Kumar Vijay, Jangid Kailash, Kumar Vishal, Kumar Naveen, Mishra Jayapriya, Arora Tania, Dwivedi Ashish Ranjan, Kumar Puneet, Bhatti Jasvinder Singh, Parkash Jyoti, Kumar Vinod
Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, India, 151401.
Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab, India, 151401.
Bioorg Chem. 2025 Feb;155:108126. doi: 10.1016/j.bioorg.2025.108126. Epub 2025 Jan 3.
The pathology of Alzheimer's disease (AD) is complex due to its multifactorial nature and single targeting drugs proved inefficient. A series of novel 4-N-substituted-2-phenylquinazoline derivatives was designed and synthesized as potential multi-target directed ligands (MTDLs) through dual inhibition of AChE and MAO-B enzymes along with Aβ aggregation inhibition for the treatment of AD. Two compounds in the series, VAV-8 and VAV-19 were found to be the most potent inhibitors of both AChE and MAO-B enzymes and moderate inhibitor of Aβ, with good thermodynamic stability at the binding pocket of the enzymes. Both the ligands showed moderate ROS inhibition and neuroprotection potential and found to be permeable to the blood-brain barrier. Furthermore, VAV-8 was subjected to toxicity evaluation and in vivo investigation using a zebrafish model. In adult zebrafish, VAV-8 (5 μM, and 10 μM) was found to be effective in reducing cognitive deterioration, neurodegeneration, and oxidative stress induced by scopolamine. Thus, these quinazoline derivatives have the potential to be developed as MTDLs for the treatment of Alzheimer's disease.
阿尔茨海默病（AD）的病理过程复杂，具有多因素性质，单一靶向药物已被证明效果不佳。设计并合成了一系列新型的4-N-取代-2-苯基喹唑啉衍生物，作为潜在的多靶点导向配体（MTDLs），通过双重抑制乙酰胆碱酯酶（AChE）和单胺氧化酶B（MAO-B）以及抑制β-淀粉样蛋白（Aβ）聚集来治疗AD。该系列中的两种化合物VAV-8和VAV-19被发现是AChE和MAO-B酶的最有效抑制剂，也是Aβ的中度抑制剂，在酶的结合口袋处具有良好的热稳定性。这两种配体均表现出适度的活性氧（ROS）抑制和神经保护潜力，并且被发现可透过血脑屏障。此外，使用斑马鱼模型对VAV-8进行了毒性评估和体内研究。在成年斑马鱼中，发现VAV-8（5μM和10μM）可有效减轻东莨菪碱诱导的认知衰退、神经退行性变和氧化应激。因此，这些喹唑啉衍生物有潜力被开发为治疗阿尔茨海默病的MTDLs。
