and BChE active sites in in-silico studies. Further, in-vitro experiments were performed to assess the cholinesterase inhibitory activity and reduction of amyloid-beta (Aβ) plaques potency, PAMPA assay permeability, and antioxidant activity, these findings suggested that compound VA10 can be a lead molecule among all the synthesized analogs. The compound VA10 binds towards AChE peripheral anionic site (PAS) property was established through propidium iodide displacement assay. Moreover, VA10 showed no notable cytotoxicity and exhibited neuroprotective nature on Aβ treated SH-SY5Y cell line. In addition, VA10 was found to be safe in rats, which was confirmed by acute oral toxicity studies. Furthermore, in-vivo studies suggested that compound VA10 (10 mg/kg, p.o) ameliorated the memory and cognition impairment in scopolamine-induced amnesia model and Aβ induced Alzheimer rat model. Ex-vivo studies of compound VA10 demonstrate improved ACh levels by inhibiting AChE activity in rat brain. Moreover, histopathological observations on rats brain sections indicate VA10 (10 mg/kg, p.o) recovered the neuronal cells at hippocampus region (DG, CA3, and CA1). These positive experimental data from in-silico, in-vitro and in-vivo studies, suggested that compound VA10 can be a lead compound for further preclinical development studies as a naturally derived alkaloid for anti-AD.
维司碱是一种吡咯并喹唑啉生物碱，已从 Adhatoda vasica 植物中分离得到。使用维司碱作为合成前体进行了受自然启发的半合成转化，以克服阿尔茨海默病（AD）。这些半合成类似物在计算机研究中表现出稳定的相互作用，并很好地位于 AChE 和 BChE 的活性部位。此外，进行了体外实验以评估胆碱酯酶抑制活性和减少淀粉样蛋白-β（Aβ）斑块效力、PAMPA 测定渗透率和抗氧化活性，这些发现表明化合物 VA10 可以成为所有合成类似物中的先导分子。通过碘化丙啶置换测定建立了化合物 VA10 与 AChE 外周阴离子部位（PAS）的结合特性。此外，VA10 在 Aβ 处理的 SH-SY5Y 细胞系上显示出无明显细胞毒性和神经保护作用。此外，VA10 在大鼠中被发现是安全的，这通过急性口服毒性研究得到证实。此外，体内研究表明，化合物 VA10（10mg/kg，po）改善了东莨菪碱诱导的健忘症模型和 Aβ 诱导的阿尔茨海默病大鼠模型中的记忆和认知障碍。化合物 VA10 的离体研究表明，通过抑制大鼠大脑中的 AChE 活性，可提高 ACh 水平。此外，大鼠脑切片的组织病理学观察表明，VA10（10mg/kg，po）恢复了海马区（DG、CA3 和 CA1）的神经元细胞。这些来自计算机、体外和体内研究的积极实验数据表明，化合物 VA10 可以作为进一步的临床前开发研究的先导化合物，作为一种天然来源的生物碱用于抗 AD。
