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...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
September 11, 2017
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| In: |
ACS omega
Year: 2017, Volume: 2, Issue: 9, Pages: 5666-5683 |
| ISSN: | 2470-1343 |
| DOI: | 10.1021/acsomega.7b00473 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1021/acsomega.7b00473 Verlag, kostenfrei, Volltext: https://doi.org/10.1021/acsomega.7b00473 
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| Author Notes: | 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 Pisa, Giacomo 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, Stefano Mangani, Luca Costantino, and Maria P. Costi |
| Summary: | 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. |
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| Item Description: | Gesehen am 25.09.2018 |
| Physical Description: | Online Resource |
| ISSN: | 2470-1343 |
| DOI: | 10.1021/acsomega.7b00473 |