Exploiting the 2‑Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery

Pteridine reductase-1 (PTR1) is a promising
drug target for the treatment of trypanosomiasis. We investigated
the potential of a previously identified class of thiadiazole inhibitors
of Leishmania major PTR1 for activity
against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new
thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based
assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m,
a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 μM,
was able to potentiate the antitrypanosomal activity of the dihydrofolate
reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of
the EC50 value. In addition, the antiparasitic activity
of the combination of 4m and MTX was reversed by addition
of folic acid. By adopting an efficient hit discovery platform, we
demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising
tool for the development of anti-T. brucei agents can be obtained.