Novel multitarget hydroxamic acids with a natural origin CAP group against alzheimer’s disease: Synthesis, docking and biological evaluation

Novel multitarget hydroxamic acids with a natural origin CAP group against alzheimer’s disease: Synthesis, docking and biological evaluation Full article

Journal

Pharmaceutics
ISSN: 1999-4923

Output data

Year: 2021, Volume: 13, Number: 11, Article number : 1893, Pages count : DOI: 10.3390/pharmaceutics13111893

Tags

5xFAD transgenic mice; Adamantane; Alzheimer’s disease; Camphane; Fenchane; Histone deacetylase 6; Hydroxamic acids; Molecular docking; Natural compounds; β-amyloid aggregation

Authors

Neganova Margarita ¹ , Aleksandrova Yulia ¹ , Suslov Evgenii ² , Mozhaitsev Evgenii ² , Munkuev Aldar ² , Tsypyshev Dmitry ² , Chicheva Maria ¹ , Rogachev Artem ² , Sukocheva Olga ³ , Volcho Konstantin ² , Klochkov Sergey ¹

Affiliations

1	Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow, 142432, Russian Federation
2	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
3	Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, SA 5042, Australia

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. Accord-ingly, 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 15 and 25, 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 15 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 15 containing an adamantane fragment linked by an amide bond to a hydrocarbon linker is a possible potential multitarget agent against Alzheimer’s disease. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Neganova M. , Aleksandrova Y. , Suslov E. , Mozhaitsev E. , Munkuev A. , Tsypyshev D. , Chicheva M. , Rogachev A. , Sukocheva O. , Volcho K. , Klochkov S.
Novel multitarget hydroxamic acids with a natural origin CAP group against alzheimer’s disease: Synthesis, docking and biological evaluation
Pharmaceutics. 2021. V.13. N11. 1893 . DOI: 10.3390/pharmaceutics13111893 WOS Scopus РИНЦ РИНЦ

Web of science	WOS:000725038700001
Scopus	2-s2.0-85119604389
Elibrary	47251469 , 47530109
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