Find in Library
Search millions of books, articles, and more
Indexed Open Access Databases
Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities
oleh: Rafael Flores, Shoaib Iqbal, Donald Sikazwe
Format: | Article |
---|---|
Diterbitkan: | MDPI AG 2023-10-01 |
Deskripsi
In search of novel multi-mechanistic approaches for treating Alzheimer’s disease (AD), we have embarked on synthesizing single small molecules for probing contributory roles of the following combined disease targets: sigma-1 (σ-1), class IIb histone deacetylase-6 (HDAC-6), and oxidative stress (OS). Herein, we report the synthesis and partial evaluation of 20 amides (i.e., phenylacetic and Trolox or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid derivatives). Target compounds were conveniently synthesized via amidation by either directly reacting acyl chlorides with amines or condensing acids with amines in the presence of coupling agents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU) or 1,1′-carbonyldiimidazole (CDI). Overall, this project afforded compound <b>8</b> as a promising lead with <i>σ-1</i> affinity (Ki = 2.1 μM), <i>HDAC-6</i> (IC<sub>50</sub> = 17 nM), and <i>antioxidant</i> (1.92 Trolox antioxidant equivalents or TEs) activities for optimization in ensuing structure–activity relationship (SAR) studies.