Development of a neuroprotective antioxidant by a â??mix-and-matchâ?� strategy

Abstract

Vijaya Kenche, Carolin Tumpach1 Kevin J. Barnham, Steven J. Collins,Cathryn L. Haigh, Simon C. Drew

The compound 4-{[(4-hydroxyphenyl)amino]methyl}-2,6-di-tert-butylphenol (TRS1) was developed using a “mix-and-match” drug design approach for antioxidant-based neuroprotection and therapy. The commonly-used antipyretic drug, paracetamol, which is also found to act as a mild anti-inflammatory, was further modified by attaching a radical scavenger moiety to design a bifunctional bioactive molecule. Using a cell-free 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical reduction assay, and a 2',7'-dichlorofluorescein (DCFH) oxidation assay in cultured N2a mouse neuroblastoma and SH-SY5Y human neuroblastoma cells exposed to oxidative insult (serum deprivation), the radical scavenging ability of TRS1 was found to be comparable with other wellstudied antioxidants such as Trolox. The maintenance of antioxidant action of this compound in cells suggests this avenue and other multi-targeted drug discovery paradigms may