Novel BuChE-IDO1 inhibitors from sertaconazole: Virtual screening, chemical optimization and molecular modeling studies

You Zhou; Xin Lu; Chenxi Du; Yijun Liu; Yifan Wang; Kwon Ho Hong; Yao Chen; Haopeng Sun

doi:10.1016/j.bmcl.2020.127756

Novel BuChE-IDO1 inhibitors from sertaconazole: Virtual screening, chemical optimization and molecular modeling studies

Bioorg Med Chem Lett. 2021 Feb 15:34:127756. doi: 10.1016/j.bmcl.2020.127756. Epub 2020 Dec 24.

Authors

You Zhou¹, Xin Lu², Chenxi Du², Yijun Liu², Yifan Wang³, Kwon Ho Hong⁴, Yao Chen⁵, Haopeng Sun⁶

Affiliations

¹ College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing 400715, China. Electronic address: zhouy701005@swu.edu.cn.
² Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
³ College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing 400715, China.
⁴ Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA.
⁵ School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
⁶ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: sunhaopeng@cpu.edu.cn.

PMID: 33359445
DOI: 10.1016/j.bmcl.2020.127756

Abstract

In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.

Keywords: Alzheimer’s disease; Butyrylcholinesterase (BuChE); Docking; Indoleamine 2,3-dioxygenase 1 (IDO1); Multifunctional agents; Sertaconazole; Virtual screening.

Publication types

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

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Butyrylcholinesterase / metabolism*
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Isoindoles / chemical synthesis
Isoindoles / chemistry
Isoindoles / pharmacology*
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / chemistry
Thiophenes / pharmacology*

Substances

1-cyclohexyl-2-(5H-imidazo(5,1-a)isoindol-5-yl)ethanol
Cholinesterase Inhibitors
IDO1 protein, human
Imidazoles
Indoleamine-Pyrrole 2,3,-Dioxygenase
Isoindoles
Thiophenes
sertaconazole
Butyrylcholinesterase