4-Oxoquinolines and monoamine oxidase: When tautomerism matters

Mesiti, Francesco; Maruca, Annalisa; Silva, Vera; Rocca, Roberta; Fernandes, Carlos; Remião, Fernando; Uriarte, Eugenio; Alcaro, Stefano; Gaspar, Alexandra; Borges, Fernanda

doi:10.1016/j.ejmech.2021.113183

Cited by 9 publications

(6 citation statements)

References 44 publications

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“…Overall, the data show that the bioisosteric replacement of O by NH or N–CH 3 atoms at the benzopyrone core results in complete loss of activity and that the amidic tautomerism, which can occur in the 2-oxoquinoline-based compounds, does not influence the h MAOs inhibition properties. A recent work on 4-hydroxyquinoline and h MAOs reveals important findings that also supported the data . In marked contrast, O to S isosteric replacement was well-tolerated leading to potent and selective i- h MAO-B.…”

Section: Results and Discussionsupporting

confidence: 60%

“…Then, carboxylic acids ( 18 or 19 ) reacted with the appropriate arylamine, using 2-(1 H -benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) as a coupling agent (Scheme D, step b) . In this case, the use of POCl 3 was not suitable for the synthesis of these amides due to the formation of several byproducts. , …”

Section: Results and Discussionmentioning

confidence: 99%

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Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas?

et al. 2021

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Chromone-3-phenylcarboxamides (Crom-1 and Crom-2) were identified as potent, selective, and reversible inhibitors of human monoamine oxidase B (hMAO-B). Since they exhibit some absorption, distribution, metabolism, and excretion (ADME)-toxicity liabilities, new derivatives were synthesized to map the chemical structural features that compose the pharmacophore, a process vital for lead optimization. Structure−activity relationship data, supported by molecular docking studies, provided a rationale for the contribution of the heterocycle's rigidity, the carbonyl group, and the benzopyran heteroatom for hMAO-B inhibitory activity. From the study, N-(3-chlorophenyl)-4H-thiochromone-3-carboxamide (31) (hMAO-B IC 50 = 1.52 ± 0.15 nM) emerged as a reversible tight binding inhibitor with an improved pharmacological profile. In in vitro ADME-toxicity studies, compound 31 showed a safe cytotoxicity profile in Caco-2, SH-SY5Y, HUVEC, HEK-293, and MCF-7 cells, did not present cardiotoxic effects, and did not affect P-gp transport activity. Compound 31 also protected SH-SY5Y cells from iron(III)-induced damage. Collectively, these studies highlighted compound 31 as the first-in-class and a suitable candidate for in vivo preclinical investigation.

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Section: Results and Discussionsupporting

confidence: 60%

Section: Results and Discussionmentioning

confidence: 99%

Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas?

et al. 2021

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“…The correlation of newly synthesized (2-phenylquinolin-4-yl)-1,3,4-oxadiazol isoindoline-1,3-dione) with previously known MAO and AChE inhibitors was investigated. It seemed that the synthesized compounds showed higher inhibition activity toward targeted enzymes compared to the reported ones ( Figure 2 ) [ 85 , 86 ]. Moreover, the synthesized compounds showed dual and multi-targeted inhibition.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Novel S-alkyl Phthalimide- and S-benzyl-oxadiazole-quinoline Hybrids as Inhibitors of Monoamine Oxidase and Acetylcholinesterase

et al. 2022

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New S-alkyl phthalimide 5a–f and S-benzyl 6a–d analogs of 5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazole-2-thiol (4) were prepared by reacting 4 with N-bromoalkylphthalimide and CF3-substituted benzyl bromides in excellent yields. Spectroscopic techniques were employed to elucidate the structures of the synthesized molecules. The inhibition activity of newly synthesized molecules toward MAO-A, MAO-B, and AChE enzymes, was also assessed. All these compounds showed activity in the submicromolar range against all enzymes. Compounds 5a and 5f were found to be the most potent compounds against MAO-A (IC50 = 0.91 ± 0.15 nM) and MAO-B (IC50 = 0.84 ± 0.06 nM), while compound 5c showed the most efficient acetylcholinesterase inhibition (IC50 = 1.02± 0.65 μM). Docking predictions disclosed the docking poses of the synthesized molecules with all enzymes and demonstrated the outstanding potency of compounds 5a, 5f, and 5c (docking scores = −11.6, −15.3, and −14.0 kcal/mol against MAO-A, MAO-B, and AChE, respectively). These newly synthesized analogs act as up-and-coming candidates for the creation of safer curative use against Alzheimer’s illness.

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“…The results found that all compounds were more active against MAO-B compared to MAO-A, with 1-methyl-2-nonyl-4 (1H)quinolone 14 and 1-methyl-2 [(6Z,9Z)-6,9-pentadecadienyl] -4-(1H) quinolone 15 being the most potent inhibitors for MAO-B with IC50 values of 2.3 μM and 3.6 μM, respectively [80]. Based on the quinolone base structure, efforts were made to modulate the activity; thus, the synthesis of a series of quinolone derivatives found N-(3,4-Dichlorophenyl)-1methyl-4-oxo-1,4-dihydroquinoline-3 carboxamide 16 as a selective inhibitor of human MAO-B with a selective index (SI) of ~1887 and an IC50 value of 5.3 nM [81]. The crininetype alkaloids crinamine 17 and epibuphanisine 18 (isolated from Crossyne guttata) and haemanthamine 19 and haemanthidine 20 (isolated from Scadoxus puniceus) showed inhibition of human MAO-B with IC50 values of 14.9, 39.2, 112.0, and 17.20 nM, respectively, with no inhibition of human MAO-A [82].…”

Section: Mao Inhibitory Activity Of Piperine Quinolone and Isoquinoli...mentioning

confidence: 99%

Natural Products Inhibitors of Monoamine Oxidases—Potential New Drug Leads for Neuroprotection, Neurological Disorders, and Neuroblastoma

et al. 2022

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Monoamine oxidase inhibitors (MAOIs) are an important class of drugs prescribed for treatment of depression and other neurological disorders. Evidence has suggested that patients with atypical depression preferentially respond to natural product MAOIs. This review presents a comprehensive survey of the natural products, predominantly from plant sources, as potential new MAOI drug leads. The psychoactive properties of several traditionally used plants and herbal formulations were attributed to their MAOI constituents. MAO inhibitory constituents may also be responsible for neuroprotective effects of natural products. Different classes of MAOIs were identified from the natural product sources with non-selective as well as selective inhibition of MAO-A and -B. Selective reversible natural product MAOIs may be safer alternatives to the conventional MAOI drugs. Characterization of MAO inhibitory constituents of natural products traditionally used as psychoactive preparations or for treatment of neurological disorders may help in understanding the mechanism of action, optimization of these preparations for desired bioactive properties, and improvement of the therapeutic potential. Potential therapeutic application of natural product MAOIs for treatment of neuroblastoma is also discussed.

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4-Oxoquinolines and monoamine oxidase: When tautomerism matters

Cited by 9 publications

References 44 publications

Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas?

Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas?

Synthesis and Evaluation of Novel S-alkyl Phthalimide- and S-benzyl-oxadiazole-quinoline Hybrids as Inhibitors of Monoamine Oxidase and Acetylcholinesterase

Natural Products Inhibitors of Monoamine Oxidases—Potential New Drug Leads for Neuroprotection, Neurological Disorders, and Neuroblastoma

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