Synthesis of new iron chelators and pharmacological evaluation in an animal model of iron overload associated with Sickle Cell Anemia

Abstract

Iron overload can occur in patients undergoing successive blood transfusions, such as patients with thalassemia and sickle cell anemia. Iron overload cardiomyopathy is described as dilated cardiomyopathy, characterized by left ventricular hypertrophy and reduced left ventricular ejection fraction. Deferiprone (DFP) is a hydroxypiridinone derivatived iron chelator, approved for iron overload treatment that has high oral bioavailability. DFP preferably bind to free iron in oxidation state +3 (Fe+3) in the ratio of 3: 1, reducing iron overload and consequent tissue damage related to oxidative stress caused by metal. The maximum concentration after oral administration is reached in about 45 minutes and after metabolization, around 85% is converted to glucuronide, which is not able to connect to iron. DFP is an alternative to deferoxamine in patients with contraindication or side effects due to parenteral administration. Compared to other chelators, such as Deferasirox, DFP has some advantages such as lower cost and iron removal capacity from the reticuloendothelial system. However, the short 2-3 hours half-life is a pharmacokinetic inconvenience that requires optimization of its chemical structure to improve patient treatment. In this respect, the objective of this work is to modify the structure of the DFP through a replacement of the methyl group with the heterocyclic system. The hypothesis is that the steric impediment caused by the presence of the heterocyclic system would decrease the phase II reaction, reducing the formation of inactive glucuronide, thus increasing the half-life in planned analogues. In addition, in the new planned structures there would be additional points for iron chelation increasing the effectiveness of new compounds in the overload removal of this atom. The presence of carboxylic acid in the heteroclinic system contributes from a pharmacodynamic point of view, with another additional point of iron chelation. As for the pharmacokinetic aspect, this group would increase water solubility and can contribute to the better distribution of new compounds in the body.