Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer’s Disease: Synthesis, Docking and Biological Evaluation

Hydroxamic acids are one of the most promising and actively studied classes of chemical compounds in medicinal chemistry. In this study, we describe the directed synthesis and effects of HDAC6 inhibitors. Fragments of adamantane and natural terpenes camphane and fenchane, combined with linkers of va...

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Autores principales:	Margarita Neganova, Yulia Aleksandrova, Evgenii Suslov, Evgenii Mozhaitsev, Aldar Munkuev, Dmitry Tsypyshev, Maria Chicheva, Artem Rogachev, Olga Sukocheva, Konstantin Volcho, Sergey Klochkov
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	natural compounds hydroxamic acids camphane fenchane adamantane molecular docking Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/1d71400901a04db7a67bc9a958131f15
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spelling	oai:doaj.org-article:1d71400901a04db7a67bc9a958131f152021-11-25T18:41:37ZNovel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer’s Disease: Synthesis, Docking and Biological Evaluation10.3390/pharmaceutics131118931999-4923https://doaj.org/article/1d71400901a04db7a67bc9a958131f152021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1893https://doaj.org/toc/1999-4923Hydroxamic acids are one of the most promising and actively studied classes of chemical compounds in medicinal chemistry. In this study, we describe the directed synthesis and effects of HDAC6 inhibitors. Fragments of adamantane and natural terpenes camphane and fenchane, combined with linkers of various nature with an amide group, were used as the CAP groups. Accordingly, 11 original target compounds were developed, synthesized, and exposed to in vitro and in vivo biological evaluations, including in silico methods. In silico studies showed that all synthesized compounds were drug-like and could penetrate through the blood–brain barrier. According to the in vitro testing, hydroxamic acids <b>15</b> and <b>25</b>, which effectively inhibited HDAC6 and exhibited anti-aggregation properties against β-amyloid peptides, were chosen as the most promising substances to study their neuroprotective activities in vivo. All in vivo studies were performed using 5xFAD transgenic mice simulating Alzheimer’s disease. In these animals, the Novel Object Recognition and Morris Water Maze Test showed that the formation of hippocampus-dependent long-term episodic and spatial memory was deteriorated. Hydroxamic acid <b>15</b> restored normal memory functions to the level observed in control wild-type animals. Notably, this effect was precisely associated with the ability to restore lost cognitive functions, but not with the effect on motor and exploratory activities or on the level of anxiety in animals. Conclusively, hydroxamic acid <b>15</b> containing an adamantane fragment linked by an amide bond to a hydrocarbon linker is a possible potential multitarget agent against Alzheimer’s disease.Margarita NeganovaYulia AleksandrovaEvgenii SuslovEvgenii MozhaitsevAldar MunkuevDmitry TsypyshevMaria ChichevaArtem RogachevOlga SukochevaKonstantin VolchoSergey KlochkovMDPI AGarticlenatural compoundshydroxamic acidscamphanefenchaneadamantanemolecular dockingPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1893, p 1893 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	natural compounds hydroxamic acids camphane fenchane adamantane molecular docking Pharmacy and materia medica RS1-441
spellingShingle	natural compounds hydroxamic acids camphane fenchane adamantane molecular docking Pharmacy and materia medica RS1-441 Margarita Neganova Yulia Aleksandrova Evgenii Suslov Evgenii Mozhaitsev Aldar Munkuev Dmitry Tsypyshev Maria Chicheva Artem Rogachev Olga Sukocheva Konstantin Volcho Sergey Klochkov Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer’s Disease: Synthesis, Docking and Biological Evaluation
description	Hydroxamic acids are one of the most promising and actively studied classes of chemical compounds in medicinal chemistry. In this study, we describe the directed synthesis and effects of HDAC6 inhibitors. Fragments of adamantane and natural terpenes camphane and fenchane, combined with linkers of various nature with an amide group, were used as the CAP groups. Accordingly, 11 original target compounds were developed, synthesized, and exposed to in vitro and in vivo biological evaluations, including in silico methods. In silico studies showed that all synthesized compounds were drug-like and could penetrate through the blood–brain barrier. According to the in vitro testing, hydroxamic acids <b>15</b> and <b>25</b>, which effectively inhibited HDAC6 and exhibited anti-aggregation properties against β-amyloid peptides, were chosen as the most promising substances to study their neuroprotective activities in vivo. All in vivo studies were performed using 5xFAD transgenic mice simulating Alzheimer’s disease. In these animals, the Novel Object Recognition and Morris Water Maze Test showed that the formation of hippocampus-dependent long-term episodic and spatial memory was deteriorated. Hydroxamic acid <b>15</b> restored normal memory functions to the level observed in control wild-type animals. Notably, this effect was precisely associated with the ability to restore lost cognitive functions, but not with the effect on motor and exploratory activities or on the level of anxiety in animals. Conclusively, hydroxamic acid <b>15</b> containing an adamantane fragment linked by an amide bond to a hydrocarbon linker is a possible potential multitarget agent against Alzheimer’s disease.
format	article
author	Margarita Neganova Yulia Aleksandrova Evgenii Suslov Evgenii Mozhaitsev Aldar Munkuev Dmitry Tsypyshev Maria Chicheva Artem Rogachev Olga Sukocheva Konstantin Volcho Sergey Klochkov
author_facet	Margarita Neganova Yulia Aleksandrova Evgenii Suslov Evgenii Mozhaitsev Aldar Munkuev Dmitry Tsypyshev Maria Chicheva Artem Rogachev Olga Sukocheva Konstantin Volcho Sergey Klochkov
author_sort	Margarita Neganova
title	Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer’s Disease: Synthesis, Docking and Biological Evaluation
title_short	Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer’s Disease: Synthesis, Docking and Biological Evaluation
title_full	Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer’s Disease: Synthesis, Docking and Biological Evaluation
title_fullStr	Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer’s Disease: Synthesis, Docking and Biological Evaluation
title_full_unstemmed	Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer’s Disease: Synthesis, Docking and Biological Evaluation
title_sort	novel multitarget hydroxamic acids with a natural origin cap group against alzheimer’s disease: synthesis, docking and biological evaluation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1d71400901a04db7a67bc9a958131f15
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Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer’s Disease: Synthesis, Docking and Biological Evaluation

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