Synthesis and biological evaluation of 3-styrylchromone derivatives as selective monoamine oxidase B inhibitors

Takao, Koichi; Takemura, Yuri; Nagai, Junko; Kamauchi, Hitoshi; Hoshi, Kaori; Mabashi, Ryo; Uesawa, Yoshihiro; Sugita, Yoshiaki

doi:10.1016/j.bmc.2021.116255

Cited by 14 publications

(7 citation statements)

References 17 publications

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“…7-methoxy-3-[(1 E )-2-phenylethenyl]-4 H -1-benzopyran-4-one (Compound A ) was synthesized by Knoevenagel condensation of 7-methoxy-3-formylchromone and phenylmalonic acid, as described previously [ 14 , 22 ]. Also, 3-[(1 E )-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4 H -1-benzopyran-4-one (Compound B ) was synthesized by condensation of 7-methoxy-3-formylchromone and 4-(methoxymethoxy)benzeneacetic acid, followed by removal of the protecting group [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs

et al. 2023

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Background. Many anti-cancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (Compound A) and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one (Compound B), showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds in comparison with four popular anti-cancer drugs. Methods: Tumor-specificity (TSM, TSE, TSN) was evaluated as the ratio of mean CC50 for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. Results: Compounds A and B showed one order of magnitude higher TSM than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two orders of magnitude lower TSE than Compounds A and B. Compounds A and B showed higher TSM, TSE, and TSN values than doxorubicin, 5-FU, and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that Compounds A and B may inhibit the signaling pathway of estrogen-related receptors.

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Section: Methodsmentioning

confidence: 99%

A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs

et al. 2023

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“…A total of thirty-seven datasets were taken from the literature [15] with the IC50 (µM) toward MAO-B inhibitors, and it was converted to PIC50 [16] with the aid of the expression -log(IC50/10 6 ), as presented in Table 1 with their molecular structures.…”

Section: Datasetmentioning

confidence: 99%

QSAR, simulation techniques, and ADMET/pharmacokinetics assessment of a set of compounds that target MAO-B as anti-Alzheimer agent

et al. 2023

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Background Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a progressive neurodegenerative disorder that gradually affects cognitive function and eventually causes death. Most approved drugs can only treat the disease alleviating the disease symptoms; therefore, there is a need to develop drugs that can treat this illness holistically. The medical community is searching for new drugs and new drug targets to cure this disease. In this study, QSAR, molecular docking evaluation, and ADMET/pharmacokinetics assessment were used as modeling methods to identify the compounds with outstanding physicochemical properties. Results The 37 MAO-B compounds were screened using the aforementioned methods and yielded a model with the following molecular properties: AATS1v, AATS3v, GATS4m, and GATS6e. Good statistical values were R2train = 0.69, R2adj = 0.63, R2pred = 0.57, LOF = 0.23, and RMSE = 0.38. The model was validated using an evaluation set that confirmed its robustness. The molecular docking was also utilized using crystal structure of human monoamine oxidase B in complex with chlorophenylchromone-carboxamide with ID code of 6FW0, and three compounds were identified with outstanding high binding affinity (13 = − 30.51 kcal mol−1, 31 = − 31.85 kcal mol−1, and 33 = − 33.70 kcal mol−1), and better than the Eldepryl (referenced) drug (− 11.40 kcal mol−1). Conclusions These three compounds (13, 31, and 33) were analyzed for ADMET/pharmacokinetics evaluation and found worthy of further analysis as promising drug candidates to cure AD and could also serve as a template to design several monoamine oxidase B inhibitors in the future to cure AD.

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“…Takao et al (2021) examined MAO-A and MAO-B inhibitory activities of several 3-styrylchromone derivatives [ 64 ]. Most derivatives inhibited MAO-B, except for compound 209 , which had an OH group at position 4 and a methoxy substitution at position 2 in its chemical structure.…”

Section: Sar Studies Of Chromone As Mao-b Inhibitorsmentioning

confidence: 99%

A Concise Review of the Recent Structural Explorations of Chromones as MAO-B Inhibitors: Update from 2017 to 2023

Ipe,

Kumar,

Benny

et al. 2023

Pharmaceuticals

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Monoamine oxidases (MAOs) are a family of flavin adenine dinucleotide-dependent enzymes that catalyze the oxidative deamination of a wide range of endogenous and exogenous amines. Multiple neurological conditions, including Parkinson’s disease (PD) and Alzheimer’s disease (AD), are closely correlated with altered biogenic amine concentrations in the brain caused by MAO. Toxic byproducts of this oxidative breakdown, including hydrogen peroxide, reactive oxygen species, and ammonia, can cause oxidative damage and mitochondrial dysfunction in brain cells. Certain MAO-B blockers have been recognized as effective treatment options for managing neurological conditions, including AD and PD. There is still a pressing need to find potent therapeutic molecules to fight these disorders. However, the focus of neurodegeneration studies has recently increased, and certain compounds are now in clinical trials. Chromones are promising structures for developing therapeutic compounds, especially in neuronal degeneration. This review focuses on the MAO-B inhibitory potential of several synthesized chromones and their structural activity relationships. Concerning the discovery of a novel class of effective chromone-based selective MAO-B-inhibiting agents, this review offers readers a better understanding of the most recent additions to the literature.

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Synthesis and biological evaluation of 3-styrylchromone derivatives as selective monoamine oxidase B inhibitors

Cited by 14 publications

References 17 publications

A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs

A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs

QSAR, simulation techniques, and ADMET/pharmacokinetics assessment of a set of compounds that target MAO-B as anti-Alzheimer agent

A Concise Review of the Recent Structural Explorations of Chromones as MAO-B Inhibitors: Update from 2017 to 2023

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