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Optimization of the chromone scaffold through QSAR and docking studies: Identification of potent inhibitors of ABCG2
- Source :
- European Journal of Medicinal Chemistry, European Journal of Medicinal Chemistry, Elsevier, 2019, 184, pp.111772. ⟨10.1016/j.ejmech.2019.111772⟩
- Publication Year :
- 2019
- Publisher :
- HAL CCSD, 2019.
-
Abstract
- 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.
- Subjects :
- Scaffold
Quantitative structure–activity relationship
Abcg2
[SDV]Life Sciences [q-bio]
Quantitative Structure-Activity Relationship
01 natural sciences
03 medical and health sciences
chemistry.chemical_compound
Drug Discovery
ATP Binding Cassette Transporter, Subfamily G, Member 2
Humans
[CHIM]Chemical Sciences
Cells, Cultured
ComputingMilieux_MISCELLANEOUS
030304 developmental biology
Pharmacology
0303 health sciences
Dose-Response Relationship, Drug
Molecular Structure
biology
010405 organic chemistry
Organic Chemistry
Transporter
General Medicine
Combinatorial chemistry
Neoplasm Proteins
0104 chemical sciences
Molecular Docking Simulation
HEK293 Cells
chemistry
Chromones
Biological target
Docking (molecular)
Chromone
biology.protein
Subjects
Details
- Language :
- English
- ISSN :
- 02235234 and 17683254
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry, European Journal of Medicinal Chemistry, Elsevier, 2019, 184, pp.111772. ⟨10.1016/j.ejmech.2019.111772⟩
- Accession number :
- edsair.doi.dedup.....6200eff2e668b732c99f998b690d9b67