Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Washington Dc : American Chemical Society
      Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
    • Subject Terms:
      Enzyme Inhibitors*/pharmacology ; Enzyme Inhibitors*/therapeutic use ; Enzyme Inhibitors*/chemistry ; Leishmaniasis*/drug therapy; Humans ; NADH, NADPH Oxidoreductases/metabolism ; Binding Sites
    • Abstract:
      Trypanothione reductase (TR) is a suitable target for drug discovery approaches against leishmaniasis, although the identification of potent inhibitors is still challenging. Herein, we harnessed a fragment-based drug discovery (FBDD) strategy to develop new TR inhibitors. Previous crystallographic screening identified fragments 1 - 3 , which provided ideal starting points for a medicinal chemistry campaign. In silico investigations revealed critical hotspots in the TR binding site, guiding our structure- and ligand-based structure-actvity relationship (SAR) exploration that yielded fragment-derived compounds 4 - 14 . A trend of improvement in Leishmania infantum TR inhibition was detected along the optimization and confirmed by the crystal structures of 9 , 10 , and 14 in complex with Trypanosoma brucei TR. Compound 10 showed the best TR inhibitory profile ( K i = 0.2 μM), whereas 9 was the best one in terms of in vitro and ex vivo activity. Although further fine-tuning is needed to improve selectivity, we demonstrated the potentiality of FBDD on a classic but difficult target for leishmaniasis.
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    • Accession Number:
      EC 1.8.1.12 (trypanothione reductase)
      0 (Enzyme Inhibitors)
      EC 1.6.- (NADH, NADPH Oxidoreductases)
    • Publication Date:
      Date Created: 20240102 Date Completed: 20240112 Latest Revision: 20240702
    • Publication Date:
      20240702
    • Accession Number:
      PMC10788915
    • Accession Number:
      10.1021/acs.jmedchem.3c01439
    • Accession Number:
      38164929