Structure-activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease

Chengyao Wu; Guijuan Zhang; Zai-Wei Zhang; Xia Jiang; Ziwen Zhang; Huanhuan Li; Hua-Li Qin; Wenjian Tang

doi:10.1080/14756366.2021.1959571

Structure-activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1860-1873. doi: 10.1080/14756366.2021.1959571.

Authors

Chengyao Wu¹, Guijuan Zhang², Zai-Wei Zhang³, Xia Jiang¹, Ziwen Zhang¹, Huanhuan Li¹, Hua-Li Qin³, Wenjian Tang¹

Affiliations

¹ School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, China.
² Management Center of Anhui Continuing Education Network Park, Anhui Open University, Hefei, China.
³ School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, China.

Abstract

To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC₅₀ = 0.021 μM for eqBChE, 3.62 μM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; -OCH₃ > -CH₃ > -Cl (-Br) for δ-aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (K_i = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aβ_1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aβ_1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.

Keywords: Acetylcholinesterase; Alzheimer’s disease; anti-amyloid; butyrylcholinesterase; sulphonyl fluoride.

MeSH terms

Alkynes / chemistry
Alzheimer Disease / drug therapy*
Amyloid / metabolism
Animals
Behavior, Animal
Blood-Brain Barrier / metabolism
Cell Survival / drug effects
Cholinesterase Inhibitors / chemistry*
Cholinesterase Inhibitors / pharmacology
Cholinesterases / metabolism*
Drug Design
Humans
Liver
Male
Mice
Mice, Inbred ICR
Molecular Docking Simulation
Molecular Structure
Morris Water Maze Test
Nervous System
Neuroprotective Agents / chemistry*
Neuroprotective Agents / pharmacology
Structure-Activity Relationship
Sulfinic Acids / chemistry*
Sulfinic Acids / pharmacology

Substances

Alkynes
Amyloid
Cholinesterase Inhibitors
Neuroprotective Agents
Sulfinic Acids
sulfuryl fluoride
Cholinesterases

Grants and funding

Financial support was provided by the National Natural Science Funding of China [22071190], Natural Science Foundation of Anhui provincial Department of Education [KJ2019ZD21], and Anhui Provincial Natural Science Foundation [2008085MH272].