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 Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery.
ACS OMEGA, 2 (9).
pp. 5666-5683.
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 |
|---|---|
| Depositing User: | Symplectic Admin |
| Date Deposited: | 23 Jan 2019 15:29 |
| Last Modified: | 19 Jan 2023 01:06 |
| 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 |
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