ArticleJournal of medicinal chemistry2014
4-Aminopyridyl-based CYP51 inhibitors as anti-Trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency.
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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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.
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Who cites it
24 citing papers in PubMed, 47 citations in OpenAlex.
- TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibition.Scientific reports · 2025Article
- Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy.Pharmaceuticals (Basel, Switzerland) · 2024Review
- N-substituted-4-(pyridin-4-ylalkyl)piperazine-1-carboxamides and related compounds as Leishmania CYP51 and CYP5122A1 inhibitors.Bioorganic & medicinal chemistry · 2024Article
- Aminopyridines in the development of drug candidates against protozoan neglected tropical diseases.Future medicinal chemistry · 2024Review
- Identification of Leucinostatins fromACS omega · 2022Article
- Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis.Molecules (Basel, Switzerland) · 2022Review
- Planning new Trypanosoma cruzi CYP51 inhibitors using QSAR studies.Molecular diversity · 2021Article
- Domain-Swap Dimerization ofMolecular pharmacology · 2020Article
- Structure-guided manipulation of the regioselectivity of the cyclosporine A hydroxylase CYP-sb21 fromSynthetic and systems biotechnology · 2020Article
- Construction and Evaluation of Molecular Models: Guide and Design of Novel SE Inhibitors.ACS medicinal chemistry letters · 2020Article
- 3-pyridyl inhibitors with novel activity against Trypanosoma cruzi reveal in vitro profiles can aid prediction of putative cytochrome P450 inhibition.Scientific reports · 2018Article
- CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM).PLoS neglected tropical diseases · 2017Article
- 4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection.PLoS neglected tropical diseases · 2017Article
- Rapid Chagas Disease Drug Target Discovery Using Directed Evolution in Drug-Sensitive Yeast.ACS chemical biology · 2017Article
- Chagas disease research and development: Is there light at the end of the tunnel?Computational and structural biotechnology journal · 2017Review
- The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations.Molecules (Basel, Switzerland) · 2016Review
- Drug Susceptibility of Genetically Engineered Trypanosoma cruzi Strains and Sterile Cure in Animal Models as a Criterion for Potential Clinical Efficacy of Anti-T. cruzi Drugs.Antimicrobial agents and chemotherapy · 2015Article
- Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease.Antimicrobial agents and chemotherapy · 2015Article
- Utilizing Chemical Genomics to Identify Cytochrome b as a Novel Drug Target for Chagas Disease.PLoS pathogens · 2015Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure-activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug-target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection.
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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.