Series Of Chromone Derivatives Research Articles

Design, Synthesis and Evaluation of substituted Chromones as Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease.

AbstractBackgroundAcetylcholinesterase (AChE) is one of the frontline targets involved in the progression of Alzheimer’s disease. AChE inhibitors are prescribed as the few drug therapies that have been proven clinically useful in the treatment of Alzheimer’s disease[1, 2]. AChE is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways[3]. The enzyme inactivation induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotine and muscarinic receptor and disrupted neurotransmission.MethodA series of chromone derivatives were virtually screened, synthesised and biologically evaluated as acetylcholinesterase inhibitors. All the compounds were characterised by 1H‐NMR, 13C‐NMR and mass spectrometry.ResultThe in‐vitro evaluation of the compounds against hAChE enzyme showed promising inhibition varying in lower micromolar range. In the synthesized series, NSS‐17 is found to be the most potent AChE inhibitors (IC50 = 1.59± 0.02 μM). In molecular docking studies, compound NSS‐17 showed similar interaction to AChE (1EVE) as shown by reference compound donepezil.ConclusionThus, NSS‐17 can be used as promising lead for the development of more potent AChE inhibitors by further biological assays and in‐vivo studies.

Modulating Triplet Excited States of Organic Semiconductors via Tuning Molecular Conformation for Dual‐ratiometric Thermometers

AbstractThe dual‐ratiometric thermometry is one of highly accurate methods for microscopic thermal measurement in biological systems. Herein, a series of chromone derivatives with noncovalently intramolecular interactions (NIIs) were designed and synthesized for ratiometric thermometers. The triplet states of these organic compounds were systematically tuned upon regulating the conformation with NIIs to yield efficient room temperature phosphorescence and large wavelength difference between fluorescence and phosphorescence simultaneously. As a result, an unprecedent organic 3D dual‐ratiometric thermometer was established based on the intensity ratio and lifetime ratio of fluorescence/phosphorescence vs temperature, which was used for in vitro and in vivo bio‐thermometry with high accuracy. This work provides a novel method to achieve organic dual ratiometric thermometers via tuning the triplet excited states.

Modulating Triplet Excited States of Organic Semiconductors via Tuning Molecular Conformation for Dual-ratiometric Thermometers.

The dual-ratiometric thermometry is one of highly accurate methods for microscopic thermal measurement in biological systems. Herein, a series of chromone derivatives with noncovalently intramolecular interactions (NIIs) were designed and synthesized for ratiometric thermometers. The triplet states of these organic compounds were systematically tuned upon regulating the conformation with NIIs to yield efficient room temperature phosphorescence and large wavelength difference between fluorescence and phosphorescence simultaneously. As a result, an unprecedent organic 3D dual-ratiometric thermometer was established based on the intensity ratio and lifetime ratio of fluorescence/phosphorescence vs temperature, which was used for in vitro and in vivo bio-thermometry with high accuracy. This work provides a novel method to achieve organic dual ratiometric thermometers via tuning the triplet excited states.

Synthesis, biological evaluation and molecular docking studies of chromone derivatives as potential α-glucosidase inhibitors

A series of chromone derivatives were designed, synthesized, and evaluated for their α-glucosidase inhibitory activity by using in vitro methods and molecular docking studies. Some new synthetic compounds showed excellent α-glucosidase inhibitory activity with IC50 values in the range from 10.9 ± 0.29 to 146.50 ± 0.49 µM. Among them, compound 6m exhibited the most potent α-glucosidase inhibitory activity with an IC50 value of 10.9 ± 0.29 μM. Enzyme kinetic study demonstrated that 6m was a mixed-type inhibitor (Ki = 16.87 μM). Circular dichroism spectra and fluorescence quenching experiments further confirmed that the secondary structure of α-glucosidase was changed by the binding of 6m. Molecular docking studies showed that the aryl groups of 6m interactions with the residues Tyr-71, Phe-157, Phe-177, and Phe-300 formed the CH-π. Cell viability assay has shown that 6m exhibited low cytotoxic activity against human normal cell lines.

