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 biol. target for the development of small compds. 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 chem. approach performed on this promising scaffold. A quant. structure-activity relationship (QSAR) study on a series of chromone derivs. was first carried out, giving a robust model that was next applied to the design of 13 novel compds. derived from this nucleus. Two of the most active according to the model's prediction, namely compds. 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 biol. potency evaluated by exptl. assays, confirming their high inhibitory activity against ABCG2 (exptl. EC50 below 0.10 μM). A supplementary docking study was then conducted on the newly designed derivs., proposing possible binding modes of these novel mols. in the putative ligand-binding site of the transporter and explaining why the two aforementioned compds. exerted the best activity according to biol. data. Results from this study are recommended as refs. for further research in hopes of discovering new potent inhibitors of ABCG2.
Références
- Titre
- Optimization of the chromone scaffold through QSAR and docking studies: identification of potent inhibitors of ABCG2.
- Type de publication
- Article de revue
- Année de publication
- 2019
- Auteurs
- Roussel, Emile, Tran-Nguyen Viet-Khoa, Bouhedjar Khalid, Dems Mohamed Abdesselem, Belaidi Amine, Matougui Brahim, Peres Basile, Azioune Ammar, Renaudet Olivier, Falson Pierre, and Boumendjel Ahcene.
- Revue
- Eur. J. Med. Chem.
- Volume
- 184
- Pagination
- 111772
- ISSN
- 0223-5234
Soumis le 15 janvier 2020