Discovery of carbamate-based N-salicyloyl tryptamine derivatives as novel pleiotropic agents for the treatment of Alzheimer's disease

Yuying Wang; Honghua Zhang; Dan Liu; Xuelin Li; Lin Long; Ying Peng; Fujian Qi; Yuqing Wang; Weifan Jiang; Zhen Wang

doi:10.1016/j.bioorg.2022.105993

Discovery of carbamate-based N-salicyloyl tryptamine derivatives as novel pleiotropic agents for the treatment of Alzheimer's disease

Bioorg Chem. 2022 Oct:127:105993. doi: 10.1016/j.bioorg.2022.105993. Epub 2022 Jul 6.

Authors

Yuying Wang¹, Honghua Zhang², Dan Liu², Xuelin Li³, Lin Long³, Ying Peng³, Fujian Qi⁴, Yuqing Wang², Weifan Jiang⁵, Zhen Wang⁶

Affiliations

¹ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
² School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
³ School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
⁴ Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
⁵ School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: jiangwf@usc.edu.cn.
⁶ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: zhenw@lzu.edu.cn.

PMID: 35834980
DOI: 10.1016/j.bioorg.2022.105993

Abstract

In this work, based on the potential anti-AD molecule previously studied by our group, we continue to introduce different substituents at different positions to improve both drug-like properties and on target activities. 33 N-salicyloyl tryptamine-carbamate hybrids were designed, synthesized and evaluated as cholinesterase inhibitors. H327 was the most potent BChE inhibitor (eqBChE IC₅₀ = 0.057 ± 0.005 μM), and showed threefold improved inhibitory potency than the positive drug rivastigmine (eqBChE IC₅₀ = 0.19 ± 0.001 μM). In addition, H327 as a pseudo-irreversible BChE inhibitor was endowed with neuroprotective, antioxidative and anti-neuroinflammatory properties. Cytotoxicity and acute toxicity tests confirmed the safety of compound H327. The pharmacokinetics study showed that compound H327 had a longer T_1/2 time and higher bioavailability than the lead compound 1 g. Compound H327 was able to cross the blood-brain barrier (BBB) in vivo. Moreover, the behavioral tests showed that compound H327 could significantly improve scopolamine-induced cognitive impairment in vivo. Overall, these results demonstrated that compound H327 is a promising multi-target agent for the treatment of AD.

Keywords: Alzheimer’s disease; Anti- neuroinflammation; Anti-oxidation; Butyrylcholinesterase inhibitor; Carbamate; Multi-target-directed ligands; Neuroprotective effect.

Publication types

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

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease* / drug therapy
Amyloid beta-Peptides
Carbamates / pharmacology
Carbamates / therapeutic use
Cholinesterase Inhibitors / pharmacology
Cholinesterase Inhibitors / therapeutic use
Humans
Molecular Structure
Neuroprotective Agents* / pharmacology
Neuroprotective Agents* / therapeutic use
Structure-Activity Relationship
Tryptamines / pharmacology
Tryptamines / therapeutic use

Substances

Amyloid beta-Peptides
Carbamates
Cholinesterase Inhibitors
Neuroprotective Agents
Tryptamines
Acetylcholinesterase