ArticleEuropean journal of medicinal chemistry2019
Discovery and characterization of trypanocidal cysteine protease inhibitors from the 'malaria box'.
Article in European journal of medicinal chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
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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
9 citing papers in PubMed, 1 synthesis or guideline pooled it, 24 citations in OpenAlex.
- Discovery of Novel Inhibitors of Cruzain Cysteine Protease ofCurrent medicinal chemistry · 2024Pooled it
- Investigation of the activity of 4-aminoquinolines as cysteine protease inhibitors with application in the treatment of Chagas disease.Memorias do Instituto Oswaldo Cruz · 2025Article
- Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain.Molecules (Basel, Switzerland) · 2024Article
- Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors TargetingACS omega · 2023Article
- Screening the Pathogen Box to Discover and Characterize New Cruzain andPathogens (Basel, Switzerland) · 2023Article
- From rational design to serendipity: Discovery of novel thiosemicarbazones as potent trypanocidal compounds.European journal of medicinal chemistry · 2022Article
- The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli-Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center.Molecules (Basel, Switzerland) · 2022Article
- Extending the Scope of the New Variant of the Castagnoli-Cushman Cyclocondensation ontoMolecules (Basel, Switzerland) · 2022Article
- Computational approaches towards the discovery and optimisation of cruzain inhibitors.Memorias do Instituto Oswaldo Cruz · 2022Review
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 3 countries.
Funding
Abstract
Chagas disease, Human African Trypanosomiasis, and schistosomiasis are neglected parasitic diseases for which new treatments are urgently needed. To identify new chemical leads, we screened the 400 compounds of the Open Access Malaria Box against the cysteine proteases, cruzain (Trypanosoma cruzi), rhodesain (Trypanosoma brucei) and SmCB1 (Schistosoma mansoni), which are therapeutic targets for these diseases. Whereas just three hits were observed for SmCB1, 70 compounds inhibited cruzain or rhodesain by at least 50% at 5 μM. Among those, 15 commercially available compounds were selected for confirmatory assays, given their potency, time-dependent inhibition profile and reported activity against parasites. Additional assays led to the confirmation of four novel classes of cruzain and rhodesain inhibitors, with potency in the low-to mid-micromolar range against enzymes and T. cruzi. Assays against mammalian cathepsins S and B revealed inhibitor selectivity for parasitic proteases. For the two competitive inhibitors identified (compounds 7 and 12), their binding mode was predicted by docking, providing a basis for structure-based optimization efforts. Compound 12 also acted directly against the trypomastigote and the intracellular amastigote forms of T. cruzi at 3 μM. Therefore, through a combination of experimental and computational approaches, we report promising hits for optimization in the development of new trypanocidal drugs.
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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.