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Design, Synthesis and Bioactivity Evaluation of Coumarin-BMT Hybrids as New Acetylcholinesterase Inhibitors.

ABSTRACT: Coumarin possesses the aromatic group and showed plentiful activities, such as antioxidant, preventing asthma and antisepsis. In addition, coumarin derivatives usually possess good solubility, low cytotoxicity and excellent cell permeability. In our study, we synthesized the compound bridge methylene tacrine (BMT), which has the classical pharmacophore structure of Tacrine (THA). Based on the principle of active substructure splicing, BMT was used as a lead compound and synthesized coumarin-BMT hybrids by introducing coumarin to BMT. In this work, 21 novel hybrids of BMT and coumarin were synthesized and evaluated for their inhibitory activity on AChE. All obtained compounds present preferable inhibition. Compound 8b was the most active compound, with the value of K_i as 49.2 nM, which was higher than Galantamine (GAL) and lower than THA. The result of molecular docking showed that the highest binding free energy was -40.43 kcal/mol for compound 8b, which was an identical trend with the calculated K_i.

SUBMITTER: Zeng F

PROVIDER: S-EPMC9000719 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Design, Synthesis and Bioactivity Evaluation of Coumarin-BMT Hybrids as New Acetylcholinesterase Inhibitors.

Zeng Fanxin F Lu Tao T Wang Jie J Nie Xuliang X Xiong Wanming W Yin Zhongping Z Peng Dayong D

Molecules (Basel, Switzerland) 20220326 7

Coumarin possesses the aromatic group and showed plentiful activities, such as antioxidant, preventing asthma and antisepsis. In addition, coumarin derivatives usually possess good solubility, low cytotoxicity and excellent cell permeability. In our study, we synthesized the compound bridge methylene tacrine (BMT), which has the classical pharmacophore structure of Tacrine (THA). Based on the principle of active substructure splicing, BMT was used as a lead compound and synthesized coumarin-BMT ...[more]

PMID: 35408542

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Project description:To discover anti-acetylcholinesterase agents for the treatment of Alzheimer's disease (AD), a series of novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), and High-Resolution Mass Spectrometry (HRMS) analyses. These hybrids were evaluated for their potential inhibitory effect on acetylcholinesterase (AChE). All of them exhibited excellent inhibitory activity against AChE. The IC50 values ranged from 87.84 to 515.59 μg/mL; hybrids 13c and 13d with IC50 values of 0.232 ± 0.011 and 0.190 ± 0.004 µM, respectively, showed the most potent activity as acetylcholinesterase inhibitors (AChEIs). The reference drug, Galantamine, yielded an IC50 of 1.142 ± 0.027 µM. Reactivity descriptors, including chemical potential (μ), chemical hardness (η), electrophilicity (ω), condensed Fukui function, and dual descriptors are calculated at wB97XD/6-311++ G (d,p) to identify reactivity changes of the designed compounds. An in-depth investigation of the natural charge pattern of the studied compounds led to a deep understanding of the important interaction centers between these compounds and the biological receptors of AChE. The molecular electrostatic surface potential (MESP) of the most active site in these derivatives was determined using high-quality information and visualization. Molecular docking analysis was performed to predict binding sites and binding energies. The structure-activity-property relationship studies indicated that the proposed compounds exhibit good oral bioavailability properties. To explore the stability and dynamic behavior of the ligand-receptor complexes, molecular dynamics simulations (MDS) were performed for 100 ns on the two best docked derivatives, 13c and 13d, with the AChE (4EY7) receptor. A popular method for determining the free binding energies (MM/GBSA) is performed using snapshots taken from the systems' trajectories at 100 ns. These results revealed that the complex system of compound 13d acquired a relatively more stable conformation and exhibited better descriptors than the complex system of compound 13c and the Galantamine drug, suggesting its potential as an effective inhibiting drug. The binding free energy analysis revealed that the 13d-4EY7 complex exhibited greater stability with AChE receptors compared to other complexes.

Dataset Information

Design, Synthesis and Bioactivity Evaluation of Coumarin-BMT Hybrids as New Acetylcholinesterase Inhibitors.

Publications

Design, Synthesis and Bioactivity Evaluation of Coumarin-BMT Hybrids as New Acetylcholinesterase Inhibitors.

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