Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer's disease

Zhang, Changjun; Yang, Ke; Yu, Shuyou; Su, Jing; Yuan, Shengli; Han, Jiaxin; Chen, Yan; Gu, Jinping; Zhou, Tao; Bai, Renren; Xie, Yuanyuan

doi:10.1016/j.ejmech.2019.07.031

Cited by 57 publications

(33 citation statements)

References 46 publications

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“…Zhang et al showed that larger substituents at this position are tolerated, where a bulky fluorobenzyl group is located further outside of the enzymes binding pocket than the here presented aniline groups. 31 The hypothesis that substitution at this position might be suitable for designing MTLs is coherent with the linear structures synthesized by Pisani et al that combine MAO B inhibition with nitric oxide releasing precursors and acetylcholine esterase (AChE) inhibition moieties. 32 In the MAO A binding pocket, the polar salicylic group of compounds 31, 33, 34, and 39 did not match the surrounding hydrophobic cavity, which might explain the loss of inhibition properties for MAO A (see Figures S1-S3 in the supplemental material).…”

Section: Biological Activity Mao a And B Inhibitionmentioning

confidence: 62%

“…The most potent MAO inhibitors were chosen for further IC 50 evaluation. Six compounds (31,33,34,39,55, and 65) showed >90% inhibition of MAO B. The most potent MAO A-preferring inhibitor (with MAO B inhibition <50%), compound 7 was also considered for additional investigations.…”

Section: Biological Activity Mao a And B Inhibitionmentioning

confidence: 99%

“…All of these ligands are substituted with a hydroxyl group at the 2-position of the benzylic site and a chloro substituent at the 5-position. The aniline moiety in all cases is para-substituted with a highly lipophilic residue, ie a bromo-substituent (34), a trifluoromethoxy group (33), and a trifluoromethyl group (31) in the para-position. The interaction of these hydrophobic residues with the lipophilic cavity of the MAO B binding pocket, including the nonpolar amino acids Pro102 and Leu164, might be responsible for their potent MAO B inhibition properties.…”

Section: Biological Activity Mao a And B Inhibitionmentioning

confidence: 99%

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<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

Hagenow¹,

Hagenow²,

Grau³

et al. 2020

DDDT

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Background: Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable targets in treatment of neurological diseases. Based on this general blueprint, we synthesized a series of 66 small aromatic amide derivatives as novel MAO A/B inhibitors. Methods: The compounds were synthesized, purified and structurally confirmed by spectroscopic methods. Fluorimetric enzymological assays were performed to determine MAO A/B inhibition properties. Mode and reversibility of inhibition was determined for the most potent MAO B inhibitor. Docking poses and pharmacophore models were generated to confirm the in vitro results. Results: N-(2,4-Dinitrophenyl)benzo[d][1,3]dioxole-5-carboxamide (55, ST-2043) was found to be a reversible competitive moderately selective MAO B inhibitor (IC 50 = 56 nM, K i = 6.3 nM), while N-(2,4-dinitrophenyl)benzamide (7, ST-2023) showed higher preference for MAO A (IC 50 = 126 nM). Computational analysis confirmed in vitro binding properties, where the anilides examined possessed high surface complementarity to MAO A/B active sites. Conclusion: The small molecule anilides with different substitution patterns were identified as potent MAO A/B inhibitors, which were active in nanomolar concentrations ranges. These small and easily accessible molecules are promising motifs, especially for newly designed multitargeted ligands taking advantage of these fragments.

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Section: Biological Activity Mao a And B Inhibitionmentioning

confidence: 62%

Section: Biological Activity Mao a And B Inhibitionmentioning

confidence: 99%

Section: Biological Activity Mao a And B Inhibitionmentioning

confidence: 99%

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<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

Hagenow¹,

Hagenow²,

Grau³

et al. 2020

DDDT

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“…Circumin has been proposed as an AD therapeutic in light of its iron-binding capability [180]. A number of derivatives have been developed, including coumarin-quinoline hybrids with acetylcholinesterase and iron chelation activity [181] and hybrids of hydroxypyridinone and coumarin, which ameliorated cognitive dysfunction in scopolamine-induced AD mice [182].…”

Section: Iron Chelators Under Development With Potential In Alzheimer's Diseasementioning

confidence: 99%

Iron and Ferroptosis as Therapeutic Targets in Alzheimer's Disease

Gleason

Bush

2021

Neurotherapeutics

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Alzheimer's disease (AD), one of the most common neurodegenerative diseases worldwide, has a devastating personal, familial, and societal impact. In spite of profound investment and effort, numerous clinical trials targeting amyloid-β, which is thought to have a causative role in the disease, have not yielded any clinically meaningful success to date. Iron is an essential cofactor in many physiological processes in the brain. An extensive body of work links iron dyshomeostasis with multiple aspects of the pathophysiology of AD. In particular, regional iron load appears to be a risk factor for more rapid cognitive decline. Existing ironchelating agents have been in use for decades for other indications, and there are preliminary data that some of these could be effective in AD. Many novel iron-chelating compounds are under development, some with in vivo data showing potential Alzheimer's disease-modifying properties. This heretofore underexplored therapeutic class has considerable promise and could yield much-needed agents that slow neurodegeneration in AD.

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“…In our previous work, some coumarin-HPO derivatives were designed and biologically evaluated as multitargeted iron chelators [25][26][27] . As a continuation of this research, we present the design, synthesis, and biological evaluation of a class of novel benzamide-HPO derivatives as multitargeting iron chelators with potent anti-AD effects here.…”

Section: Introductionmentioning

confidence: 99%

Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease

Jiang

Guo

Zhang

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d , benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe 3+ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC 50 = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d . In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment.

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Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer's disease

Cited by 57 publications

References 46 publications

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

Iron and Ferroptosis as Therapeutic Targets in Alzheimer's Disease

Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease

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