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Design, Spectroscopy, and Assessment of Cholinesterase Inhibition and Antimicrobial Activities of Novel Coumarin-Thiadiazole Hybrids.

ABSTRACT: A novel series of coumarin-thiadiazole hybrids, derived from substituted coumarin-3-carboxylic acids was isolated and fully characterized with the use of a number of spectroscopic techniques and XRD crystallography. Several of the novel compounds showed intensive fluorescence in the visible region, comparable to that of known coumarin-based fluorescence standards. Moreover, the new compounds were tested as potential antineurodegenerative agents via their ability to act as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. Compared to the commercial standards, only a few compounds demonstrated moderate AChE and BuChE activities. Moreover, the novel derivatives were tested for their antimicrobial activity against a panel of pathogenic bacterial and fungal species. Their lack of activity and toxicity across a broad range of biochemical assays, together with the exceptional emission of some hybrid molecules, highlights the possible use of a number of the novel hybrids as potential fluorescence standards or fluorescence imaging agents.

SUBMITTER: Karcz D

PROVIDER: S-EPMC9180949 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Design, Spectroscopy, and Assessment of Cholinesterase Inhibition and Antimicrobial Activities of Novel Coumarin-Thiadiazole Hybrids.

Karcz Dariusz D Starzak Karolina K Ciszkowicz Ewa E Lecka-Szlachta Katarzyna K Kamiński Daniel D Creaven Bernadette B Miłoś Anna A Jenkins Hollie H Ślusarczyk Lidia L Matwijczuk Arkadiusz A

International journal of molecular sciences 20220605 11

A novel series of coumarin-thiadiazole hybrids, derived from substituted coumarin-3-carboxylic acids was isolated and fully characterized with the use of a number of spectroscopic techniques and XRD crystallography. Several of the novel compounds showed intensive fluorescence in the visible region, comparable to that of known coumarin-based fluorescence standards. Moreover, the new compounds were tested as potential antineurodegenerative agents via their ability to act as acetylcholinesterase (A ...[more]

PMID: 35682998

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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.

Project description:A series of new coumarin-N-heterocyclic hybrids, coumarin-quinolines 7a-e, coumarin-acridines 10b,c and coumarin-neocryptolepines 13b,c were synthesized and evaluated for their anticancer and antimicrobial activities. The structures of all synthesized hybrids were confirmed by FT-IR, 1H-NMR, 13C-NMR, and MS spectrometry. The anti-proliferative activity of hybrids 7a-e, 10c and 13c were bio-evaluated using MTT-assay against colon (CaCo-2), lung (A549), breast (MDA-MB-231), and hepatocellular carcinoma (HepG-2) human cancer cell lines using doxorubicin as a reference drug. The results demonstrated that, all hybrids displayed moderate to good anti-proliferative activity against the cell lines. The most active hybrids were 7a-d and 10c against CaCo-2 cancer cell line with IC50: 57.1, 52.78, 57.29, 51.95 and 56.74 µM, and selectivity index 1.38, 1.76, 2.6, 1.96 and 0.77; respectively. While, 7a,d were potent against A549 cancer cell line with IC50: 51.72, 54.8 µM and selectivity index 1.5, 0.67; respectively. Moreover, 7c showed the most potency against MDA-MB-231 cancer cell line with IC50: 50.96 µM and selectivity index 2.20. Interestingly, docking results revealed that binding energy of the current compounds showed marked affinity values ranging from -6.54 to -5.56 kcal with interactions with the reported key amino acid SER 79. Furthermore, the antimicrobial activity of the synthesized hybrids 7a-e, 10b,c, 13b and 13c were evaluated against Gram-positive and Gram-negative bacterial and fungal strains. The hybrids 10b, 13b, 10c, and 13c exhibited broad-spectrum antibacterial activity against E.coli, S. mutans, and S. aureus with MIC from 3.2 to 66 µM, this hybrids also displayed antifungal activity against C. albicans with MIC values ranging from 0.0011 to 29.5 µM. In-silico investigation of the pharmacokinetic properties indicated that tested hybrids had high GI absorption, low Blood Brain Barrier (BBB) permeability in addition to cell membrane penetrability.

Dataset Information

Design, Spectroscopy, and Assessment of Cholinesterase Inhibition and Antimicrobial Activities of Novel Coumarin-Thiadiazole Hybrids.

Publications

Design, Spectroscopy, and Assessment of Cholinesterase Inhibition and Antimicrobial Activities of Novel Coumarin-Thiadiazole Hybrids.

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