Publication

Article Metrics

Citations


Online attention

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

DOI: 10.1021/acsomega.7b00473 DOI Help

Authors: Pasquale Linciano (Università degli Studi di Modena e Reggio Emilia) , Alice Dawson (University of Dundee) , Ina Pöhner (Heidelberg Institute for Theoretical Studies) , David M. Costa (Universidade do Porto) , Monica S. Sá (Universidade do Porto) , Anabela Cordeiro-da-silva (Universidade do Porto) , Rosaria Luciani (Università degli Studi di Modena e Reggio Emilia) , Sheraz Gul (Fraunhofer-IME SP) , Gesa Witt (Fraunhofer-IME SP) , Bernhard Ellinger (Fraunhofer-IME SP) , Maria Kuzikov (Fraunhofer-IME SP) , Philip Gribbon (Fraunhofer-IME SP) , Jeanette Reinshagen (Fraunhofer-IME SP) , Markus Wolf (Fraunhofer-IME SP) , Birte Behrens (Fraunhofer-IME SP) , Véronique Hannaert (Université catholique de Louvain) , Paul A. M. Michels (Universitécatholique de Louvain) , Erika Nerini (Università degli Studi di Modena e Reggio Emilia) , Cecilia Pozzi (University of Siena) , Flavio Di Pisa (University of Siena) , Giacomo Landi (University of Siena) , Nuno Santarem (Universidade do Porto) , Stefania Ferrari (Università degli Studi di Modena e Reggio Emilia) , Puneet Saxena (Università degli Studi di Modena e Reggio Emilia) , Sandra Lazzari (Università degli Studi di Modena e Reggio Emilia) , Giuseppe Cannazza (Università degli Studi di Modena e Reggio Emilia) , Lucio H. Freitas-junior (Centro Nacional de Pesquisa em Energia e Materials) , Carolina B. Moraes (Centro Nacional de Pesquisa em Energia e Materials) , Bruno S. Pascoalino (Centro Nacional de Pesquisa em Energia e Materials) , Laura M. Alcântara (Centro Nacional de Pesquisa em Energia e Materials) , Claudia P. Bertolacini (Centro Nacional de Pesquisa em Energia e Materials) , Vanessa Fontana (Centro Nacional de Pesquisa em Energia e Materials) , Ulrike Wittig (Heidelberg Institute for Theoretical Studies) , Wolfgang Müller (Heidelberg Institute for Theoretical Studies) , Rebecca C. Wade (Heidelberg Institute for Theoretical Studies; Heidelberg University) , William N. Hunter (University of Dundee) , Stefano Mangani (University of Siena) , Luca Costantino (Università degli Studi di Modena e Reggio Emilia) , Maria P. Costi (Università degli Studi di Modena e Reggio Emilia)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Omega , VOL 2 , PAGES 5666 - 5683

State: Published (Approved)
Published: September 2017
Diamond Proposal Number(s): 8574

Open Access Open Access

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 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.

Journal Keywords: Crystal structure; Medicinal chemistry; Molecular structure; Parasite; Structure-activity relationship

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Other Facilities: Elettra Synchrotron; European Synchrotron Radiation Facility

Documents:
acsom4554ega.pdf