ArticleJournal of medicinal chemistry2018
Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.
Article in Journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 43 citations in OpenAlex.
- Computer-Aided Discovery of Drugs Against Chagas Disease.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Evolutionary analysis of the Leishmania major orthologues for the newly identified cyclic AMP response proteins.Archives of microbiology · 2025Article
- Discovery of an Orally Efficacious Pyrazolo[3,4-Journal of medicinal chemistry · 2025Article
- Adhesion ofmSphere · 2024Article
- Identification of potent and orally efficacious phosphodiesterase inhibitors in Cryptosporidium parvum-infected immunocompromised male mice.Nature communications · 2024Article
- Lead Optimization of the 5-Phenylpyrazolopyrimidinone NPD-2975 toward Compounds with Improved Antitrypanosomal Efficacy.Journal of medicinal chemistry · 2024Article
- Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy.Journal of medicinal chemistry · 2023Article
- To Target or Not to TargetInternational journal of molecular sciences · 2023Article
- Novel kinetoplastid-specific cAMP binding proteins identified by RNAi screening for cAMP resistance inFrontiers in cellular and infection microbiology · 2023Article
- Current Treatments to Control African Trypanosomiasis and One Health Perspective.Microorganisms · 2022Review
- Exploring the Activity Profile of TbrPDEB1 and hPDE4 Inhibitors Using Free Energy Perturbation.ACS medicinal chemistry letters · 2022Article
- Tetrahydrophthalazinone Inhibitor of Phosphodiesterase withAntimicrobial agents and chemotherapy · 2021Article
- Evaluation of Various Solvent Extracts ofMolecules (Basel, Switzerland) · 2020Article
- Cloning and functional complementation of ten Schistosoma mansoni phosphodiesterases expressed in the mammalian host stages.PLoS neglected tropical diseases · 2020Article
- Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening.Frontiers in chemistry · 2020Article
- Screening of a PDE-focused library identifies imidazoles with in vitro and in vivo antischistosomal activity.International journal for parasitology. Drugs and drug resistance · 2019Article
- Imidazole Derivatives as Promising Agents for the Treatment of Chagas Disease.Antimicrobial agents and chemotherapy · 2019Article
- Flagellar cAMP signaling controls trypanosome progression through host tissues.Nature communications · 2019Article
Corrections and comments
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Authors and funding
27 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, and pharmacological evaluation and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B, and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series. Two of these, 8 (NPD-008) and 9 (NPD-039), were potent ( K
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