ArticlePLoS neglected tropical diseases2015
Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors.
Article in PLoS neglected tropical diseases, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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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
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 81 citations in OpenAlex.
- Discovery of Novel Inhibitors of Cruzain Cysteine Protease ofCurrent medicinal chemistry · 2024Pooled it
- Assessment of the Binding Affinity of Covalent Inhibitors of Cruzain and Cathepsin L Using Relative Binding Free Energy.ChemMedChem · 2026Article
- Machine Learning-Guided Repositioning of a SARS-CoV-2-Targeting Molecular Series as Cruzain Inhibitors.ChemMedChem · 2026Article
- Target Selectivity of Cysteine Protease Inhibitors: A Strategy to Address Neglected Tropical Diseases.Current medicinal chemistry · 2026Review
- Advances in Cysteine Protease B Inhibitors for Leishmaniasis Treatment.Current drug targets · 2025Review
- Article
- Covalent Inhibitors for Neglected Diseases: An Exploration of Novel Therapeutic Options.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization.Life (Basel, Switzerland) · 2022Review
- Identification of Potential Antiviral Inhibitors from Hydroxychloroquine and 1,2,4,5-Tetraoxanes Analogues and Investigation of the Mechanism of Action in SARS-CoV-2.International journal of molecular sciences · 2022Article
- Multiparameter Optimization of Trypanocidal Cruzain Inhibitors WithFrontiers in pharmacology · 2021Article
- Insights Into Amentoflavone: A Natural Multifunctional Biflavonoid.Frontiers in pharmacology · 2021Review
- Article
- On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors.RSC medicinal chemistry · 2020Article
- Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents.PLoS neglected tropical diseases · 2020Article
- Apoferritin encapsulation of cysteine protease inhibitors for cathepsin L inhibition in cancer cells.RSC advances · 2019Article
- Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors.PloS one · 2019Article
- Structure-Based and Molecular Modeling Studies for the Discovery of Cyclic Imides as Reversible Cruzain Inhibitors With Potent Anti-Frontiers in chemistry · 2019Article
- Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi.Journal of medicinal chemistry · 2017Article
- Anti-trypanosomal activity of non-peptidic nitrile-based cysteine protease inhibitors.PLoS neglected tropical diseases · 2017Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions. A Ki value of 16 nM was observed for the most potent of these inhibitors which reflects a degree of non-additivity in the SAR. An X-ray crystal structure was determined for the ligand-protein complex for the structural prototype for the series. Twenty three inhibitors were also evaluated for their anti-trypanosomal effects and an EC50 value of 28 μM was observed for the most potent of these. Although there remains scope for further optimization, the knowledge gained from this study is also transferable to the design of cruzain inhibitors based on warheads other than nitrile as well as alternative scaffolds.
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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.