para-Aminosalicylic acid in the treatment of manganese toxicity. Complexation of Mn2+ with 4-amino-2-hydroxybenzoic acid and its N-acetylated metabolite

Manganese excess can induce in humans a neurological disorder known as manganism. A possible remedy should be chelation therapy, even though a chelation schedule for manganism has not been currently established. para-Aminosalicylic acid (PAS) has demonstrated effectiveness in reducing manganism symptoms. In this work, a study of the protonation equilibria of para-aminosalicylic acid and of its N-acetylated metabolite (Ac-PAS) and of their complexation reactions with Mn2+ is presented, and also extended to the main essential metal ions Cu2+ and Fe3+. A number of complementary techniques (potentiometry, spectrophotometry, fluorimetry, EPR) have been used for a thorough comprehension of the protonation and complex formation equilibria, with the addition of DFT calculations, which provide insights into the relative stabilities and electronic properties of the formed species. Both PAS and Ac-PAS form 1 : 1 and 1 : 2 metal : ligand complexes with the target Mn2+ ion; surprisingly the N-acetylated metabolite forms stronger complexes, whose implications in chelation therapy have been pointed out by a speciation study. It is presumed that the relatively small metabolite can penetrate across the blood-brain-barrier and exert its Mn-mobilizing action intracellularly in vulnerable neurons.