Design and synthesis of novel 1,2,3-triazole linked hybrids: Molecular docking, MD simulation, and their antidiabetic efficacy as α-Amylase inhibitors

Journal of Molecular Structure, Journal Year: 2023, Volume and Issue: 1285, P. 135493 - 135493

Published: April 1, 2023

Language: Английский

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Isatin-tethered halogen-containing acylhydrazone derivatives as monoamine oxidase inhibitor with neuroprotective effect

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 13, 2024

Abstract Sixteen isatin-based hydrazone derivatives ( IS1 – IS16 ) were synthesized and assessed for their ability to inhibit monoamine oxidases (MAOs). All the molecules showed improved inhibitory MAO-B activity compared MAO-A. Compound IS7 most potently inhibited with an IC 50 value of 0.082 μM, followed by IS13 IS6 (IC = 0.104 0.124 respectively). IS15 MAO-A 1.852 IS3 2.385 μM). had highest selectivity index (SI) 263.80, (233.85 212.57, In kinetic study, K i values , 0.068 ± 0.022, 0.044 0.002, 0.061 0.001 respectively, that was 1.004 0.171 compounds reversible-type inhibitors. The lead central nervous system (CNS) permeable, as per parallel artificial membrane permeability assay (PAMPA) test results. examined cytotoxicity potential neuroprotective benefits in hazardous lipopolysaccharide (LPS)-exposed SH-SY5Y neuroblastoma cells. Pre-treatment enhanced anti-oxidant levels (SOD, CAT, GSH, GPx) decreased ROS pro-inflammatory cytokine (IL-6, TNF-alpha, NF-kB) production LPS-intoxicated To confirm promising effects compound, molecular docking, dynamics, MM-GBSA binding energy used examine basis -MAO-B interaction. Our findings indicate are therapeutic agents treat neurological illnesses, such Parkinson's disease.

Language: Английский

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Novel 6-hydroxybenzothiazol-2-carboxamides as potent and selective monoamine oxidase B inhibitors endowed with neuroprotective activity

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 269, P. 116266 - 116266

Published: Feb. 28, 2024

In neurodegenerative diseases, using a single molecule that can exert multiple effects to modify the disease may have superior activity over classical "one molecule-one target" approach. Herein, we describe discovery of 6-hydroxybenzothiazol-2-carboxamides as highly potent and selective MAO-B inhibitors. Variation amide substituent led several compounds having diverse side chains with cyclohexylamide 40 displaying highest potency towards (IC50 = 11 nM). To discover new extended efficacy against neurotoxic mechanisms in inhibitors were screened PHF6, R3 tau, cellular tau α-synuclein (α-syn) aggregation. We identified phenethylamide 30 multipotent inhibitor 41 nM) α-syn It showed no cytotoxic on SH-SY5Y neuroblastoma cells, while also providing neuroprotection toxicities induced by tau. The evaluation key physicochemical vitro-ADME properties revealed great potential drug-like small molecules multitarget neuroprotective activity.

Language: Английский

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A structural approach to investigate halogen substituted MAO-B inhibitors using QSAR modeling, molecular dynamics, and conceptual DFT analysis

Journal of Saudi Chemical Society, Journal Year: 2023, Volume and Issue: 27(4), P. 101675 - 101675

Published: June 19, 2023

Halogenated inhibitors showed robust, reversible, and selective monoamine oxidase-B (MAO-B) inhibitory efficacy in candidates that were derived from them. Our team has previously synthesized assessed a panel of halogenated chalcones coumarin for the study on MAO-B inhibition. The aim this was to build GA-MLR based QSAR models predictive 3D Pharmacophore models, as well investigate relationship between derivatives activity. robust statistical significance parameter (R2=0.78 Q2=0.69) demonstrated. Best Hypo1 contains one hydrophobic two aromatic rings. lead molecule quantum mechanics performed, it revealed would bind proteins provide stability. To determine stability ligand-enzyme complex, thorough molecular dynamics analysis compounds accomplished.

