Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents

Oliveira Catarina; Bagetta Donatella; Cagide Fernando; Teixeira Jose; Amorim Ricardo; Silva Tiago; Garrido Jorge; Remiao Fernando; Uriarte Eugenio; Oliveira Paulo J.; Alcaro Stefano; Ortuso Francesco; Borges Fernanda

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Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents

机译：苯甲酸衍生的硝基：一种新的潜在乙酰胆碱酯酶抑制剂和神经保护剂

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The discovery of new chemical entities endowed with potent and selective acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) inhibitory activity is still a relevant subject for Alzheimer's disease therapy. Therefore, a small library of benzoic based amide nitrones (compounds 24 to 42) was synthesized and screened toward cholinesterase enzymes. SAR studies showed that the tert-butyl moiety is the most favourable nitrone pattern. In general, tert-butyl derivatives effectively inhibited AChE, being compound 33 the most potent (IC50 = 8.3 +/- 0.3 mu M; Ki 5.2 mu M). The data pointed to a non-competitive inhibition mechanism of action, which was also observed for the standard donepezil. None of compounds showed BChE inhibitory activity. Molecular modelling studies provided insights into the enzyme-inhibitor interactions and rationalised the experimental data, confirming that the binding mode of nitrones 33 and 38 towards AChE has the most favourable binding free energy.

机译：发现具有有效和选择性乙酰胆碱酯酶（ACHE）和/或丁酰基胆碱酯酶（BCHE）抑制活性的新化学实体仍然是阿尔茨海默病治疗的相关主题。因此，合成并筛选基于苯甲酸的酰胺硝基氨酸（化合物24至42），并筛选朝向胆碱酯酶酶。 SAR研究表明，叔丁基部分是最有利的亚硝石图案。通常，叔丁基衍生物有效地抑制疼痛，是化合物33最有效的（IC50 = 8.3 +/-0.3μm; ki5.2μm）。指出的数据指向非竞争性抑制机制，也针对标准的多奈哌齐观察到。没有一种化合物显示BCHE抑制活性。分子建模研究提供了酶抑制剂相互作用的见解，并合理化了实验数据，证实亚硝酮33和38朝向疼痛的结合模式具有最有利的无限化能量。

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来源
《European Journal of Medicinal Chemistry: Chimie Therapeutique》 |2019年第2019期|共14页
作者
Oliveira Catarina; Bagetta Donatella; Cagide Fernando; Teixeira Jose; Amorim Ricardo; Silva Tiago; Garrido Jorge; Remiao Fernando; Uriarte Eugenio; Oliveira Paulo J.; Alcaro Stefano; Ortuso Francesco; Borges Fernanda;
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作者单位

Univ Porto Fac Sci Dept Chem &

Biochem CIQUP Rua Campo Alegre S-N P-4169007 Porto Portugal;

Magna Graecia Univ Catanzaro Dept Sci Salute Campus Univ S Venuta Catanzaro Italy;

Univ Porto Fac Sci Dept Chem &

Biochem CIQUP Rua Campo Alegre S-N P-4169007 Porto Portugal;

Univ Porto Fac Sci Dept Chem &

Biochem CIQUP Rua Campo Alegre S-N P-4169007 Porto Portugal;

Univ Porto Fac Sci Dept Chem &

Biochem CIQUP Rua Campo Alegre S-N P-4169007 Porto Portugal;

Univ Porto Fac Sci Dept Chem &

Biochem CIQUP Rua Campo Alegre S-N P-4169007 Porto Portugal;

Univ Porto Fac Sci Dept Chem &

Biochem CIQUP Rua Campo Alegre S-N P-4169007 Porto Portugal;

Univ Porto Fac Pharm Dept Biol Sci UCIBIO REQUIMTE Lab Toxicol Porto Portugal;

Univ Santiago Compostela Fac Pharm Dept Organ Chem Santiago De Compostela Spain;

Univ Coimbra UC Biotech CNC Ctr Neurosci &

Cell Biol Biocant Pk P-3060197 Cantanhede Portugal;

Magna Graecia Univ Catanzaro Dept Sci Salute Campus Univ S Venuta Catanzaro Italy;

Magna Graecia Univ Catanzaro Dept Sci Salute Campus Univ S Venuta Catanzaro Italy;

