Abstract
Background: Alzheimer’s disease (AD), a chronic neurodegenerative disorder predominantly occurs among the elderly, is the leading cause of dementia. The accumulation of β-amyloid (Aβ) is considered the main pathogenies of AD, and β-site APP-cleaving enzyme 1 (BACE1) plays an important role in the formulation of Aβ.
Objective: In order to find a new scaffold as BACE1 inhibitors, a series of novel 2-amino-1-phenylbenzimidazole derivatives were designed and synthesized in this work.
Methods: Using our previous L-5 as a lead compound, we applied a scaffold hopping method and merged 2-amino-1-methyl-4-phenyl-1H-imidazol-5 (4H)-one into benzimidazole, so a novel class of BACE1 inhibitors T1~T20 with the structure of 2-amino-1-phenyl-benzimidazole were designed and synthesized.
Results: The biological activity evaluation indicated that the target compounds showed inhibitory activities against BACE1, with T14 being the most potent (IC50 = 0.45 μM), it also exhibited good logP value and tPSA. The docking studies indicated that compound T14 could form important hydrogen bonds with Asp289 and Asp93.
Conclusion: Compound T14 could be used as a potential BACE1 inhibitor for further modification to treat AD.
Keywords: Alzheimer's disease, BACE-1 inhibitor, benzimidazole derivatives, FRET, Compound T14, β-amyloid (Aβ).
[http://dx.doi.org/10.1056/NEJMra0909142] [PMID: 20107219]
[http://dx.doi.org/10.1016/S1474-4422(13)70276-X] [PMID: 24556009]
[http://dx.doi.org/10.1038/nature11283] [PMID: 22801501]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00307] [PMID: 27933948]
[http://dx.doi.org/10.1002/jcph.950] [PMID: 28618005]
[http://dx.doi.org/10.1080/14737175.2018.1531706] [PMID: 30277096]
[http://dx.doi.org/10.1016/j.trci.2016.08.001] [PMID: 29067308]
[http://dx.doi.org/10.1358/dot.2015.51.7.2375989] [PMID: 26261847]
[http://dx.doi.org/10.1016/j.bmcl.2019.126772] [PMID: 31711785]
[http://dx.doi.org/10.1016/j.bmcl.2010.09.029] [PMID: 20880704]
[http://dx.doi.org/10.1021/jm060642i] [PMID: 17181137]
[http://dx.doi.org/10.1016/j.bmcl.2012.02.013] [PMID: 22390835]
[http://dx.doi.org/10.1021/ol403672p] [PMID: 24479902]
[http://dx.doi.org/10.1002/chem.200902054] [PMID: 20077532]
[http://dx.doi.org/10.1523/JNEUROSCI.3647-11.2011] [PMID: 22090477]
[http://dx.doi.org/10.1021/cn200100h] [PMID: 22267984]
[http://dx.doi.org/10.1155/2018/1421438] [PMID: 29854073]