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

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

Journal

Organic & Biomolecular Chemistry
ISSN: 1477-0520 , E-ISSN: 1477-0539

Output data

Year: 2018, Volume: 16, Number: 38, Pages: 6900-6908 Pages count : 9 DOI: 10.1039/c8ob01039k

Authors

Dorokhov Valentin S ^1,2 , Golovanov Ivan S ¹ , Tartakovsky Vladimir A ¹ , Sukhorukov Alexey Yu ¹ , Ioffe Sema L ¹

Affiliations

1	N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect, 47, Moscow, Russian Federation
2	Higher Chemical College of the Russian Academy of Sciences, D. Mendeleev University of Chemical Technology of Russia, Miusskaya sq., 9, Moscow, Russian Federation

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.

Dorokhov V.S. , Golovanov I.S. , Tartakovsky V.A. , Sukhorukov A.Y. , Ioffe S.L.
Diastereoselective synthesis and profiling of bicyclic imidazolidinone derivatives bearing a difluoromethylated catechol unit as potent phosphodiesterase 4 inhibitors
Organic & Biomolecular Chemistry. 2018. V.16. N38. P.6900-6908. DOI: 10.1039/c8ob01039k WOS Scopus OpenAlex

Web of science:	WOS:000446337600011
Scopus:	2-s2.0-85054384288
OpenAlex:	W2842837170

DB	Citing
OpenAlex	13
Scopus	12
Web of science	11