RESUMO
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 (pKa, 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.
Assuntos
Alopurinol/síntese química , Pró-Fármacos/síntese química , Tripanossomicidas/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Alopurinol/farmacologia , Química Farmacêutica , Humanos , Pró-Fármacos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/fisiologiaRESUMO
Synthesis of six prodrugs of allopurinol (4-hydroxypyrazolo-(3,4-d)pyrimidine) is described. These compounds were given orally to male and female BALB/C (sensitive) and C57BL/6 (partially resistant) strains of mice, wich had been previously infected with Leishmania mexicana. The results show that at end of the treatment there was weak regression of lesions confirmed through measurement of nodule diameter in the infected animals