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

Pasquale Linciano, Alice Dawson, Ina Pöhner, David M. Costa, Monica S. Sá, Anabela Cordeiro Da Silva, Rosaria Luciani, Sheraz Gul, Gesa Witt, Bernhard Ellinger, Maria Kuzikov, Philip Gribbon, Jeanette Reinshagen, Markus Wolf, Birte Behrens, Véronique Hannaert, Paul A. M. Michels, Erika Nerini, Cecilia Pozzi, Flavio di PisaGiacomo Landi, Nuno Santarem, Stefania Ferrari, Puneet Saxena, Sandra Lazzari, Giuseppe Cannazza, Lucio H. Freitas-Junior, Carolina B. Moraes, Bruno S. Pascoalino, Laura M. Alcântara, Claudia P. Bertolacini, Vanessa Fontana, Ulrike Wittig, Wolfgang Müller, Rebecca C. Wade, William N. Hunter (Lead / Corresponding author), Stefano Mangani (Lead / Corresponding author), Luca Costantino (Lead / Corresponding author), Maria P. Costi (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)5666-5683
Number of pages18
JournalACS Omega
Issue number9
Early online date11 Sept 2017
Publication statusPublished - 30 Sept 2017


  • Journal article
  • Crystal structure
  • Medicinal chemistry
  • Molecular structure
  • Parasite
  • Structure-activity relationship


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