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.CHIA-RON YANGLiou J.-P.2021-06-042021-06-042018222623https://www.scopus.com/inward/record.uri?eid=2-s2.0-85050635071&doi=10.1021%2facs.jmedchem.8b00151&partnerID=40&md5=0e6278aafb36eae87b8307658802ff46https://scholars.lib.ntu.edu.tw/handle/123456789/565269This paper reports the development of a series of 5-aroylindolyl-substituted 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. ? Copyright 2018 American Chemical Society.[SDGs]SDG33 [3 [5 (3,4 dimethoxy benzoyl)indole 1 sulfonyl]phenyl] n hydroxy acrylamide; 3 [3 [5 (4 fluoro benzoyl)indole 1 sulfonyl]phenyl] n hydroxy acrylamide; 4 [5 (3,4 dimethoxy benzoyl)indol 1 ylmethyl] n hydroxy benzamide; 4 [5 (4 chloro benzoyl)indol 1 ylmethyl] n hydroxy benzamide; 4 [5 (4 fluoro benzoyl)indol 1 ylmethyl] n hydroxy benzamide; 5 aroylindole derivative; histone deacetylase 1; histone deacetylase 2; histone deacetylase 3; histone deacetylase 6; histone deacetylase inhibitor; hydroxamic acid derivative; indole derivative; n hydroxy 3 [3 [5 (3 methoxy benzoyl)indole 1 sulfonyl]phenyl]acrylamide; n hydroxy 3 [3 [5 (3,4,5 trimethoxy benzoyl)indole 1 sulfonyl]phenyl]acrylamide; n hydroxy 3 [3 [5 (4 methoxy benzoyl)indole 1 sulfonyl]phenyl]acrylamide; n hydroxy 3 [3 [5 (4 methyl benzoyl)indole 1 sulfonyl]phenyl]acrylamide; n hydroxy 3 [4 [5 (3,4,5 trimethoxy benzoyl)indol 1 ylmethyl]phenyl]acrylamide; n hydroxy 3 [4 [5 (3,4,5 trimethoxy benzoyl)indole 1 sulfonyl]phenyl]acrylamide; n hydroxy 3 [4 [5 (4 methoxy benzoyl)indol 1 ylmethyl]phenyl]acrylamide; n hydroxy 3 [4 [5 (4 methoxy benzoyl)indole 1 sulfonyl]phenyl]acrylamide; n hydroxy 4 [5 (3 methoxy benzoyl)indol 1 ylmethyl]benzamide; n hydroxy 4 [5 (3,4,5 trimethoxy benzoyl)indol 1 ylmethyl]benzamide; n hydroxy 4 [5 (4 methoxy benzoyl)indol 1 ylmethyl]benzamide; n hydroxy 4 [5 (4 methyl benzoyl)indol 1 ylmethyl]benzamide; neuroprotective agent; nootropic agent; tau protein; trichostatin A; unclassified drug; vorinostat; HDAC6 protein, human; histone deacetylase 6; histone deacetylase inhibitor; hydroxamic acid; indole derivative; neuroprotective agent; tau protein; Alzheimer disease; animal cell; animal experiment; animal model; animal tissue; Article; blood brain barrier; brain-to-plasma ratio; cognitive defect; comparative study; concentration response; controlled study; down regulation; drug blood level; drug brain level; drug selectivity; drug synthesis; elevated plus maze test; enzyme activity; enzyme inhibition; histone ubiquitination; human; human cell; IC50; learning disorder; male; maximum tolerated dose; memory disorder; Morris water maze test; neuroprotection; nonhuman; protein aggregation; protein phosphorylation; rat; SH-SY5Y cell line; Alzheimer disease; animal; binding site; cell line; chemistry; cognition assessment; disease model; drug effect; female; metabolism; molecular docking; phosphorylation; Sprague Dawley rat; synthesis; transgenic mouse; ubiquitination; Wistar rat; Alzheimer Disease; Animals; Binding Sites; Blood-Brain Barrier; Cell Line; Disease Models, Animal; Female; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Male; Memory and Learning Tests; Mice, Transgenic; Molecular Docking Simulation; Neuroprotective Agents; Phosphorylation; Rats, Sprague-Dawley; Rats, Wistar; tau Proteins; Ubiquitinationjournal article10.1021/acs.jmedchem.8b00151300286162-s2.0-85050635071