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

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Linciano, P (Author) Other; Dawson, A (Author) Other; Pohner, I (Author) Other; Costa, DM (Author) Other; Sa, MS (Author) Other; Anabela Cordeiro da Silva (Author) FFUP; Luciani, R (Author) Other; Gul, S (Author) Other; Witt, G (Author) Other; Ellinger, B (Author) Other; Kuzikov, M (Author) Other; Gribbon, P (Author) Other; Reinshagen, J (Author) Other; Wolf, M (Author) Other; Behrens, B (Author) Other; Hannaert, V (Author) Other; Michels, PAM (Author) Other; Nerini, E (Author) Other; Pozzi, C (Author) Other; di Pisa, F (Author) Other; Landi, G (Author) Other; Santarem, N (Author) Other; Ferrari, S (Author) Other; Saxena, P (Author) Other; Lazzari, S (Author) Other; Cannazza, G (Author) Other; Freitas, LH (Author) Other; Moraes, CB (Author) Other; Pascoalino, BS (Author) Other; Alcantara, LM (Author) Other; Bertolacini, CP (Author) Other; Fontana, V (Author) Other; Wittig, U (Author) Other; Muller, W (Author) Other; Wade, RC (Author) Other; Hunter, WN (Author) Other; Mangani, S (Author) Other; Costantino, L (Author) Other; Costi, MP (Author) Other

Journal

Title: ACS Omega

Vol. 2 No. 12

Pages: 5666-5683

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 7 Citations

Scopus - 23 Citations

Other information

Authenticus ID: P-00N-FR0

DOI: 10.1021/acsomega.7b00473

Abstract (EN): 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 mu M, 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 18