Abstract
The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer’s disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13–15, with compound 15 exhibiting balanced, low micromolar inhibition of hMAO-B (IC50 of 4.3 µM) and hBChE (IC50 of 8.5 µM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder characterized by memory deterioration, behavioral changes, and impaired cognitive functions [1,2]. the exact aetiology of AD remains to be clarified, the pathogenesis is considered to be multifactorial [1,3]
I.e., amyloid β and tau, bind to pattern recognition receptors on astrocytes and microglia, and trigger an innate immune response characterized by a release of pro-inflammatory mediators, which further exacerbates the loss of neurons [10,11]
In the study presented we introduced a carbamate moiety on the aromatic ring to gain ChE inhibition as well, through the carbamoylation of catalytic Ser198
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder characterized by memory deterioration, behavioral changes, and impaired cognitive functions [1,2]. the exact aetiology of AD remains to be clarified, the pathogenesis is considered to be multifactorial [1,3]. The proposed pathophysiological mechanisms include amyloid β deposition [4], protein tau aggregation [5], increased oxidative stress [6], imbalance of metal ions [7], mitochondrial dysfunction [6,8], and neuronal and synaptic loss in the central nervous system [9]. I.e., amyloid β and tau, bind to pattern recognition receptors on astrocytes and microglia, and trigger an innate immune response characterized by a release of pro-inflammatory mediators, which further exacerbates the loss of neurons [10,11]. Additional potential for the mitigation of AD progress arises through the inhibition of monoamine oxidases (MAOs), which during the oxidative deamination reaction produce mediators of oxidative stress, such as hydrogen peroxide, aldehydes, and ammonia.
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