ArticleJournal of medicinal chemistry2011
Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: discovery, synthesis, and characterization of their binding mode by protein crystallography.
Article in Journal of medicinal chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 130 citations in OpenAlex.
- Beyond the Active Site: First-In-Class Leishmania Infantum Trypanothione Reductase Dimerization Disruptors as Antileishmanial Leads.ChemMedChem · 2026Review
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- Rapid assembly of structurally diverse 3,4-dihydroquinazolines with anticancer activity via SDS-promoted aqueous synthesis.Molecular diversity · 2026Article
- Structural basis of ligand selectivity in FAD/NAD(P)H-dependent dehydrogenases: insights from trypanothione reductase and type II NADH dehydrogenase.Protein science : a publication of the Protein Society · 2026Article
- Development of dihydroquinazoline compounds as novel therapeutics against Naegleria fowleri.Bioorganic & medicinal chemistry letters · 2025Article
- Targeting Trypanothione Synthetase and Trypanothione Reductase: Development of Common Inhibitors to Tackle Trypanosomatid Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase.International journal for parasitology. Drugs and drug resistance · 2025Article
- Tandem Synthesis of Tetrahydropyrroloquinazolines and Related Polyannular Scaffolds.The Journal of organic chemistry · 2025Article
- Acid-Catalyzed, Metal- and Oxidant-Free C=C Bond Cleavage of Enaminones: One-Pot Synthesis of 3,4-Dihydroquinazolines.Molecules (Basel, Switzerland) · 2025Article
- Chitosan-Zinc-Ligated Hydroxychloroquine: Molecular Docking, Synthesis, Characterization, and Trypanocidal Activity againstPolymers · 2024Article
- Product Selectivity Control in the Brønsted Acid-Mediated Reactions with 2-Alkynylanilines.Molecules (Basel, Switzerland) · 2024Article
- Targeting Trypanothione Metabolism in Trypanosomatids.Molecules (Basel, Switzerland) · 2024Review
- Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis.Journal of medicinal chemistry · 2024Article
- Preliminary Structure-Activity Relationship Study of the MMV Pathogen Box Compound MMV675968 (2,4-Diaminoquinazoline) Unveils Novel Inhibitors ofMolecules (Basel, Switzerland) · 2022Article
- Article
- Innovative Approach for a Classic Target: Fragment Screening on Trypanothione Reductase Reveals New Opportunities for Drug Design.Frontiers in molecular biosciences · 2022Article
- Advances in Proteasome Enhancement by Small Molecules.Biomolecules · 2021Review
- Druggable hot spots in trypanothione reductase: novel insights and opportunities for drug discovery revealed by DRUGpy.Journal of computer-aided molecular design · 2021Article
- Identification of 3-Methoxycarpachromene and Masticadienonic Acid as New Target Inhibitors against Trypanothione Reductase fromMolecules (Basel, Switzerland) · 2021Article
- Efficient Dimerization Disruption ofJournal of medicinal chemistry · 2021Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.
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