Design, synthesis and biological evaluation of novel donepezil–coumarin hybrids as multi-target agents for the treatment of Alzheimer’s disease

Xie, Sai‐Sai; Lan, Jin‐Shuai; Wang, Xiaobing; Wang, Zhimin; Jiang, Neng; Li, Fan; Wu, Jiajia; Wang, Jin

doi:10.1016/j.bmc.2016.02.023

Cited by 79 publications

(41 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Xie et al designed novel donepezil‐coumarin hybrids ( 43a‐m and 44a‐b ) by combining N ‐benzylpiperidine moiety of donepezil and coumarin into a single molecule with the flexible side chain and introducing different substituents at position 3 and/or 4 of coumarin ring and investigated them for MAO‐B inhibitory activity (Figure ). The biological screening results indicated that all compounds effectively and selectively inhibited MAO‐B at micromolar range (IC 50 = 1.93‐33.9 µM; SI = 2.47‐51.81).…”

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

confidence: 99%

“…Donepezil‐coumarin hybrids ( 43a ‐ m and 44a ‐ b ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration; SI, selectivity index…”

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%

See 2 more Smart Citations

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

Tripathi

Ayyannan

2019

Medicinal Research Reviews

View full text Add to dashboard Cite

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.

show abstract

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

confidence: 99%

“…Donepezil‐coumarin hybrids ( 43a ‐ m and 44a ‐ b ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration; SI, selectivity index…”

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

confidence: 99%

Section: Phenylxanthine Derivativesmentioning

confidence: 99%

See 1 more Smart Citation

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

Tripathi

Ayyannan

2019

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

“…With structures of most targets available, in silico screening is a useful tool for examining large chemical databases (Hughes et al, 2016; Nikolic et al, 2016). Combining known drugs for each target into one molecule has also produced promising compounds by incorporating elements of proven inhibitors for each target into new multi-potent molecules (Bolognesi et al, 2007; Piazzi et al, 2008; Zhu et al, 2009; Kupershmidt et al, 2012; Luo et al, 2013; Sun et al, 2014; Bautista-Aguilera et al, 2014b; Wang L. et al, 2014; Pisani et al, 2016; Weichert et al, 2016; Xie et al, 2016). One example that progressed to clinical trials against AD is ladostigil, designed to inhibit MAOs and ChEs but also incorporating potent anti-apoptotic and neuroprotective activities (Weinreb et al, 2012; Youdim, 2013).…”

Section: Addressing the Pathology Of Neurodegeneration: The Targets Cmentioning

confidence: 99%

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

et al. 2016

View full text Add to dashboard Cite

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...

show abstract

“…The accumulation of Aβ peptides in the cerebral cortex of the brain has been suggested as a part of AD pathogenesis [37,38]. Thus, additionally preventing the aggregation of Aβ and/or disrupting the existing Aβ plaques are potential therapeutic approaches for treating AD [22,[39][40][41].There are currently reports in the literature investigating new scaffolds with two or more pharmacophores connected to each other through a linker aimed at interacting with more than one biological target [42][43][44][45][46][47][48][49][50][51]. Previously, our group as well as others studied donepezil, the current drug of choice for treating AD with its AChE and BChE inhibiting capacity [52][53][54][55][56][57].…”

mentioning

confidence: 99%

Combining Chalcones with Donepezil to Inhibit Both Cholinesterases and Aβ Fibril Assembly

et al. 2019

View full text Add to dashboard Cite

The fact that the number of people with Alzheimer's disease is increasing, combined with the limited availability of drugs for its treatment, emphasize the need for the development of novel effective therapeutics for treating this brain disorder. Herein, we focus on generating 12 chalcone-donepezil hybrids, with the goal of simultaneously targeting amyloid-β (Aβ) peptides as well as cholinesterases (i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). We present the design, synthesis, and biochemical evaluation of these two series of novel 1,3-chalcone-donepezil (15a-15f) or 1,4-chalcone-donepezil (16a-16f) hybrids. We evaluate the relationship between their structures and their ability to inhibit AChE/BChE activity as well as their ability to bind Aβ peptides. We show that several of these novel chalcone-donepezil hybrids can successfully inhibit AChE/BChE as well as the assembly of N-biotinylated Aβ oligomers. We also demonstrate that the Aβ binding site of these hybrids differs from that of Pittsburgh Compound B (PIB).Molecules 2020, 25, 77 2 of 32 Despite extensive research efforts, the causative factors of AD remain unclear [18]. However, various characteristics, such as low levels of acetylcholine (ACh), accumulation of amyloid-β (Aβ) deposits, tau (τ) protein aggregation, oxidative stress, inflammation, metal ion imbalance, and breakdown of homeostatic systems, play crucial roles in AD progression [19][20][21][22][23][24][25]. Currently, most of the primary therapeutic options for treating AD are based on AChEIs [26][27][28][29][30][31]. Low levels of acetylcholine (ACh) can lead to cognitive and memory deficits. The two types of cholinesterases present in the central nervous system, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are capable of hydrolyzing ACh [32][33][34][35]. In healthy brains, BChE plays a secondary role to AChE, but as AD progresses the activity and expression of BChE in the brain increases [36]. Although developing inhibitors against these enzymes alone will not lead to a cure, combining their effect with another hallmark of AD progression, such as Aβ peptide accumulation, could potentially be beneficial. The accumulation of Aβ peptides in the cerebral cortex of the brain has been suggested as a part of AD pathogenesis [37,38]. Thus, additionally preventing the aggregation of Aβ and/or disrupting the existing Aβ plaques are potential therapeutic approaches for treating AD [22,[39][40][41].There are currently reports in the literature investigating new scaffolds with two or more pharmacophores connected to each other through a linker aimed at interacting with more than one biological target [42][43][44][45][46][47][48][49][50][51]. Previously, our group as well as others studied donepezil, the current drug of choice for treating AD with its AChE and BChE inhibiting capacity [52][53][54][55][56][57]. In addition, we explored the use of chalcone derivatives as AChE inhibitors as well as Aβ peptide and metal-Aβ complex-targeting compounds [58,59]. Here, we ...

show abstract

Design, synthesis and biological evaluation of novel donepezil–coumarin hybrids as multi-target agents for the treatment of Alzheimer’s disease

Cited by 79 publications

References 56 publications

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

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

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

Combining Chalcones with Donepezil to Inhibit Both Cholinesterases and Aβ Fibril Assembly

Contact Info

Product

Resources

About