Novel coumarin benzamides as potent and reversible monoamine oxidase-B inhibitors: Design, synthesis, and neuroprotective effects

El-Damasy, Ashraf K.; Oh, Jong Min; Kim, Hyun Ji; Mun, Seul-Ki; Al-Karmalawy, Ahmed A.; Alnajjar, Radwan; Choi, Yu-Jeong; Kim, Jong-Jin; Nam, Ghilsoo; Kim, Hoon; Keum, Gyochang

doi:10.1016/j.bioorg.2023.106939

Cited by 4 publications

(1 citation statement)

References 57 publications

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“…Fen was subjected to two molecular docking studies [38,39] against both CBS and VEGFR-2 targets to investigate its affinity and binding interactions as well. The chemical structure of Fen was extracted as smiles from the PubChem database and introduced into the working window of the drug design program.…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

Investigating the Promising Anticancer Activity of Cetuximab and Fenbendazole Combination as Dual CBS and VEGFR‐2 Inhibitors and Endowed with Apoptotic Potential

Eid,

Al‐Karmalawy,

Eldebss

et al. 2024

Chemistry & Biodiversity

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In this work, the cytotoxicity of monoclonal antibody (Cetuximab, Ce) and Fenbendazole (Fen), as well as their combination therapy were tested with the MTT assay. On the other side, Ce, Fen, and a combination between them were subjected to a colchicine–tubulin binding test, which was conducted and compared to Colchicine as a reference standard. Besides, Ce, Fen, and the combination of them were tested against the VEGFR‐2 target receptor, compared to Sorafenib as the standard medication. Moreover, the qRT‐PCR technique was used to investigate the levels of apoptotic genes (p53 and Bax) and anti‐apoptotic gene (Bcl‐2) as well. Also, the effect of Ce, Fen, and the combination of them on the level of ROS was studied. Furthermore, the cell cycle analysis and Annexin V apoptosis assay were carried out for Ce, Fen, and a combination of them. In addition, the molecular docking studies were used to describe the molecular levels of interactions for both (Fen and colchicine) or (Fen and sorafenib) within the binding pockets of the colchicine binding site (CBS) and vascular endothelial growth factor‐2 receptor (VEGFR‐2), respectively.

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Section: Molecular Docking Studiesmentioning

confidence: 99%

Investigating the Promising Anticancer Activity of Cetuximab and Fenbendazole Combination as Dual CBS and VEGFR‐2 Inhibitors and Endowed with Apoptotic Potential

Eid,

Al‐Karmalawy,

Eldebss

et al. 2024

Chemistry & Biodiversity

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A Comprehensive Review of The Molecular Dynamic Study Of Chalcones, Coumarins and Chromones as Selective MAO‐B Inhibitors [2015‐Till Date]

Rachel Thomas,

Chandran,

Thomas Parambi

et al. 2024

ChemistrySelect

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Molecular dynamics (MD) simulation is an in silico method used in the biomolecular level of research to study how the protein interacts with the target with time. It provides a detailed information of the protein dynamics and ligand structure with the crucial amino acid interactions. Monoamine oxidase B (MAO−B) is a crucial isoenzyme responsible for the catalyses of oxidative deamination of various biogenic amines in the brain and peripheral tissues. The selective inhibitors of MAO−B are considered as the management of symptoms of neurodegenerative disorders like Alzheimer's disease(AD) and Parkinson disease(PD). Recently the structural scaffolds containing chalcones, coumarins and chromones derived candidates shown potent, selective, competitive and reversible type of MAO−B inhibitors. The structural similarities between the above scaffolds can produce almost similar type of interactions in the inhibitor binding cavity of MAO−B. Numerous molecular simulation reports were supported by the above mentioned fact. The current review focus on the last ten year molecular dynamics report of chalcones, coumarins and chromones towards MAO−B inhibition. The review also focuses on the software details used in the MD dynamics simulation and the structural requirement from each class of compound for the recognition of MAO−B inhibitory activity.

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Synthesis, biochemistry, and in silico investigations of isatin-based hydrazone derivatives as monoamine oxidase inhibitors

Maliyakkal,

Oh,

Kumar

et al. 2024

Appl Biol Chem

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Ten isatin-based hydrazone derivatives were synthesized using two subseries, IA (isatin + acetophenone) and IB (isatin + benzaldehyde), and evaluated for their monoamine oxidases (MAOs) inhibitory activity. All the compounds showed stronger MAO-A inhibition than MAO-B, and the IB series showed more effective MAO-A inhibitory activity than IA series. Compound IB4 most potently inhibited MAO-A (half maximal inhibitory concentration IC50 = 0.015 µM), followed by IB3 (IC50 = 0.019 µM). On the contrary, compound IB3 showed the highest MAO-B inhibition (IC50 = 0.068 µM), followed by IB4 (IC50 = 1.87 µM). Compound IB3 and IB4 had low selectivity indices of 3.68 and 8.50, respectively. Structurally, the methyl group of IA series decreased the inhibition of both MAO-A and MAO-B. Among them, IB3 and IB4 (4-Cl and 4-Br in B-ring, respectively) showed higher MAO-A and MAO-B inhibition than the other substitutions. Inhibition constant Ki values of IB3 and IB4 for MAO-A were 0.0088 and 0.0063 µM, respectively, and those for MAO-B were 0.048 and 0.060 µM, respectively. IB3 and IB4 were competitive, reversible inhibitors of MAO-A and MAO-B. Molecular docking analysis predicted that IB3 and IB4 formed stable hydrogen bonds between Asn181 and the NH atom of isatin in the ligand-protein complex. Dynamic analysis revealed that IB3 and IB4 are stable with both MAO isoforms. These observations suggest IB3 and IB4 are potent and reversible MAO-A and MAO-B inhibitors and both compounds can be used as therapeutic agents for neurological disorders.

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Novel coumarin benzamides as potent and reversible monoamine oxidase-B inhibitors: Design, synthesis, and neuroprotective effects

Cited by 4 publications

References 57 publications

Investigating the Promising Anticancer Activity of Cetuximab and Fenbendazole Combination as Dual CBS and VEGFR‐2 Inhibitors and Endowed with Apoptotic Potential

Investigating the Promising Anticancer Activity of Cetuximab and Fenbendazole Combination as Dual CBS and VEGFR‐2 Inhibitors and Endowed with Apoptotic Potential

A Comprehensive Review of The Molecular Dynamic Study Of Chalcones, Coumarins and Chromones as Selective MAO‐B Inhibitors [2015‐Till Date]

Synthesis, biochemistry, and in silico investigations of isatin-based hydrazone derivatives as monoamine oxidase inhibitors

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