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

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Linciano, Pasquale, Dawson, Alice, Poehner, Ina, Costa, David M, Sa, Monica S, Cordeiro-da-Silva, Anabela, Luciani, Rosaria, Gul, Sheraz, Witt, Gesa, Ellinger, Bernhard et al (show 29 more authors) , Kuzikov, Maria, Gribbon, Philip, Reinshagen, Jeanette, Wolf, Markus, Behrens, Birte, Hannaert, Veronique, Michels, Paul AM, Nerini, Erika, Pozzi, Cecilia, di Pisa, Flavio, Landi, Giacomo, Santarem, Nuno, Ferrari, Stefania, Saxena, Puneet, Lazzari, Sandra, Cannazza, Giuseppe, Freitas-Junior, Lucio H, Moraes, Carolina B, Pascoalino, Bruno S, Alcantara, Laura M, Bertolacini, Claudia P, Fontana, Vanessa ORCID: 0000-0002-0146-9113, Wittig, Ulrike, Muller, Wolfgang, Wade, Rebecca C, Hunter, William N, Mangani, Stefano, Costantino, Luca and Costi, Maria P (2017) Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit <i>Trypanosoma brucei</i> Pteridine Reductase in Support of Early-Stage Drug Discovery. ACS OMEGA, 2 (9). pp. 5666-5683.

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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.

Item Type:	Article
Uncontrolled Keywords:	Vector-Borne Diseases, Rare Diseases, Infectious Diseases, 5.1 Pharmaceuticals, 5 Development of treatments and therapeutic interventions, Infection, 3 Good Health and Well Being
Depositing User:	Symplectic Admin
Date Deposited:	23 Jan 2019 15:29
Last Modified:	15 Mar 2024 12:07
DOI:	10.1021/acsomega.7b00473
Open Access URL:	https://pubs.acs.org/doi/ipdf/10.1021/acsomega.7b0...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3031693