Issue 5, 2011

Edaravone containing isoindoline nitroxides for the potential treatment of cardiovascular ischaemia

Abstract

A novel antioxidant for the potential treatment of ischaemia was designed by incorporating an isoindoline nitroxide into the framework of the free radical scavenger edaravone. 5-(3-Methyl-pyrazol-5-ol-1-yl)-1,1,3,3-tetramethylisoindolin-2-yloxyl 7 was prepared by N-arylation of 3-methyl-5-pyrazolone with 5-iodo-1,1,3,3-tetramethylisoindoline-2-yloxyl 8 in the presence of catalytic copper(I)iodide. Evaluation of 7, its methoxyamine derivative 10 and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) against edaravone 1 in ischaemic rat atrial cardiomyocytes revealed significant decreases in cell death after prolonged ischaemia for each agent; however the protective effect of the novel antioxidant 7 (showing greater than 85% reduction in cell death at 100 μM) was significantly enhanced over that of edaravone 1 alone. Furthermore, the activity for 7 was found to be equal to or greater than the potent cardioprotective agent N6-cyclopentyladenosine (CPA). The methoxyamine adduct 10 and edaravone 1 showed no difference between the extent of reduction in cell death whilst CTMIO had only a modest protective effect.

Graphical abstract: Edaravone containing isoindoline nitroxides for the potential treatment of cardiovascular ischaemia

Supplementary files

Article information

Article type
Concise Article
Submitted
10 Feb 2011
Accepted
04 Mar 2011
First published
17 Mar 2011

Med. Chem. Commun., 2011,2, 436-441

Edaravone containing isoindoline nitroxides for the potential treatment of cardiovascular ischaemia

J. R. Walker, K. E. Fairfull-Smith, K. Anzai, S. Lau, P. J. White, P. J. Scammells and S. E. Bottle, Med. Chem. Commun., 2011, 2, 436 DOI: 10.1039/C1MD00041A

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