Diastereoselective synthesis and profiling of bicyclic imidazolidinone derivatives bearing a difluoromethylated catechol unit as potent phosphodiesterase 4 inhibitors

文献情報

出版日 2018-07-10

DOI 10.1039/C8OB01039K

インパクトファクター 3.876

著者

Ivan S. Golovanov, Vladimir A. Tartakovsky, Alexey Yu. Sukhorukov, Sema L. Ioffe

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要旨

Metal-mediated C–H functionalization of cyclic N-oxides was exploited to access a series of new difluoromethylated analogs of imidazolidinone-based PDE4 inhibitor CMPI in a diastereoselective manner. Among the products synthesized, compounds with fine-tuned activity/selectivity profiles compared to both CMPI and the clinically applied apremilast were identified. From these studies, an unusual fused 1,2-oxazinoimidazolidinone heterocyclic system was suggested as a novel scaffold for the design of potent and selective PDE4 inhibitors. Computational studies suggest that the oxygen atom in the imidazolidinone unit can bind to the metal ion center (most likely Mg2+). DFT calculations of the relative interaction energies of inhibitors with Mg2+ and Zn2+ ions were performed on a model of the bimetal active site of PDE4.

掲載誌

Organic & Biomolecular Chemistry

CiteScore: 3.4

自己引用率: 10.3%

年間論文数: 1041

Organic & Biomolecular Chemistry (OBC) publishes original and high impact research and reviews in organic chemistry. We welcome research that shows new or significantly improved protocols or methodologies in total synthesis, synthetic methodology or physical and theoretical organic chemistry as well as research that shows a significant advance in the organic chemistry or molecular design aspects of chemical biology, catalysis, supramolecular and macromolecular chemistry, theoretical chemistry, mechanism-oriented physical organic chemistry, medicinal chemistry or natural products. Articles published in the journal should report new work which makes a highly-significant impact in the field. Routine and incremental work is generally not suitable for publication in the journal. More details about key areas of our scope are below. In all cases authors should include in their article clear rationale for why their research has been carried out.

Diastereoselective synthesis and profiling of bicyclic imidazolidinone derivatives bearing a difluoromethylated catechol unit as potent phosphodiesterase 4 inhibitors

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