Journal of Medicinal Chemistry p. 3989 - 4012 (2019)
Update date:2022-08-15
Topics:
Linciano, Pasquale
Pozzi, Cecilia
Iacono, Lucia Dello
Di Pisa, Flavio
Landi, Giacomo
Bonucci, Alessio
Gul, Sheraz
Kuzikov, Maria
Ellinger, Bernhard
Witt, Gesa
Santarem, Nuno
Baptista, Catarina
Franco, Caio
Moraes, Carolina B.
Müller, Wolfgang
Wittig, Ulrike
Luciani, Rosaria
Sesenna, Antony
Quotadamo, Antonio
Ferrari, Stefania
P?hner, Ina
Cordeiro-Da-Silva, Anabela
Mangani, Stefano
Costantino, Luca
Costi, Maria Paola
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.
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