Biological activity of analogs of guanine and guanosine against American Trypanosoma and Leishmania spp

Abstract

The growth inhibitory effects of six guanine and guanosine analogs, 3-deazaguanine (compound 1); 3-deazaguanosine (compound 2); 6-aminoallopurinol (compound 3); 9-I-xylofuranosyl guanine (compound 4); a ribosylated derivative of compound 3, 6-aminopyrazolo(3,4-d)pyrimidin-4-one (compound 5); and 5-aminoformycin B (compound 6), were tested against some pathogenic members of the family of American Trypanosomatidae. Compounds 1 and 2 were highly active against Trypanosoma cruzi, Trypanosoma rangeli, and American Leishmania spp. in in vitro culture forms. Both compounds also showed antiprotozoal activity in T. cruzi-infected mice, with the optimal dose being about 30 mg/kg of body weight per day given as 10 consecutive doses. Compound 3 was the most active compound in vitro, inhibiting all of the American Trypanosomatidae culture forms tested. It was also highly inhibitory in mice that were acutely infected with T. cruzi, with the optimal dose being about 10 mg/kg of body weight per day. Ribosylation of compound 3 resulted in a derivative that showed decreased inhibitory activity on Trypanosomatidae multiplication. Compound 6 was highly inhibitory of in vitro multiplication of American Leishmania and T. rangeli but had no effect on T. cruzi epimastigotes and on mice that were acutely infected with T. cruzi. Compound 4 showed only a slight effect on T. cruzi epimastigotes.Recent reviews on the chemotherapy of Chagas' disease and American cutaneous leishmaniasis have emphasized the deficiencies of currently available therapeutic agents and the need for new ones (1, 31). These diseases are still important health problems in the Western Hemisphere, while Trypanosoma rangeli, which is apparently a harmless parasite of humans and a variety of birds and domestic animals, infects about 52% of exposed people in endemic areas (23).With regard to purine metabolism, with the exception of adenine, the incorporation of purine bases by Trypanosoma cruzi is similar to that of Leishmania spp. (11). Because purine bases are incorporated more readily than their respective ribonucleosides, it appears that the major biosynthetic pathway from a purine base to its ribonucleoside is direct, via purine phosphoribosyltransferases, rather than a sequential conversion from base to ribonucleoside to ribonucleotide (11). In contrast to Leishmania spp. (19,22) and African trypanosomes (15), which have very high nucleosidecleaving activities, purine ribonucleosides are remarkably stable in T. cruzi (11).With regard to guanine metabolism in members of the family Trypanosomatidae, data are consistent with a direct conversion of guanine to GMP which could be converted sequentially to IMP and AMP by GMP reductase (EC 1.6.6.8) and the adenylosuccinate synthetase (EC 6.3.4.4) to GTP. For guanosine analogs to reach the nucleotide stage, they must be modified by purine nucleoside-cleaving enzymes, which have been demonstrated in several Trypanosomatidae (16,21,24), to produce the parent heterocyclic compound, which then acts as a substrate for hypoxanthin...

Purine and pyrimidine transport in pathogenic protozoa: From biology to therapy

“…Even though various nucleoside and nucleobase analogues display good activity in vitro and/or in vivo (e.g. [41–45]) only the pyrimidine antifolate pyrimethamine is widely used clinically, particularly in combination with sulphadoxine against malaria [46], and also against toxoplasmosis [47,48]. In addition the purine nucleobase allopurinol is used in combinations against leishmaniasis [49,50].…”

A novel non-stochastic quadratic fingerprints-based approach for the ‘in silico’ discovery of new antitrypanosomal compounds

“…The antitrypanosomals considered on this study are representatives of families with diverse structural patterns. [29][30][31][32][33][34][35][36][37][38] Figure 2 shows the whole active set collected from the literature for this work. The selected inactive group included antivirals, sedative/hypnotics, diuretics, anticonvulsivants, hemostatics, oral hypoglycemics, antihypertensives, antihelminthics, anticancer compounds as well as some other kinds of drugs, guaranteeing at the same time a great structural variability.…”

Antileishmanial IgG and IgE antibodies recognize predominantly carbohydrate epitopes of glycosylated antigens in visceral leishmaniasis

“…Furthermore, Leishmania glycolipids (Avila et al 1991) could induce both anti-carbohydrate IgE and IgG antibodies, as demonstrated in schistosomiasis (van der Kleij et al 1999). At present, we do not know the biological role played by these anti-carbohydrate IgG and IgE antibodies in the host-Leishmania relationship nor the factors influencing their production.…”