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

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.

Neuroprotective Effects of an N-Salicyloyl Tryptamine Derivative against Cerebral Ischemia/Reperfusion Injury

“…Melatonin also inhibits the NF-κB pathway in OGD/R or H 2 O 2 -treated SH-SY5Y cells and shows anti-inflammatory and neuroprotective effects. , However, the poor pharmacokinetic properties of melatonin, such as the short plasma half-life (∼30 min), limit its use in neurological disorders; thus, rational modifications based on the template of melatonin have been conducted. Wang et al found that the N -salicyl tryptamine derivative LZWL02003 outperformed all other compounds in terms of its anti-inflammatory, free radical scavenging, and neuroprotective capabilities. , Neuroprotective effects of LZWL02003 were also shown in in vivo and in vitro models of Alzheimer’s disease conferred by Aβ . Therefore, LZWL02003 could also be neuroprotective in the case of cerebral I/R.…”

“…Wang et al found that the N-salicyl tryptamine derivative LZWL02003 outperformed all other compounds in terms of its anti-inflammatory, free radical scavenging, and neuroprotective capabilities. 10,25 Neuroprotective effects of LZWL02003 were also shown in in vivo and in vitro models of Alzheimer's disease conferred by Aβ. 13 Therefore, LZWL02003 could also be neuroprotective in the case of cerebral I/R.…”

Navigating the Gene Co-Expression Network and Drug Repurposing Opportunities for Brain Disorders Associated with Neurocognitive Impairment

“…Neurocognitive disorders encompass a range of conditions that adversely lead to the impairment of cognitive abilities, including memory, executive function, and attention, often due to underlying neurological disorders, damage, or even dementia, where the decline in cognitive function is severe enough to interfere with daily life [1,2]. Among 2 of 30 many others, these disorders include Alzheimer's disease (AD), Parkinson's disease with Dementia (PDD), HIV-associated neurocognitive disorders (HAND), and glioma, each of which presents with distinct causes and clinical manifestations [3,4]. Moreover, the molecular changes resulting from these diseases occur in various brain regions, involving various genes and proteins.…”