Sharma Amit, Rudrawar Santosh, Sharma Ankita, Bharate Sandip B, Jadhav Hemant R
Pharmaceutical Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani Pilani Campus, Vidya Vihar Pilani - 333031 RJ India
The Institute for Biomedicine and Glycomics, Griffith University Gold Coast 4222 Australia.
RSC Adv. 2024 Jul 30;14(33):23853-23872. doi: 10.1039/d4ra04315d. eCollection 2024 Jul 26.
Considering the failure of many enzyme inhibitors for Alzheimer's disease (AD), research is now focused on multi-target directed drug discovery. In this paper, inhibition of two essential enzymes implicated in AD pathologies, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), has been explored. Taking clues from our previous work, 41 novel indol-3-yl phenyl allylidene hydrazine carboximidamide derivatives were synthesized. The results indicated that compounds inhibited both enzymes in micromolar concentrations. Compound 1l is proposed as the most active. , it was seen to occupy the binding pocket of AChE and BACE 1. The ADME predictions showed that these compounds have acceptable physicochemical characteristics. This study provides new leads for the assessment of AChE and BACE 1 dual inhibition as a promising strategy for AD treatment.
鉴于许多用于治疗阿尔茨海默病(AD)的酶抑制剂均告失败,目前研究重点在于多靶点导向药物的研发。本文探讨了对AD病理过程中涉及的两种关键酶,即乙酰胆碱酯酶(AChE)和β-分泌酶1(BACE 1,β位点淀粉样前体蛋白裂解酶)的抑制作用。基于我们之前的研究工作,合成了41种新型吲哚-3-基苯基烯丙叉肼甲酰胺衍生物。结果表明,这些化合物在微摩尔浓度下对两种酶均有抑制作用。化合物1l被认为是活性最高的。研究发现,它能够占据AChE和BACE 1的结合口袋。药物代谢动力学(ADME)预测显示,这些化合物具有可接受的理化特性。本研究为评估AChE和BACE 1双重抑制作为一种有前景的AD治疗策略提供了新的线索。