Language: Английский

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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]

ChemistrySelect, Journal Year: 2024, Volume and Issue: 9(27)

Published: July 16, 2024

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

Language: Английский

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An investigation of the monoamine oxidase inhibition properties of benzothiazole derivatives

Results in Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 102142 - 102142

Published: Feb. 1, 2025

Language: Английский

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Integrating Atom‐Based 3D‐QSAR, Molecular Docking, and Molecular Dynamics: A Multistep Approach for the Discovery of Potent Adenosine A₂A Receptor Antagonists

ChemistrySelect, Journal Year: 2025, Volume and Issue: 10(12)

Published: March 1, 2025

Abstract The rational design of adenosine A 2A receptor antagonists offers a non‐dopaminergic approach to alleviate symptoms Parkinson's disease (PD). Preclinical studies indicate that may inhibit neuronal loss, although human are essential for validating effectiveness. This research focuses on optimizing ligands the through multifaceted method uniting 3D quantitative structure–activity relationship (QSAR) modeling, molecular docking, binding energy calculations, dynamics (MD) simulations, and interaction analysis. robust atom‐based 3D‐QSAR model was developed, achieving predictive performance metrics (R 2 = 0.80, Q 0.65) identifying key structural features associated with bioactivity. Screening 3,958 compounds, five lead molecules (CHEMBL16687, 113142, 1760901, 4289874, 482436) were prioritized based energies (ranging from −12.938 −9.986 kcal/mol). Binding affinity confirmations MMGBSA highlighted significant electrostatic van der Waals interactions. 200 ns MD simulation assessed stability these CHEMBL4289874 showcasing exceptional occupying smallest phase space in principal component analysis (PCA), indicating superior relative other compounds. 2D diagrams elucidated critical ligand‐residue interactions fundamental maintaining integrity. comprehensive investigation positions as an exceptionally promising candidate further development PD treatment.

Language: Английский

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Inhibitory Activity of Chalcones as MAO‐B Inhibitors: An Insight from Molecular Docking, ADME Analysis, MD Simulation, and MM‐PBSA Calculations

ChemistrySelect, Journal Year: 2025, Volume and Issue: 10(13)

Published: March 30, 2025

Abstract Alzheimer's disease, which is recognized as a progressive, multifaceted neurodegenerative disorder, the main factor in late‐life dementia. Monoamine oxidase‐B (MAO‐B) has recently been identified potential therapeutic target for disease (AD). This research explores inhibitory effects of specific chalcones on MAO‐B utilizing molecular docking, dynamics (MD) simulations, MM‐PBSA free energy calculations, and ADME analysis. The results docking reveal that demonstrate significant binding affinities with MAO‐B, CHA 22.4 22.5 exhibiting most substantial −8.68 −8.65 kcal/mol, mainly due to hydrogen bonding hydrophobic interactions. MD simulations validate stability protein‐ligand complexes, showing RMSD values stabilizing around 0.4 nm. Meanwhile, analysis reveals favorable energies, demonstrating highest (−111.27 kJ/mol), indicating robust interaction MAO‐B. shows all chosen adhere Lipinski's rule five exhibit blood‐brain barrier (BBB) permeability, suggesting possible CNS activity. indicate may act effective inhibitors, necessitating additional experimental validation investigate their treatment disease.

Language: Английский

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Novel 2-aminothiazole derivatives incorporating 9-alkyl purine moiety: design, synthesis, crystal structure, and bioactivity evaluation

Molecular Diversity, Journal Year: 2025, Volume and Issue: unknown

Published: April 12, 2025

Language: Английский

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Design, synthesis, molecular docking, molecular dynamic simulation, and MMGBSA analysis of 7-O-substituted 5-hydroxy flavone derivatives

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(12), P. 6378 - 6392

Published: Aug. 7, 2023

AbstractA series of chrysin derivatives were designed, synthesized, and evaluated for their antibacterial activity against four different bacterial strains. We have synthesized new propyl-substituted butyl-substituted chrysin-piperazine derivatives, which show marvellous inhibition E. coli S. aureus. The free hydroxyl group at the C-5 position improved therapeutic efficacy in vivo was a beneficial formulation chemotherapy. All compounds confirmed by various spectroscopic techniques such as IR, NMR, HPLC, mass spectrometry. exhibited moderate to good inhibition, structure–activity relationship (SAR) has also been illustrated. Among synthesised compounds, 4 10 most active pyogenes coli, with 12.5 g/mL MICs; additionally, compound 12 exhibits significant on both aureus stains. Based promising profile docking score 12, it selected 100 ns MD simulation post-dynamic binding energy analysis within sites TyrRS (PDB ID: 1JIJ) DNA GyrB 6YD9) investigate stability molecular contacts establish how newly inhibitors fit together stable conformations.Communicated Ramaswamy H. SarmaKeywords: Flavone derivativesmolecular dockingMD simulationsynthesisand MMGBSA AcknowledgmentThis research supported Sardar Vallabhbhai National Institute Technology. Authors would like thank Mahrshee laboratory, Darshan health care Jaydev chemical gifting piperazine derivatives. are thankful Micro laboratory Nirma university compounds.Disclosure statementNo potential conflict interest reported author(s).Additional informationFundingThe author(s) there is no funding associated work featured this article.

Language: Английский

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