Alkynyl and β-ketophosphonates: Selective and potent butyrylcholinesterase inhibitors

被引：16

作者：

Cavallaro, Valeria ^{[1
]}

Moglie, Yanina F. ^{[1
]}

Murray, Ana P. ^{[1
]}

Radivoy, Gabriel E. ^{[1
]}

机构：

[1] Univ Nacl Sur, CONICET, INQUISUR, Inst Quim Sur,Dept Quim, Ave Alem 1253, RA-8000 Bahia Blanca, Buenos Aires, Argentina

来源：

BIOORGANIC CHEMISTRY | 2018年 / 77卷

关键词：

Organophosphorus compounds; Phosphonates; Enzymatic inhibition; Butyrylcholinesterase; PHOSPHINE OXIDES; BIOLOGICAL EVALUATION; H-PHOSPHONATES; ACETYLCHOLINESTERASE; ALKYNYLPHOSPHONATES; PHOSPHATES; SITE; CHOLINESTERASES; DERIVATIVES; ANALOGS;

D O I：

10.1016/j.bioorg.2018.01.030

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of thirty-three alkynyl and beta-ketophosphonates were evaluated for their in vitro acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitory activities using Ellman's spectrophotometric method. None of the examined compounds inhibited AChE activity at tested concentrations while twenty-nine of them showed significant and selective inhibition of BChE with IC50 values between 38.60 mu M and 0.04 mu M. In addition, structure-activity relationships were discussed. The most effective inhibitors were the dibutyl o-methoxyphenyl alkynylphosphonate 3dc and dibutyl o-methoxyphenyl beta-ketophosphonate 4dc. Activities of most potent compounds were also compared with a commercial organophosphorus compound. These results could inspire the design of new inhibitors with stronger activity against BChE. (C) 2018 Elsevier Inc. All rights reserved.

引用

页码：420 / 428

页数：9

共 39 条

[1] Synthesis and anti-acetylcholinesterase properties of novel β- and γ-substituted alkoxy organophosphonates [J].

Ahmed, S. Kaleem ;

Belabassi, Yamina ;

Sankaranarayanan, Lakshmi ;

Chao, Chih-Kai ;

Gerdes, John M. ;

Thompson, Charles M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (07) :2048-2051

[2] Efficient synthesis of novel dialkyl-3-cyanopropylphosphate derivatives and evaluation of their anticholinesterase activity [J].

Aouani, Iyadh ;

Sellami, Badreddine ;

Lahbib, Karima ;

Cavalier, Jean-Francois ;

Touil, Soufiane .

BIOORGANIC CHEMISTRY, 2017, 72 :301-307

[3] Organophosphates/nerve agent poisoning: Mechanism of action, diagnosis, prophylaxis, and treatment [J].

Bajgar, J .

ADVANCES IN CLINICAL CHEMISTRY, VOL. 38, 2004, 38 :151-216

[4] Structure-activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun [J].

Carletti, Eugenie ;

Aurbek, Nadine ;

Gillon, Emilie ;

Loiodice, Melanie ;

Nicolet, Yvain ;

Fontecilla-Camps, Juan-Carlos ;

Masson, Patrick ;

Thiermann, Horst ;

Nachon, Florian ;

Worek, Franz .

BIOCHEMICAL JOURNAL, 2009, 421 :97-106

[5] Serine hydrolase targets of organophosphorus toxicants [J].

Casida, JE ;

Quistad, GB .

CHEMICO-BIOLOGICAL INTERACTIONS, 2005, 157 :277-283

[6] Room temperature alkynylation of H-phosphi(na)tes and secondary phosphine oxides with ethynylbenziodoxolone (EBX) reagents [J].

Chen, C. Chun ;

Waser, Jerome .

CHEMICAL COMMUNICATIONS, 2014, 50 (85) :12923-12926

[7] Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer's disease [J].

Chen, Yao ;

Zhu, Jie ;

Mo, Jun ;

Yang, Hongyu ;

Jiang, Xueyang ;

Lin, Hongzhi ;

Gu, Kai ;

Pei, Yuqiong ;

Wu, Liang ;

Tan, Renxiang ;

Hou, Jing ;

Chen, Jingyi ;

Lv, Yang ;

Bian, Yaoyao ;

Sun, Haopeng .

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2017, 33 (01) :290-302

[8] Ruthenium-Catalyzed [2+2] Cycloadditions of Bicyclic Alkenes with Alkynyl Phosphonates [J].

Cockburn, Neil ;

Karimi, Elham ;

Tam, William .

JOURNAL OF ORGANIC CHEMISTRY, 2009, 74 (15) :5762-5765

[9] Alzheimer's disease drug-development pipeline: few candidates, frequent failures [J].

Cummings, Jeffrey L. ;

Morstorf, Travis ;

Zhong, Kate .

ALZHEIMERS RESEARCH & THERAPY, 2014, 6 (04)

[10]

CYGLER M, 1993, PROTEIN SCI, V2, P366

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