Scaffold Based Search on the Desferithiocin Archetype

Abstract

Iron overload disorder and diseases where iron mismanagement plays a crucial role require orally available iron chelators with favourable pharmacokinetic and toxicity profile. Desferrithiocin (DFT), a tridentate and orally available iron chelator has a favourable pharmacokinetic profile but its use has been clinically restricted due to its nephrotoxic potential. The chemical architecture of the DFT has been naturally well optimized for better iron chelation and iron clearance from human biological system. Equally they are also responsible for its toxicity. Hence, subsequent research has been devoted to develop a non-nephrotoxic analogue of DFT without losing its iron clearance ability. The review has been designed to classify the compounds reported till date and to discuss the structure activity relationship with reference to modifications attempted at different positions over pyridine and thiazoline ring of DFT. Compounds are clustered under two major classes: (i) Pyridine analogues and (ii) phenyl analogue and further each class has been further subdivided based on the presence or absence and the number of hydroxy functional groups present over pyridine or phenyl ring of the DFT analogues. Finally a summary and few insights into the development of newer analogues are provided.

Keywords: Iron Chelators; desferrithiocin analogues; fenton’s reaction; iron toxicity; pyridine analogues.; siderophores..