ABSTRACT
In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (σ1R) and inhibition of key enzymes in Alzheimer's disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N-(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4H-chromene-2-carboxamide (18) is highlighted due to its interesting biological profile in σ1R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and σ1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs.
Subject(s)
Alzheimer Disease/enzymology , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Indans/pharmacology , Neurogenesis/drug effects , Neuroprotective Agents/pharmacology , Piperidines/pharmacology , Receptors, sigma/metabolism , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Animals , Cell Line , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Donepezil , Enzyme Inhibitors/chemistry , Flavonoids/chemistry , Humans , Indans/chemistry , Lipoxygenase Inhibitors/chemistry , Lipoxygenase Inhibitors/pharmacology , Male , Mice, Inbred BALB C , Models, Molecular , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Neuroprotective Agents/chemistry , Piperidines/chemistry , Sigma-1 ReceptorABSTRACT
Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2â nM), strong antioxidant activity (4.29â equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good ß-amyloid (Aß) anti-aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000â µM), affording good neuroprotection against toxic insults such as Aß1-40 , Aß1-42 , H2 O2 , and oligomycinâ A/rotenone on SH-SY5Y cells, at 1â µM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Coumaric Acids/chemistry , Coumaric Acids/pharmacology , Tacrine/chemistry , Tacrine/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/enzymology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacokinetics , Antioxidants/pharmacology , Blood-Brain Barrier/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacokinetics , Coumaric Acids/chemical synthesis , Coumaric Acids/pharmacokinetics , Drug Discovery , Hep G2 Cells , Humans , Models, Molecular , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/pharmacology , Rats, Wistar , Tacrine/chemical synthesis , Tacrine/pharmacokineticsABSTRACT
On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.
