7-Aryl-7-deazapurine 3'-deoxyribonucleoside derivative as a novel lead for Chagas' disease therapy: and pharmacology.

Background: The protozoan 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 (Cpd), revealing promising anti- activity.

Objectives: To further evaluate Cpd  and to fully assess its therapeutic potential against CD, covering cell culture sterilization through washout assays, drug combination with benznidazole and long-term administration in -infected mice.

4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in .

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets.

6-Methyl-7-Aryl-7-Deazapurine Nucleosides as Anti-Trypanosoma cruzi Agents: Structure-Activity Relationship and in vivo Efficacy.

Chagas disease is a tropical infectious disease resulting in progressive organ-damage and currently lacks efficient treatment and vaccine options. The causative pathogen, Trypanosoma cruzi, requires uptake and processing of preformed purines from the host because it cannot synthesize these de novo, instigating the evaluation of modified purine nucleosides as potential trypanocides. By modifying the pyrimidine part of a previously identified 7-aryl-7-deazapurine nucleoside, we found that substitution of a 6-methyl for a 6-amino group allows retaining T.

Revisiting Pyrazolo[3,4-]pyrimidine Nucleosides as Anti- and Antileishmanial Agents.

Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a continued need for new drug discovery. As both kinetoplastid parasites are incapable of purine synthesis, they depend on purine salvage pathways that allow them to acquire and process purines from the host to meet their demands.

Drug screening using shape-based virtual screening and experimental models of cutaneous Leishmaniasis.

Cutaneous leishmaniasis (CL) is one of the most disregarded tropical neglected disease with the occurrence of self-limiting ulcers and triggering mucosal damage and stigmatizing scars, leading to huge public health problems and social negative impacts. Pentavalent antimonials are the first-line drug for CL treatment for over 70 years and present several drawbacks in terms of safety and efficacy. Thus, there is an urgent need to search for non-invasive, non-toxic and potent drug candidates for CL.

Evaluation of phthalazinone phosphodiesterase inhibitors with improved activity and selectivity against Trypanosoma cruzi.

Background: Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, needs urgent alternative therapeutic options as the treatments currently available display severe limitations, mainly related to efficacy and toxicity.

Objectives: As phosphodiesterases (PDEs) have been claimed as novel targets against T. cruzi, our aim was to evaluate the biological aspects of 12 new phthalazinone PDE inhibitors against different T.

New pyrazolopyrimidine derivatives as Leishmania amazonensis arginase inhibitors.

Arginase performs the first enzymatic step in polyamine biosynthesis in Leishmania and represents a promising target for drug development. Polyamines in Leishmania are involved in trypanothione synthesis, which neutralize the oxidative burst of reactive oxygen species (ROS) and nitric oxide (NO) that are produced by host macrophages to kill the parasite. In an attempt to synthesize arginase inhibitors, six 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives with different substituents at the 4-position of the phenyl group were synthesized.