Design, synthesis, biological evaluation and molecular modeling of N-isobutyl-N-((2-(p-tolyloxymethyl)thiazol-4yl)methyl)benzo[d][1,3] dioxole-5-carboxamides as selective butyrylcholinesterase inhibitors

Meiyang Xi; Chengjie Feng; Kui Du; Weiping Lv; Chenxi Du; Runpu Shen; Haopeng Sun

doi:10.1016/j.bmcl.2022.128602

Design, synthesis, biological evaluation and molecular modeling of N-isobutyl-N-((2-(p-tolyloxymethyl)thiazol-4yl)methyl)benzo[d][1,3] dioxole-5-carboxamides as selective butyrylcholinesterase inhibitors

Bioorg Med Chem Lett. 2022 Apr 1:61:128602. doi: 10.1016/j.bmcl.2022.128602. Epub 2022 Feb 3.

Authors

Meiyang Xi¹, Chengjie Feng², Kui Du¹, Weiping Lv³, Chenxi Du³, Runpu Shen⁴, Haopeng Sun⁵

Affiliations

¹ College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing 312000, China.
² College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing 312000, China; Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing 312000, China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
⁴ College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing 312000, China; Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing 312000, China. Electronic address: srunpu@usx.edu.cn.
⁵ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: sunhaopeng@163.com.

PMID: 35124202
DOI: 10.1016/j.bmcl.2022.128602

Abstract

Butyrylcholinesterase (BuChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD). Development of selective BuChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Recently, we reported the N-isobutyl-N-((2-(p-tolyloxymethyl)thiazol-4-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (1) as a selective BuChE inhibitor. Subsequently, 33 analogs were synthesized and assessed by AChE/BuChE activities, indicating an optimal compound 23. Further kinetic tests suggested a competitive manner. Molecular docking and Molecular dynamics (MD) simulation showed that it interacted with several residues in active site gorge of BuChE, possibly contributing to its selectivity and competitive pattern. Moreover, it showed low cytotoxicity and high blood brain barrier (BBB) permeability. Taken together, 23 was a promising BuChE inhibitor for the treatment of AD.

Keywords: AD; Docking; MD simulation; Selective BuChE inhibitors.

Publication types

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

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Butyrylcholinesterase / metabolism*
Cell Line
Cell Survival / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Models, Molecular
Molecular Structure
Structure-Activity Relationship

Substances

Cholinesterase Inhibitors
Acetylcholinesterase
Butyrylcholinesterase