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

Daniela Corrêa Santos; Ruan Roberto Henriques; Marcos Antonio de Abreu Lopes Junior; André Borges Farias; Thayssa Lisboa do Couto Nogueira; João Victor Fernandes Quimas; Nelilma Correia Romeiro; Leandro Louback da Silva; Andréa Luzia Ferreira de Souza

doi:10.1016/j.bmc.2020.115470

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

Bioorg Med Chem. 2020 May 15;28(10):115470. doi: 10.1016/j.bmc.2020.115470. Epub 2020 Mar 31.

Authors

Daniela Corrêa Santos¹, Ruan Roberto Henriques², Marcos Antonio de Abreu Lopes Junior³, André Borges Farias⁴, Thayssa Lisboa do Couto Nogueira¹, João Victor Fernandes Quimas¹, Nelilma Correia Romeiro³, Leandro Louback da Silva⁵, Andréa Luzia Ferreira de Souza⁶

Affiliations

¹ Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Avenida Aluizio da Silva Gomes, 50, CEP 27930-560, Granja dos Cavaleiros, Macaé, RJ, Brazil.
² Universidade Federal do Rio de Janeiro, Cidade Universitária, Avenida Horácio Macedo, 2030, CEP 21941-598, Rio de Janeiro - RJ, Brazil.
³ Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Avenida Aluizio da Silva Gomes, 50, CEP 27930-560, Granja dos Cavaleiros, Macaé, RJ, Brazil; Programa de Pós-Graduação em Produtos Bioativos e Biociências - PPG-PRODBIO, Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Avenida Aluizio da Silva Gomes, 50, CEP 27930-560, Granja dos Cavaleiros, Macaé - RJ, Brazil.
⁴ Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Avenida Aluizio da Silva Gomes, 50, CEP 27930-560, Granja dos Cavaleiros, Macaé, RJ, Brazil; Programa de Pós-Graduação em Química - PPGQu, Universidade Federal do Rio de Janeiro, Cidade Universitária, Avenida Athos da Silveira Ramos, 149, Bloco A, CEP 21941-909, Rio de Janeiro - RJ, Brazil.
⁵ Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Avenida Aluizio da Silva Gomes, 50, CEP 27930-560, Granja dos Cavaleiros, Macaé, RJ, Brazil. Electronic address: lelouback@macae.ufrj.br.
⁶ Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Avenida Aluizio da Silva Gomes, 50, CEP 27930-560, Granja dos Cavaleiros, Macaé, RJ, Brazil; Programa de Pós-Graduação em Produtos Bioativos e Biociências - PPG-PRODBIO, Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Avenida Aluizio da Silva Gomes, 50, CEP 27930-560, Granja dos Cavaleiros, Macaé - RJ, Brazil. Electronic address: andrealuzia@iq.ufrj.br.

PMID: 32278712
DOI: 10.1016/j.bmc.2020.115470

Abstract

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.

Keywords: Acetylcholinesterase; Acylhydrazone; Antioxidant; Biometal chelation; Isoniazid; Molecular docking; Myeloperoxidase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Animals
Antioxidants / chemical synthesis
Antioxidants / chemistry
Antioxidants / pharmacology*
Biphenyl Compounds / antagonists & inhibitors
Chelating Agents / chemical synthesis
Chelating Agents / chemistry
Chelating Agents / pharmacology*
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Electrophorus
Humans
Hydrazones / chemical synthesis
Hydrazones / chemistry
Hydrazones / pharmacology*
Molecular Docking Simulation
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Peroxidase / antagonists & inhibitors
Peroxidase / metabolism
Picrates / antagonists & inhibitors
Structure-Activity Relationship

Substances

Antioxidants
Biphenyl Compounds
Chelating Agents
Cholinesterase Inhibitors
Hydrazones
Neuroprotective Agents
Picrates
1,1-diphenyl-2-picrylhydrazyl
MPO protein, human
Peroxidase
Acetylcholinesterase