7-Aryl-7-deazapurine 3′-deoxyribonucleoside derivative as a novel lead for Chagas’ disease therapy: in vitro and in vivo pharmacology

Abstract

Background The protozoan Trypanosoma cruzi is auxotrophic for purines and causes Chagas’ disease (CD), a neglected illness affecting >6 million people. Combining the 3-deoxyribofuranose part of cordycepin with the modified purine ring of a nucleoside ‘hit’ led to the discovery of 4-amino-5-(4-chlorophenyl)-N7-(3′-deoxy-β-d-ribofuranosyl)-pyrrolo[2,3-d]pyrimidine (Cpd1), revealing promising anti-T. cruzi activity. Objectives To further evaluate Cpd1 in vitro and in vivo to fully assess its therapeutic potential against CD, covering cell culture sterilization through washout assays, drug combination with benznidazole and long-term administration in T. cruzi-infected mice. Results Although less susceptible to Cpd1 than amastigotes, trypomastigotes present an impaired capacity to successfully establish intracellular infection of cardiac cultures. Combination of benznidazole with Cpd1 indicated no interaction (additive effect) (FIC index = 0.72) while administration to mice at one-tenth of the optimal dose (2.5 mg/kg and 10 mg/kg for Cpd1 and benznidazole, respectively) suppressed parasitaemia but failed to avoid mortality. Long-term treatment (60 days) gave a rapid drop of the parasitaemia (>98% decline) and 100% mice survival but only 16% cure. In vitro washout experiments demonstrated that although parasite release into the supernatant of infected cardiac cultures was reduced by >94%, parasite recrudescence did occur after treatment. Conclusions Parasite recrudescence did occur after treatment corroborating the hypothesis of therapeutic failure due to subpopulations of dormant forms and/or genetic factors in persister parasites involved in natural drug resistance.

Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease

“…The isobologram graph was built plotting the FICI for each proportion of the compounds. The xΣFICI was used to classify the interaction as synergistic xΣFICI ≤ 0.5, no interaction xΣFICI > 0.5–4, and antagonistic for xΣFICI > 4 [ 38 , 39 ].…”

Perspectives for a new drug candidate for Chagas disease therapy

“… 28 Similar results were found using nucleoside derivatives assayed against T. cruzi infection. 29 , 30 As kinetoplastids parasites are incapable of de novo purine synthesis, depending on purine salvage pathways to acquire and process these elements from the hosts, purine nucleoside analogues represent an important source of novel antiparasitic agents. One of these promising compounds (7-aryl-7-deazapurine 3′-deoxyribonucleoside derivative) gave parasitaemia suppression and 100% animal survival in acute mouse models of experimental CD but even after long periods of drug exposure, failed to induce cure in vivo identified after cycles of cyclophosphamide administration.…”

“…In fact, in vitro wash-out experiments showed that that although parasite release into the supernatant of infected cultures was substantially lessened (> 94%), parasite recrudescence was achieved after compound withdraw. 30 The bulk of these results (cure failure in vitro and in vivo ) strongly suggest the occurrence of a heterogeneous parasite population in vitro that is not affected by the drug exposure, possibly quiescent/dorment/persister-like stages. 28 , 29 , 30 …”

“… 30 The bulk of these results (cure failure in vitro and in vivo ) strongly suggest the occurrence of a heterogeneous parasite population in vitro that is not affected by the drug exposure, possibly quiescent/dorment/persister-like stages. 28 , 29 , 30 …”

“… 29 The different levels of drug permeability into different cells and organs could also explain why some compounds (such as this nucleoside derivative, cp44) do not cure T. cruzi infection experimentally. 29 , 30 Also, a n-phenyl-substituted analogue (DB569) of furamidine (DB75) presented different outcomes in vitro depending on the nature of the host cell employed for T. cruzi infection. 35 DB569 has equivalent DNA binding properties compared to DB75 but is more potent upon T. cruzi (EC 50 levels in low-micromolar range).…”