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

• 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
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115470

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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.