Enhancement of Benzothiazoles as Pteridine Reductase‑1 Inhibitors for the Treatment of Trypanosomatidic Infections

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.