Multifunctional thioxanthone derivatives with acetylcholinesterase, monoamine oxidases and β -amyloid aggregation inhibitory activities as potential agents against Alzheimer’s disease

Luo, Li; Li, Yan; Qiang, Xiaoming; Cao, Zhongcheng; Xu, Rui; Yang, Xia; Xiao, Ganyuan; Song, Qing; Tan, Zhenghuai; Deng, Yong

doi:10.1016/j.bmc.2017.02.027

Cited by 26 publications

(16 citation statements)

References 51 publications

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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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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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“…Luo et al designed a series of 1‐hydroxyl‐3‐aminoalkoxy‐thioxanthone derivatives by combining 1,3‐dihydroxy‐9 H ‐thioxanthen‐9‐one with appropriate secondary amines using different lengths of carbon spacers ( 231 ‐ 233 ) and tested them for their hMAO‐B inhibitory potential (Figure ). Among them,compound 232b was better inhibitor for MAO‐B (IC 50 = 0.27 ± 0.01 μM).…”

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

confidence: 99%

“…Thioxanthones ( 231‐233 ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration…”

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

confidence: 99%

“…On account of tangled multifactorial pathology of NDDs, multifunctional drugs have been extensively apprehended as promising therapeutics. With the emerging trend on the design of hybrid analogs by multitarget directed ligand (MTDL) strategy, targeting multiple enzymes/receptors/protein in the CNS, MAOs being one primary target has been explored largely with ChEs 160,161,164,167,171,172,175,177,182,193,213,215,219,222,225,231,242,243,250,253 (as dual MAO-B/ChEs inhibitors), Aβ (as dual MAO-B/Aβ-aggregation inhibitors), 166,183,232,233 and HIS H3 receptors 248,249 (as dual MAO/ChE inhibitors with H3R antagonism and sigma 1R agonism) for intervention of AD in addition to adenosine A2A receptors 252 F I G U R E 9 5 Popular scaffolds with potential monoamine oxidase-B inhibitory profile (as dual adenosine A2A receptor antagonists/MAO-BIs) for PD. This MTDL approach has resulted in the identification of several lead molecular entities with multifunctional properties which can simultaneously target several pathological involvements thereby offering a ray of hope for discovery and development of new and effective molecules for the treatment of NDDs.…”

Section: Phenylxanthine Derivativesmentioning

confidence: 99%

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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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“…Multimodal brain permeable drugs affecting a few brain targets involved in the disease pathology such as MAO [ 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ] and ChE enzymes [ 37 , 38 , 39 , 40 ], iron accumulation and Aβ generation/aggregation were extensively examined as an essential therapeutic approach in AD treatment. In an example, a hybrid compound contains the key pharmacophores from three drugs such astacrine, rivastigmine (ChEIs), and rasagiline/ladostigil (MAO-B inhibitor) while NCE (New Chemical Entity) contain the pharmacophores of the drugs donepezil (ChEIs) and clorgiline (MAO-A inhibitor).…”

Section: Introductionmentioning

confidence: 99%

Computer-Aided Multi-Target Management of Emergent Alzheimer’s Disease

Kim

Han

2018

Bioinformation

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Alzheimer's disease (AD) represents an enormous global health burden in terms of human suffering and economic cost. AD management requires a shift from the prevailing paradigm targeting pathogenesis to design and develop effective drugs with adequate success in clinical trials. Therefore, it is of interest to report a review on amyloid beta (Aβ) effects and other multi-targets including cholinesterase, NFTs, tau protein and TNF associated with brain cell death to be neuro-protective from AD. It should be noted that these molecules have been generated either by target-based or phenotypic methods. Hence, the use of recent advancements in nanomedicine and other natural compounds screening tools as a feasible alternative for circumventing specific liabilities is realized. We review recent developments in the design and identification of neuro-degenerative compounds against AD generated using current advancements in computational multi-target modeling algorithms reflected by theragnosis (combination of diagnostic tests and therapy) concern.

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Multifunctional thioxanthone derivatives with acetylcholinesterase, monoamine oxidases and β -amyloid aggregation inhibitory activities as potential agents against Alzheimer’s disease

Cited by 26 publications

References 51 publications

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

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

Computer-Aided Multi-Target Management of Emergent Alzheimer’s Disease

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