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



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) (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.

Access the full-text of this item by clicking on the Open Access link.

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 IC<sub>50</sub> = 16 μM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC<sub>50</sub> 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: 3404 Medicinal and Biomolecular Chemistry, 34 Chemical Sciences, Rare Diseases, Orphan Drug, Vector-Borne Diseases, Emerging Infectious 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: 21 Jun 2024 06:57
DOI: 10.1021/acsomega.7b00473
Open Access URL: https://pubs.acs.org/doi/ipdf/10.1021/acsomega.7b0...
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3031693