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Acylhydrazones as isoniazid derivatives with multi-target profiles for the treatment of Alzheimer's disease: Radical scavenging, myeloperoxidase/acetylcholinesterase inhibition and biometal chelation.
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2020-03-31 , DOI: 10.1016/j.bmc.2020.115470
Daniela Corrêa Santos 1 , Ruan Roberto Henriques 2 , Marcos Antonio de Abreu Lopes Junior 3 , André Borges Farias 4 , Thayssa Lisboa do Couto Nogueira 1 , João Victor Fernandes Quimas 1 , Nelilma Correia Romeiro 3 , Leandro Louback da Silva 1 , Andréa Luzia Ferreira de Souza 3
Affiliation  

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.

中文翻译:

酰基hydr作为异烟肼衍生物,具有多种目标物,可用于治疗阿尔茨海默氏病:清除自由基,抑制髓过氧化物酶/乙酰胆碱酯酶和生物金属螯合。

合成并衍生了异烟肼制的酰基hydr 1a-o对髓过氧化物酶(MPO)和乙酰胆碱酯酶(AChE)的抑制作用以及它们的抗氧化和金属螯合活性,目的是研究潜在的多靶点治疗阿尔茨海默氏病的方法。疾病。合成的化合物使用2,2-二苯基-2-甲基苯并肼(DPPH)方法进行测试,并且1i,1j和1m显示出自由基清除能力。化合物1b,1 h,1i,1 m和1o分别以96.1±5.5%,90±2.1%,100.3±1.7%,80.1±9.4%和82.2±10.6%抑制MPO活性(10μM) 1 m能够抑制54.2±1.7%的AChE活性(100μM)。对最有效的化合物1 m进行了对接研究,计算结果为酶抑制提供了理论依据。此外,
更新日期:2020-04-20
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