Univ Porto Fac Sci Dept Chem &

Biochem CIQUP Rua Campo Alegre S-N P-4169007 Porto Portugal;

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原文格式 PDF
正文语种 eng
中图分类药学;
关键词
Benzoic acid; Nitrones; Spin traps; Alzheimer's disease; Cholinesterase inhibitors; Acetylcholinesterase; Oxidative stress;

机译：苯甲酸;硝酸盐;旋转陷阱;阿尔茨海默病;胆碱酯酶抑制剂;乙酰胆碱酯酶;氧化应激;

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1. Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents [J] . Oliveira Catarina, Bagetta Donatella, Cagide Fernando, European Journal of Medicinal Chemistry: Chimie Therapeutique . 2019,第期

机译：苯甲酸衍生的硝基：一种新的潜在乙酰胆碱酯酶抑制剂和神经保护剂
2. α-aryl-N-alkyl nitrones, as potential agents for stroke treatment: Synthesis, theoretical calculations, antioxidant, anti-inflammatory, neuroprotective, and brain-blood barrier permeability properties [J] . Chioua M., Sucunza D., Soriano E., Journal of Medicinal Chemistry . 2012,第1期

机译：α-芳基-N-烷基硝酮，作为中风治疗的潜在药物：合成，理论计算，抗氧化剂，抗炎，神经保护和脑血屏障通透性
3. Synthesis and evaluation of novel 4-[(3H,3aH,6aH)-3-phenyl)-4,6-dioxo-2- phenyldihydro-2H-pyrrolo[3,4-d]isoxazol-5(3H,6H,6aH)-yl]benzoic acid derivatives as potent acetylcholinesterase inhibitors and anti-amnestic agents [J] . AnandP., SinghB. Bioorganic and medicinal chemistry . 2012,第1期

机译：新型4-[（（3H，3aH，6aH）-3-苯基）-4,6-二氧-2--2-苯基二氢-2H-吡咯并[3,4-d]异恶唑-5（3H，6H，6aH）的合成和评价）-基]苯甲酸衍生物作为有效的乙酰胆碱酯酶抑制剂和抗记忆药
4. The combating of corrosion with the help of alkyl benzoic acids salts. Note I. The testing of the sodium salts of p-isopropyl benzoic acid as corrosion inhibitor [C] . P. Chipurici, L. Papahagi, R. Avram, 12th Romanian International Conference on Chemistry and Chemical Engineering Sep 13-15, 2001 Bucharest, Romania . 2001

机译：借助烷基苯甲酸盐来消除腐蚀。注释I.对异丙基苯甲酸钠盐作为缓蚀剂的测试
5. Study of Neuroprotective Effect of Cryptotanshinone, an Acetylcholinesterase Inhibitor, in Cell and Animal Models. [D] . Wong, Kin Kwan Kelvin. 2009

机译：乙酰胆碱酯酶抑制剂隐丹参酮在细胞和动物模型中的神经保护作用研究。
6. New 2-Aryl-9-methyl-β-carbolinium salts as Potential Acetylcholinesterase Inhibitor agents: Synthesis Bioactivity and Structure–Activity Relationship [O] . Bohang Zhou, Bingyu Zhang, Xingqiang Li, -1

机译：新型2-芳基-9-甲基-β-咔啉鎓盐作为潜在的乙酰胆碱酯酶抑制剂：合成生物活性和结构-活性关系
7. Î±-aryl-N-alkyl nitrones, as potential agents for stroke treatment: Synthesis, theoretical calculations, antioxidant, anti-inflammatory, neuroprotective, and brain-blood barrier permeability properties [O] . Chioua Mourad, Sucunza D., Soriano Elena, 2015

机译：α-芳基-N-烷基硝酮，作为中风治疗的潜在药物：合成，理论计算，抗氧化剂，抗炎，神经保护和脑血屏障通透性
8. Acetylcholinesterase Inhibiting Activity of Organophosphate Nerve Agents inPrimary Cultures of Mouse Embryo Neurons [R] . Sawyer, T. W., Weiss, M. T. 1990

机译：乙酰胆碱酯酶抑制小鼠胚胎神经元原代培养物中有机磷酸盐神经毒剂的活性

Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents

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