From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders

Junbo Wu; Honghua Zhang; Yuying Wang; Gaofeng Yin; Qien Li; Linsheng Zhuo; Hongjin Chen; Zhen Wang

doi:10.3389/fphar.2022.1036030

From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders

Front Pharmacol. 2022 Nov 28:13:1036030. doi: 10.3389/fphar.2022.1036030. eCollection 2022.

Authors

Junbo Wu^{1

2}, Honghua Zhang², Yuying Wang³, Gaofeng Yin⁴, Qien Li⁵, Linsheng Zhuo², Hongjin Chen¹, Zhen Wang^{2

1}

Affiliations

¹ Department of Colorectal Surgery, The Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
² School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
³ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China.
⁴ School of Pharmacy, Lanzhou University, Lanzhou, China.
⁵ Tibetan Medical College, Qinghai University, Xining, Qinghai, China.

Abstract

A novel class of benzyl-free and benzyl-substituted carbamylated tryptamine derivatives (CDTs) was designed and synthesized to serve as effective building blocks for the development of novel multi-target directed ligands (MTDLs) for the treatment of neurological disorders linked to cholinesterase (ChE) activity. The majority of them endowed butyrylcholinesterase (BuChE) with more substantial inhibition potency than acetylcholinesterase (AChE), according to the full study of ChE inhibition. Particularly, hybrids with dibenzyl groups (2b-2f, 2j, 2o, and 2q) showed weak or no neuronal toxicity and hepatotoxicity and single-digit nanomolar inhibitory effects against BuChE. Through molecular docking and kinetic analyses, the potential mechanism of action on BuChE was first investigated. In vitro H₂O₂-induced HT-22 cells assay demonstrated the favorable neuroprotective potency of 2g, 2h, 2j, 2m, 2o, and 2p. Besides, 2g, 2h, 2j, 2m, 2o, and 2p endowed good antioxidant activities and COX-2 inhibitory effects. This study suggested that this series of hybrids can be applied to treat various ChE-associated neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), as well as promising building blocks for further structure modification to develop efficient MTDLs.

Keywords: MTDLs; anti-neuroinflammation; benzylation; carbamylated tryptamine derivatives; cholinesterase inhibitors; neurodegenerative disorders; neuroprotection; promising building blocks.