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

Abstract

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 <i>Leishmania major</i> PTR1 for activity against <i>Trypanosoma brucei</i> (<i>Tb</i>). We solved crystal structures of several <i>Tb</i>PTR1-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 <i>Tb</i>PTR1 with low toxicity. In particular, compound <b>4m</b>, 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 <b>4m</b> 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-<i>T. brucei</i> agents can be obtained.