Synthesis and evaluation of selegiline derivatives as monoamine oxidase inhibitor, antioxidant and metal chelator against Alzheimer’s disease

Xie, Shishun; Chen, Jie; Li, Xiruo; Wu, Kai; Wang, Yali; Wang, Zhiren; Huang, Ling; Li, Xingshu

doi:10.1016/j.bmc.2015.04.009

Cited by 55 publications

(23 citation statements)

References 33 publications

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“…Additionally, MAOs are thought to promote oxidative stress when highly expressed in neuronal tissues. This can force increased neuronal cell death, a condition observed in Alzheimer’s disease19. Thus, we hypothesize that reversible or more probably irreversible MAO inhibitors and H3R inverse agonists/antagonists can have overlapping pharmacological utilities, suggesting ligands, interacting with both targets, as promising candidates for treatment of neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B

Hagenow

Stasiak

Ramsay

et al. 2017

Sci Rep

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Ciproxifan is a well-investigated histamine H3 receptor (H3R) inverse agonist/antagonist, showing an exclusively high species-specific affinity at rodent compared to human H3R. It is well studied as reference compound for H3R in rodent models for neurological diseases connected with neurotransmitter dysregulation, e.g. attention deficit hyperactivity disorder or Alzheimer’s disease. In a screening for potential monoamine oxidase A and B inhibition ciproxifan showed efficacy on both enzyme isoforms. Further characterization of ciproxifan revealed IC50 values in a micromolar concentration range for human and rat monoamine oxidases with slight preference for monoamine oxidase B in both species. The inhibition by ciproxifan was reversible for both human isoforms. Regarding inhibitory potency of ciproxifan on rat brain MAO, these findings should be considered, when using high doses in rat models for neurological diseases. As the H3R and monoamine oxidases are all capable of affecting neurotransmitter modulation in brain, we consider dual targeting ligands as interesting approach for treatment of neurological disorders. Since ciproxifan shows only moderate activity at human targets, further investigations in animals are not of primary interest. On the other hand, it may serve as starting point for the development of dual targeting ligands.

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Section: Discussionmentioning

confidence: 99%

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B

Hagenow

Stasiak

Ramsay

et al. 2017

Sci Rep

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“…Inhibiting MAO helps by preventing the formation of H 2 O 2 and aldehydes, but the main drive has been to incorporate antioxidants or metal chelation activity into the compounds. Recent examples of this strategy have been reported [ 228 , 229 , 230 , 231 , 232 ]. Antioxidants may also help cell survival, so they may be valuable for neuroprotection.…”

Section: Inhibition For Effective Drugsmentioning

confidence: 99%

Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs

2017

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The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

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“…Xie et al designed and synthesized a series of selegiline hybrids ( 202a ‐ b and 203a ‐ i ) by carrying out fusion of important pharmacophores of selegiline and clioquinol and evaluated them for MAO‐B inhibitory activity (Figure ). The in vitro assay revealed that most of the compounds exhibited MAO‐B inhibitory activities with submicromolar IC 50 values.…”

Section: Discovery and Development Of Mao‐b Inhibitors (2015‐2018)mentioning

confidence: 99%

“…Selegiline hybrids ( 202a ‐ b and 203a ‐ i ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration…”

Section: Discovery and Development Of Mao‐b Inhibitors (2015‐2018)mentioning

confidence: 99%

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

Tripathi

Ayyannan

2019

Medicinal Research Reviews

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Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO‐A/MAO‐B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO‐B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO‐B inhibitors (MAO‐BIs) belonging to diverse chemical scaffolds, arising from intensive chemical‐mechanistic and computational studies documented during past 3 years (2015‐2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO‐BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO‐BIs with superior activity profiles and critical discussions will inflict more caution in the decision‐making process in the MAOIs discovery.

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Synthesis and evaluation of selegiline derivatives as monoamine oxidase inhibitor, antioxidant and metal chelator against Alzheimer’s disease

Cited by 55 publications

References 33 publications

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B

Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

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