Abstract
The thiol-ene coupling reaction is emerging as an important conjugation reaction that is suitable for use in a biological setting. Here, we explore the utility of this reaction for the synthesis of glutathione-S-conjugates (GSX) and present a general, operationally simple, protocol with a wide substrate scope. The GSX afforded are an important class of compounds and provide invaluable molecular tools to study glutathione-binding proteins. In this study we apply the diverse library of GSX synthesised to further our understanding of the structural requirements for binding to the glutathione-binding protein, Kef, a bacterial K+ efflux system, found in many bacterial pathogens. This system is vital to the survival of bacteria upon exposure to electrophiles, and plays an essential role in the maintenance of intracellular pH and K+ homeostasis. Consequently, Kef is an appealing target for the development of novel antibacterial drugs.
Highlights
The rapid and continual rise of bacterial resistance to many frontline antibiotic treatments necessitates the urgent identification of novel antibiotic targets.[1]
Kef’s protective effect stems from the associated drop in the cytoplasmic pH on activation of K+ efflux, which is thought to result in protonation of the nucleophilic groups on DNA and proteins – preventing damage caused by exposure to electrophiles.[3]
Our interest in the thiol–ene coupling (TEC) reaction was motivated by our desire to synthesise a stable S-dansyl-labelled GSH derivative (3, Scheme 1)
Summary
The rapid and continual rise of bacterial resistance to many frontline antibiotic treatments necessitates the urgent identification of novel antibiotic targets.[1].
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More From: Organic chemistry frontiers : an international journal of organic chemistry
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