This paper reports the development of a series of 5-aroylindolyl-substitued hydroxamic acids. N-hydroxy-4-((5-(4-methoxybenzoyl)-1H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC50 value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain-barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer's disease in the future.
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Lee, H. Y., Fan, S. J., Huang, F. I., Chao, H. Y., Hsu, K. C., Lin, T. E., Yeh, T. K., Lai, M. J., Li, Y. H., Huang, H. L., Yang, C. R., & Liou, J. P. (認可的出版社/出版中). 5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer's Disease Phenotypes. Journal of Medicinal Chemistry. https://doi.org/10.1021/acs.jmedchem.8b00151