Optimization of the chromone scaffold through QSAR and docking studies: Identification of potent inhibitors of ABCG2

The membrane transporter BCRP/ABCG2 has emerged as a privileged biological target for the development of small compounds capable of abolishing multidrug resistance. In this context, the chromone skeleton was found as an excellent scaffold for the design of ABCG2 inhibitors. With the aims of optimizing and developing more potent modulators of the transporter, we herewith propose a multidisciplinary medicinal chemistry approach performed on this promising scaffold. A quantitative structure-activity relationship (QSAR) study on a series of chromone derivatives was first carried out, giving a robust model that was next applied to the design of 13 novel compounds derived from this nucleus. Two of the most active according to the model’s prediction, namely compounds 22 (5-((3,5-dibromobenzyl)oxy)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide) and 31 (5-((2,4-dibromobenzyl)oxy)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide), were synthesized and had their biological potency evaluated by experimental assays, confirming their high inhibitory activity against ABCG2 (experimental EC50 below 0.10 μM). A supplementary docking study was then conducted on the newly designed derivatives, proposing possible binding modes of these novel molecules in the putative ligand-binding site of the transporter and explaining why the two aforementioned compounds exerted the best activity according to biological data. Results from this study are recommended as references for further research in hopes of discovering new potent inhibitors of ABCG2.

Synthesis, nematicidal activity and docking study of novel chromone derivatives containing substituted pyrazole

A series of chromone derivatives containing substituted pyrazole were designed and synthesized. Preliminary bioassays showed that most of the synthesized compounds exhibited good nematicidal activity in vivo against Meloidogyne incognita at 10mg/L. Among the tested compounds, A10 and A11 exhibited 100% inhibition rates. In addition, the molecular docking results indicated that both compound A10 and A11 interacts with amino acid residue Tyr121, Trp279, Tyr70, Trp84 and Phe330 of AChE via hydrogen bond and π–π stacking. This investigation suggested that the chromone containing substituted pyrazole scaffold could be further optimized to explore novel, high-bioactivity nematicidal leads.

Synthesis and pharmacological evaluation of novel chromone derivatives as balanced multifunctional agents against Alzheimer's disease

In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer’s disease (AD), a series of chromone derivatives were designed, synthesized and evaluated. In vitro assay indicated that most of the target compounds have both MAOs inhibition activities, antioxidant activity and biometal chelating ability. Especially, compound s19 exhibits good inhibitory potency for inhibition of MAOs (IC50 value of 5.12μM for hMAO-A and 0.816μM for hMAO-B), moderate inhibition of Aβ aggregation (75.1% at 20μM), metal chelation, control of ROS generation and antioxidant activity (ORAC=3.62). In addition, s19 could reduce PC12 cells death induced by oxidative stress and penetrate the blood–brain barrier (BBB). Taken together, these results suggested that s19 might be a promising multitargeted compound for AD treatment.

Biological activity evaluation and molecular docking study of chromone derivatives as cyclooxygenase-2 inhibitors

A series of chromone derivatives have been evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. The four most potent compounds, 48, 41, 39, and 35 displayed IC50 values of 3.30, 6.86, 7.36 and 7.46 µM, respectively. Compounds 35 and 38 showed higher selectivity for COX-2 (selectivity index, SI = 7.48 and 5.46, respectively) than celecoxib (SI = 4.17 in the same test) whereas compound 39 showed comparable selectivity (SI = 4.19) to celecoxib. The molecular volumes of compounds 35 (312.84 A3) and 38 (314.18 A3) were similar to celecoxib (299.28 A3) but larger than ibuprofen (211.83 A3). Docking results were in good agreement with the experimental biological data in terms of evaluation of binding energy and binding mode. Compounds 35, 38, and 39 had higher binding affinity against COX-2 (binding energy between −9.77 and −11.42 kcal/mole) than COX-1 (binding energy between −6.28 and −7.88 kcal/mole). These three chromone compounds also displayed active conformation in the same orientation as that of celecoxib. Thus, compounds in this series has the potential to be a new class of selective COX-2 inhibitor.

Synthesis, Topoisomerase I Inhibitory and Cytotoxic Activities of Chromone Derivatives

A series of chromone derivatives were designed as potential topoisomerase I (Top I) inhibitors based on the docking simulation study. Sixteen synthesized compounds were evaluated for Top I inhibitory activity and some compounds were further tested for in vitro cytotoxic activity. The most potent inhibitor, chromone 11b showed greater inhibitory activity (IC50 = 1.46 μM) than the known Top I inhibitors, i.e., camptothecin, fisetin and morin, but inactive against breast cancer cell (MCF-7), oral cavity cancer cell (KB) and small cell lung cancer (NCI-H187). Chromone 11c, another potent inhibitor (IC50 = 6.16 μM), exhibited cytotoxic activity against KB (IC50 = 73.32 μM) and NCI-H187 (IC50 = 36.79 μM).

N‐Heterocyclic Carbene Catalyzed Intramolecular Hydroacylation of Activated Alkynes: Synthesis of Chromones

AbstractAn organocatalytic intramolecular Stetter‐type hydroacylation reaction between an aldehyde and an activated alkyne has been developed. This study induces salicylaldehyde‐derived alkyne derivatives to assemble into a series of chromone derivatives using a catalytic amount of thiazolium‐based carbene catalyst.