ArticleAntimicrobial agents and chemotherapy2012
Activation of benznidazole by trypanosomal type I nitroreductases results in glyoxal formation.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
100 citing papers in PubMed, 235 citations in OpenAlex.
- Population pharmacokinetic-pharmacodynamic analysis of benznidazole monotherapy and combination therapy with fosravuconazole in chronic Chagas disease (BENDITA).PLoS neglected tropical diseases · 2025Trial
- Human Histatin 5 Exerts Anti-Trypanosomal Activity AgainstInternational journal of molecular sciences · 2026Article
- Phenotypic Analysis of the Anti-Molecules (Basel, Switzerland) · 2026Article
- Revisiting cysteine protease function inMicrobiology spectrum · 2026Article
- Overcoming Trypanosoma cruzi persistence with a mechanistically distinct drug combination.npj antimicrobials and resistance · 2026Article
- Contribution to the Chemotherapy of Human Trypanosomiasis: Design, Synthesis, and Biological Evaluation of Dimeric 2‑Nitroimidazoles againstACS omega · 2026Article
- Advances and challenges in the search for new treatments for Chagas disease.Memorias do Instituto Oswaldo Cruz · 2026Review
- Optimization of anBiology methods & protocols · 2026Article
- Trypanosomatid parasites, translational research in a One Health, One World environment.Frontiers in chemistry · 2026Review
- Structure-enabled enhancement of potency in a metronidazole-benznidazole hybrid: design, synthesis, and evaluation of antitrypanosomal activity of a benzylamide-linked 5-nitroimidazole.Frontiers in pharmacology · 2026Article
- In vitro anti-Trypanosomatid activity and chemical profile of crude extracts of Chromolaena hookeriana and Campuloclinium macrocephalum (Asteraceae).Memorias do Instituto Oswaldo Cruz · 2026Article
- Fexinidazole results in specific effects on DNA synthesis and DNA damage in the African trypanosome.PLoS neglected tropical diseases · 2025Article
- Design, Synthesis, and Trypanosomicidal Evaluation of Eugenol-Based Azole Hybrids: Discovery of anACS omega · 2025Article
- Targeting Trypanothione Synthetase and Trypanothione Reductase: Development of Common Inhibitors to Tackle Trypanosomatid Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease.Science translational medicine · 2025Article
- ToxACoL: an endpoint-aware and task-focused compound representation learning paradigm for acute toxicity assessment.Nature communications · 2025Article
- TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Synthesis and Biological Evaluation of 4‑(4-Nitrophenyl)‑1ACS omega · 2025Article
- Pharmacokinetic-pharmacodynamic modeling of benznidazole and its antitrypanosomal activity in a murine model of chronic Chagas disease.PLoS neglected tropical diseases · 2025Article
- Transforming the chemotherapy of human African trypanosomiasis.Clinical microbiology reviews · 2025Review
40 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Benznidazole, a 2-nitroimidazole, is the front-line treatment used against American trypanosomiasis, a parasitic infection caused by Trypanosoma cruzi. Despite nearly 40 years of use, the trypanocidal activity of this prodrug is not fully understood. It has been proposed that benznidazole activation leads to the formation of reductive metabolites that can cause a series of deleterious effects, including DNA damage and thiol depletion. Here, we show that the key step in benznidazole activation involves an NADH-dependent trypanosomal type I nitroreductase. This catalyzes an oxygen-insensitive reaction with the interaction of enzyme, reductant, and prodrug occurring through a ping-pong mechanism. Liquid chromatography/mass spectrometry (LC/MS) analysis of the resultant metabolites identified 4,5-dihydro-4,5-dihydroxyimidazole as the major product of a reductive pathway proceeding through hydroxylamine and hydroxy intermediates. The breakdown of this product released the reactive dialdehyde glyoxal, which, in the presence of guanosine, generated guanosine-glyoxal adducts. These experiments indicate that the reduction of benznidazole by type I nitroreductase activity leads to the formation of highly reactive metabolites and that the expression of this enzyme is key to the trypanocidal properties displayed by the prodrug.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.