Jain Priti, Wadhwa Pankaj K, Rohilla Shilpa, Jadhav Hemant R
Computational Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India; Medicinal Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India.
Medicinal Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India.
Bioorg Med Chem Lett. 2016 Jan 1;26(1):33-7. doi: 10.1016/j.bmcl.2015.11.044. Epub 2015 Nov 14.
BACE-1 (β-secretase) is considered to be one of the promising targets for treatment of Alzheimer's disease as it catalyzes the rate limiting step of Aβ-42 production. Herein, we report a novel class of allylidene hydrazinecarboximidamide derivatives as moderately potent BACE-1 inhibitors, having aminoguanidine substitution on allyl linker with two aromatic groups on either side. A library of derivatives was designed based on the docking studies, synthesized and evaluated for BACE-1 inhibition in vitro. The designed ligands displayed interactions with the catalytic aspartate dyad through guanidinium functionality. Further, the aromatic rings placed on either side of the linker occupied S1 and S3 active site regions contributing to the activity. These ligands were also predicted to follow Lipinski rule and cross blood brain barrier. Compound 2.21, having high docking score, was found to be most active with IC50 of 6.423μM indicating good correlation with docking prediction.
β-分泌酶1（BACE-1）被认为是治疗阿尔茨海默病的有前景的靶点之一，因为它催化β淀粉样蛋白42（Aβ-42）生成的限速步骤。在此，我们报道了一类新型的亚烯丙基肼甲脒衍生物，作为中等效力的BACE-1抑制剂，在烯丙基连接基上有氨基胍取代基，两侧各有两个芳香基团。基于对接研究设计了一系列衍生物，进行合成并在体外评估其对BACE-1的抑制作用。设计的配体通过胍基官能团与催化天冬氨酸二元体相互作用。此外，连接基两侧的芳香环占据S1和S3活性位点区域，对活性有贡献。这些配体还预计符合Lipinski规则并能穿过血脑屏障。对接分数高的化合物2.21被发现活性最高，IC50为6.423μM，表明与对接预测有良好的相关性。
