Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities
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)....
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/20/15295 |
| _version_ | 1797573655914348544 |
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| author | Rafael Flores Shoaib Iqbal Donald Sikazwe |
| author_facet | Rafael Flores Shoaib Iqbal Donald Sikazwe |
| author_sort | Rafael Flores |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T21:12:13Z |
| format | Article |
| id | doaj.art-d5e753b01bbd4d34bd5cceb304092823 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:12:13Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d5e753b01bbd4d34bd5cceb3040928232023-11-19T16:44:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124201529510.3390/ijms242015295Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant ActivitiesRafael Flores0Shoaib Iqbal1Donald Sikazwe2Pharmaceutical Sciences Department, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, TX 78209, USAPharmaceutical Sciences Department, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, TX 78209, USAPharmaceutical Sciences Department, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, TX 78209, USAIn 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.https://www.mdpi.com/1422-0067/24/20/15295phenylaceticTroloxhistone-deacetylase-6antioxidantdrug-likeness |
| spellingShingle | Rafael Flores Shoaib Iqbal Donald Sikazwe Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities International Journal of Molecular Sciences phenylacetic Trolox histone-deacetylase-6 antioxidant drug-likeness |
| title | Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities |
| title_full | Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities |
| title_fullStr | Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities |
| title_full_unstemmed | Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities |
| title_short | Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities |
| title_sort | phenylacetyl trolox amides synthesis sigma 1 hdac 6 and antioxidant activities |
| topic | phenylacetic Trolox histone-deacetylase-6 antioxidant drug-likeness |
| url | https://www.mdpi.com/1422-0067/24/20/15295 |
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