Enhancement of Benzothiazoles as Pteridine Reductase‑1 Inhibitors for the Treatment of Trypanosomatidic Infections
datasetposted on 25.03.2019, 00:00 by Pasquale Linciano, Cecilia Pozzi, Lucia dello Iacono, Flavio di Pisa, Giacomo Landi, Alessio Bonucci, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Gesa Witt, Nuno Santarem, Catarina Baptista, Caio Franco, Carolina B. Moraes, Wolfgang Müller, Ulrike Wittig, Rosaria Luciani, Antony Sesenna, Antonio Quotadamo, Stefania Ferrari, Ina Pöhner, Anabela Cordeiro-da-Silva, Stefano Mangani, Luca Costantino, Maria Paola Costi
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 μM; LmPTR1 IC50 = 1.9 μM) and low μM 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 μM). Formulation of 4c with hydroxypropyl-β-cyclodextrin yielded good oral bioavailability, encouraging progression to in vivo studies.