Synthesis and pharmaceutical properties of N-acyloxymethyl prodrugs of Allop with potential anti-trypanosomal activity

• Published in: Drug development and industrial pharmacy 2016-04, Vol.42 (4), p.602-610
• Main Authors: Gualdesi, M. S., Ortiz, C. S., Raviolo, M. A.
• Format: Article
• Language: English
• Subjects: Allopurinol - chemical synthesis; Allopurinol - pharmacology; Chagas disease; Chemistry, Pharmaceutical; Humans; N-acyloxymethyl prodrugs; physicochemical and pharmacokinetic properties; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - pharmacology; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - physiology; trypanosomal activity
• ISSN: 0363-9045; 1520-5762
• DOI: 10.3109/03639045.2015.1061539

We report herein the synthesis, and the physicochemical and pharmacokinetic properties of N-acyloxymethyl prodrugs of allopurinol (Allop) (2a-f). Allop is a compound with activity against Trypanosoma cruzi, a causative agent of Chagas disease. Its pathology leads to a huge number of infections and deaths per year, because in addition to many sufferers only having limited access to health services only an inefficient chemotherapy is available. Relevant pharmaceutical properties (pK a , stability, solubility, lipophilicity, in vitro permeability, binding protein, xanthine oxidase binding) were also determined. The results obtained showed that derivatives behave as prodrugs of Allop, since they exhibit improved physicochemical and pharmacokinetic properties relative to their precursor. This behavior turns these compounds into active reservoirs of Allop, and reduces its unfavorable characteristics, so 2a-f compounds are excellent candidates for the treatment of Chagas disease. This work is therefore an important contribution leading to the suppression of Chagas disease.