ArticleJournal of medicinal chemistry2012
Urea-based inhibitors of Trypanosoma brucei methionyl-tRNA synthetase: selectivity and in vivo characterization.
Article in Journal of medicinal chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 63 citations in OpenAlex.
- Discovery of a triple-site inhibitor targeting bacterial methionyl-tRNA synthetase through combined drug repurposing screening and generative AI-assisted optimization.Nucleic acids research · 2026Article
- Transcriptome Analysis of Trigeminal Ganglion and Medullary Dorsal Horn in Mice to Identify Potential Targets for Pulpitis-Induced Pain.ACS omega · 2025Article
- Small Molecule Inhibitors against the Bacterial PathogenCurrent medicinal chemistry · 2024Review
- ExploringPharmaceuticals (Basel, Switzerland) · 2023Article
- Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites.ACS omega · 2023Review
- Synthesis and Structure-Activity Relationships of Imidazopyridine/Pyrimidine- and Furopyridine-Based Anti-infective Agents against Trypanosomiases.ChemMedChem · 2021Article
- Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity againstRSC medicinal chemistry · 2020Article
- Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase.ACS infectious diseases · 2020Article
- Design, Synthesis, and Evaluation of Novel Anti-Trypanosomal Compounds.Tetrahedron · 2020Article
- Urea Derivatives in Modern Drug Discovery and Medicinal Chemistry.Journal of medicinal chemistry · 2020Article
- Optimization of Methionyl tRNA-Synthetase Inhibitors for Treatment ofAntimicrobial agents and chemotherapy · 2019Article
- The crystal structure of the drug target Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with a catalytic intermediate.Acta crystallographica. Section F, Structural biology communications · 2018Article
- Development of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram-Positive Bacterial Infections.Antimicrobial agents and chemotherapy · 2017Article
- Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani.ACS infectious diseases · 2017Article
- Synthesis ofMolecules (Basel, Switzerland) · 2017Article
- Article
- Optimization of a binding fragment targeting the "enlarged methionine pocket" leads to potent Trypanosoma brucei methionyl-tRNA synthetase inhibitors.Bioorganic & medicinal chemistry letters · 2017Article
- From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis.ACS infectious diseases · 2017Article
- Discovery of N-(2-aminoethyl)-N-benzyloxyphenyl benzamides: New potent Trypanosoma brucei inhibitors.Bioorganic & medicinal chemistry · 2017Article
- Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis.Journal of medicinal chemistry · 2017Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Urea-based methionyl-tRNA synthetase inhibitors were designed, synthesized, and evaluated for their potential toward treating human African trypanosomiasis (HAT). With the aid of a homology model and a structure-activity-relationship approach, low nM inhibitors were discovered that show high selectivity toward the parasite enzyme over the closest human homologue. These compounds inhibit parasite growth with EC(50) values as low as 0.15 μM while having low toxicity to mammalian cells. Two compounds (2 and 26) showed excellent membrane permeation in the MDR1-MDCKII model and encouraging oral pharmacokinetic properties in mice. Compound 2 was confirmed to enter the CNS in mice. Compound 26 had modest suppressive activity against Trpanosoma brucei rhodesiense in the mouse model, suggesting that more potent analogues or compounds with higher exposures need to be developed. The urea-based inhibitors are thus a promising starting point for further optimization toward the discovery of orally available and CNS active drugs to treat HAT.
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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.