Exploring the structural basis of the selective inhibition of monoamine oxidase A by dicarbonitrile aminoheterocycles: Role of Asn181 and Ile335 validated by spectroscopic and computational studies

Juárez-Jiménez, Jordi; Mendes, Eduarda; Galdeano, Carles; Martins, Carla P.; Silva, Daniel da; Marco‐Contelles, José; Carreiras, María do Carmo; Luque, F. Javier; Ramsay, Rona R.

doi:10.1016/j.bbapap.2013.11.003

Cited by 17 publications

(13 citation statements)

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“…Compounds can often bind with either end of the molecule close to the flavin in MAO, 57 or in rotated configuration. 58 In the latter article, molecular dynamics were used to understand a change in affinity, but that is beyond the scope of this exploratory study for these relatively weak inhibitors of MAO. …”

Section: Blood-brain Barrier Permeation and Physicochemical Propertiesmentioning

confidence: 99%

Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment

Hroch

Guest

Benek

et al. 2017

Bioorganic & Medicinal Chemistry

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Section: Blood-brain Barrier Permeation and Physicochemical Propertiesmentioning

confidence: 99%

Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment

Hroch

Guest

Benek

et al. 2017

Bioorganic & Medicinal Chemistry

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“…Simply changing one substituent can alter affinity for one form but not the other. For example, adding a second carbonitrile group to a small furan scaffold, increased the affinity for MAO A by 10-fold but not for MAO B (Juárez-Jiménez et al, 2014) due to a hydrogen bond to asparagine 181 in MAO A. At that position (172 in MAO B) MAO B has a cysteine residue that can contribute to MAO B-selective binding.…”

Section: Neurotransmitter Degrading Enzymesmentioning

confidence: 99%

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

et al. 2016

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HIGHLIGHTS Compounds that interact with multiple targets but minimally with the cytochrome P450 system (CYP) address the many factors leading to neurodegeneration.Acetyl- and Butyryl-cholineEsterases (AChE, BChE) and Monoamine Oxidases A/B (MAO A, MAO B) are targets for Multi-Target Designed Ligands (MTDL).ASS234 is an irreversible inhibitor of MAO A >MAO B and has micromolar potency against the cholinesterases.ASS234 is a poor CYP substrate in human liver, yielding the depropargylated metabolite.SMe1EC2, a stobadine derivative, showed high radical scavenging property, in vitro and in vivo giving protection in head trauma and diabetic damage of endothelium.Control of mitochondrial function and morphology by manipulating fission and fusion is emerging as a target area for therapeutic strategies to decrease the pathological outcome of neurodegenerative diseases.Growing evidence supports the view that neurodegenerative diseases have multiple and common mechanisms in their aetiologies. These multifactorial aspects have changed the broadly common assumption that selective drugs are superior to “dirty drugs” for use in therapy. This drives the research in studies of novel compounds that might have multiple action mechanisms. In neurodegeneration, loss of neuronal signaling is a major cause of the symptoms, so preservation of neurotransmitters by inhibiting the breakdown enzymes is a first approach. Acetylcholinesterase (AChE) inhibitors are the drugs preferentially used in AD and that one of these, rivastigmine, is licensed also for PD. Several studies have shown that monoamine oxidase (MAO) B, located mainly in glial cells, increases with age and is elevated in Alzheimer (AD) and Parkinson's Disease's (PD). Deprenyl, a MAO B inhibitor, significantly delays the initiation of levodopa treatment in PD patients. These indications underline that AChE and MAO are considered a necessary part of multi-target designed ligands (MTDL). However, both of these targets are simply symptomatic treatment so if new drugs are to prevent degeneration rather than compensate for loss of neurotransmitters, then oxidative stress and mitochondrial events must also be targeted. MAO inhibitors can protect neurons from apoptosis by mechanisms unrelated to enzyme inhibition. Understanding the involvement of MAO and other proteins in the induction and regulation of the apoptosis in mitochondria will aid progress toward strategies to prevent the loss of neurons. In general, the oxidative stress observed both in PD and AD indicate that antioxidant properties are a desirable part of MTDL molecules. After two or more properties are incorporated into one molecule, the passage from a lead compound to a therapeutic tool is strictly linked to its pharmacokinetic and toxicity. In this context the interaction of any new molecules with cytochrome P450 and other xenobiotic metabolic processes is a crucial point. The present review covers the biochemistry of enzymes targeted in the design of drugs against neurodegeneration and the cytochrome P450-dependent met...

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“…A series of carbonitrile‐containing aminoheterocycles were examined experimentally and computationally to explore the role of nitriles in determining the inhibitory activity against MAO. Dicarbonitrile aminofurans were found to be potent, selective inhibitors against MAO A (Juárez‐Jiménez et al, ). An earlier study examined the inhibition of MAO B by a series of C4‐substituted phthalonitriles and a series of homologs lacking the nitrile units (Manley‐King et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Based on the MAO inhibition properties of aminofurans with the carbonitrile group (Juárez‐Jiménez et al, ), the present study aimed to identify classes of nitrile‐containing compounds endowed with dual AChE and MAO inhibitory activities, and Aβ anti‐aggregating properties. In this context, we have carried out the synthesis, biological evaluation, and molecular modeling of a number of arylidenepropanedinitriles (Compounds 16–41 , Scheme , Tables and , and Tables S1, S3, S8, and S9), ((phenylamino)methylidene)propanedinitriles (Compounds 42–52 , Scheme , Table and Table S6), 4‐amino‐1‐phenyl‐1 H ‐pyrrole‐3‐carbonitriles (Compounds 53–57 , Scheme , Table , and Tables S7 and S10), and 3‐amino‐1‐phenyl‐1 H ‐pyrrole‐2,4‐dicarbonitriles (Compounds 58–62 , Scheme 3, Tables and , and Tables S7 and S10), (phenylhydrazinylidene)propanedinitriles (Compounds 63–67 , Scheme , Tables and , and Table S4), 4‐arylazo‐3,5‐diamino‐1 H ‐pyrazoles (Compounds 68–72 , Scheme , Table and Table S5), and ( E,E )‐4‐amino‐1‐aryl‐3‐cyano‐4‐methoxy‐2‐azabutadienes (Compounds 73–75 , Scheme , Table ).…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, biological evaluation, and molecular modeling of nitrile‐containing compounds: Exploring multiple activities as anti‐Alzheimer agents

Silva

Mendes

Summers

et al. 2019

Drug Development Research

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Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aβ anti‐aggregating properties. Eighty‐three nitrile‐containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 μM), MAO B (0.26 μM), and AChE (52 μM), while 32 exhibited a lead for selective MAO A (0.12 μM) inhibition coupled to AChE (48 μM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against Aβ1–42, was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate Aβ1–42 fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 μM), making it a potential lead for Alzheimer's disease application.

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Exploring the structural basis of the selective inhibition of monoamine oxidase A by dicarbonitrile aminoheterocycles: Role of Asn181 and Ile335 validated by spectroscopic and computational studies

Cited by 17 publications

References 59 publications

Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment

Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

Synthesis, biological evaluation, and molecular modeling of nitrile‐containing compounds: Exploring multiple activities as anti‐Alzheimer agents

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