2-Amino-benzo[ d]thiazole was identified as a new scaffold for the development of improved pteridine reductase-1 (PTR1) inhibitors and anti-trypanosomatidic agents. Molecular docking and crystallography guided the design and synthesis of 42 new benzothiazoles. The compounds were assessed for Trypanosoma brucei and Leishmania major PTR1 inhibition and in vitro activity against T. brucei and amastigote Leishmania infantum. We identified several 2-amino-benzo[ d]thiazoles with improved enzymatic activity ( TbPTR1 IC50 = 0.35 muM; LmPTR1 IC50 = 1.9 muM) and low muM antiparasitic activity against T. brucei. The ten most active compounds against TbPTR1 were able to potentiate the antiparasitic activity of methotrexate when evaluated in combination against T. brucei, with a potentiating index between 1.2 and 2.7. The compound library was profiled for early ADME toxicity, and 2-amino- N-benzylbenzo[ d]thiazole-6-carboxamide (4c) was finally identified as a novel potent, safe, and selective anti-trypanocydal agent (EC50 = 7.0 muM). Formulation of 4c with hydroxypropyl-beta-cyclodextrin yielded good oral bioavailability, encouraging progression to in vivo studies.
PubMed ID: 30908048
Publication type: Journal
Journal: J Med Chem
Citation: J Med Chem. 2019 Apr 25;62(8):3989-4012. doi: 10.1021/acs.jmedchem.8b02021. Epub 2019 Apr 9.
Date Published: 25th Apr 2019
Registered Mode: by PubMed ID
Created: 22nd Jul 2020 at 15:43