Acylhydrazones as isoniazid derivatives with multi-target profiles for the treatment of Alzheimer’s disease: Radical scavenging, myeloperoxidase/acetylcholinesterase inhibition and biometal chelation

Acylhydrazones as isoniazid derivatives with multi-target profiles for the treatment of Alzheimer’s disease: Radical scavenging, myeloperoxidase/acetylcholinesterase inhibition and biometal chelation

[Display omitted] Acylhydrazones 1a-o, derived from isoniazid, were synthesized and evaluated for Myeloperoxidase (MPO) and Acetylcholinesterase (AChE) inhibition, as well as their antioxidant and metal chelating activities, with the purpose of investigating potential multi-target profiles for the t...

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Published in:Bioorganic & medicinal chemistry Vol. 28; no. 10; p. 115470
Main Authors: Santos, Daniela Corrêa, Henriques, Ruan Roberto, Junior, Marcos Antonio de Abreu Lopes, Farias, André Borges, Nogueira, Thayssa Lisboa do Couto, Quimas, João Victor Fernandes, Romeiro, Nelilma Correia, Silva, Leandro Louback da, Souza, Andréa Luzia Ferreira de
Format: Journal Article
Language:English
Published: England Elsevier Ltd 15-05-2020
Subjects:
Acetylcholinesterase
Acylhydrazone
Antioxidant
Biometal chelation
Isoniazid
Molecular docking
Myeloperoxidase
Biometal chelation
Acylhydrazone
Myeloperoxidase
Antioxidant
Acetylcholinesterase
Isoniazid
Molecular docking
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Summary:[Display omitted] Acylhydrazones 1a-o, derived from isoniazid, were synthesized and evaluated for Myeloperoxidase (MPO) and Acetylcholinesterase (AChE) inhibition, as well as their antioxidant and metal chelating activities, with the purpose of investigating potential multi-target profiles for the treatment of Alzheimer’s disease. Synthesized compounds were tested using the 2,2-diphenyl-2-picrylhydrazyl (DPPH) method and 1i, 1j and 1 m showed radical scavenging ability. Compounds 1b, 1 h, 1i, 1 m and 1o inhibited MPO activity (10 μM) at 96.1 ± 5.5%, 90 ± 2.1%, 100.3 ± 1.7%, 80.1 ± 9.4% and 82.2 ± 10.6%, respectively, and only compound 1 m was able to inhibit 54.2 ± 1.7% of AChE activity (100 μM). Docking studies of the most potent compound 1 m were carried out, and the computational results provided the theoretical basis of enzyme inhibition. Furthermore, compound 1 m was able to form complexes with Fe2+ and Zn2+ ions in a 2:1 ligand:metal ratio according to the Job Plot method.
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ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2020.115470