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

Pasquale Linciano; Alice Dawson; Ina Pöhner; David M. Costa; Monica S. Sá; Anabela Cordeiro Da Silva; Rosaria Luciani; Sheraz Gul; Gesa Witt; Bernhard Ellinger; Maria Kuzikov; Philip Gribbon; Jeanette Reinshagen; Markus Wolf; Birte Behrens; Véronique Hannaert; Paul A. M.  Michels; Erika Nerini; Cecilia Pozzi; Flavio di Pisa; Giacomo Landi; Nuno Santarem; Stefania Ferrari; Puneet Saxena; Sandra Lazzari; Giuseppe Cannazza; Lucio H. Freitas-Junior; Carolina B. Moraes; Bruno S. Pascoalino; Laura M. Alcântara; Claudia P. Bertolacini; Vanessa Fontana; Ulrike Wittig; Wolfgang Müller; Rebecca C. Wade; William N. Hunter; Stefano Mangani; Luca Costantino; Maria P. Costi

doi:10.1021/acsomega.7b00473

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

Pasquale Linciano, Alice Dawson, Ina Pöhner, David M. Costa, Monica S. Sá, Anabela Cordeiro Da Silva, Rosaria Luciani, Sheraz Gul, Gesa Witt, Bernhard Ellinger, Maria Kuzikov, Philip Gribbon, Jeanette Reinshagen, Markus Wolf, Birte Behrens, Véronique Hannaert, Paul A. M. Michels, Erika Nerini, Cecilia Pozzi, Flavio di PisaGiacomo Landi, Nuno Santarem, Stefania Ferrari, Puneet Saxena, Sandra Lazzari, Giuseppe Cannazza, Lucio H. Freitas-Junior, Carolina B. Moraes, Bruno S. Pascoalino, Laura M. Alcântara, Claudia P. Bertolacini, Vanessa Fontana, Ulrike Wittig, Wolfgang Müller, Rebecca C. Wade, William N. Hunter (Lead / Corresponding author), Stefano Mangani (Lead / Corresponding author), Luca Costantino (Lead / Corresponding author), Maria P. Costi (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

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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 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.

Original language	English
Pages (from-to)	5666-5683
Number of pages	18
Journal	ACS Omega
Volume	2
Issue number	9
Early online date	11 Sept 2017
DOIs	https://doi.org/10.1021/acsomega.7b00473
Publication status	Published - 30 Sept 2017

Keywords

Journal article
Crystal structure
Medicinal chemistry
Molecular structure
Parasite
Structure-activity relationship

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10.1021/acsomega.7b00473Licence: CC BY

Final Published Version
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Final published version, 4.8 MBLicence: CC BY

State-of-the-Art Facilities for Structural Biology at the University of Dundee
Hunter, B. (Investigator), Lilley, D. (Investigator), Owen-Hughes, T. (Investigator), Wyatt, P. (Investigator) & van Aalten, D. (Investigator)
1/03/12 → 28/02/17
Project: Research

Hunter, Bill
- Biological Chemistry and Drug Discovery - Emeritus Professor of Structural Biology, Associate Staff of Structural Biology
Person: Associate Staff, Honorary

Cite this

Linciano, P., Dawson, A., Pöhner, I., Costa, D. M., Sá, M. S., Cordeiro Da Silva, A., Luciani, R., Gul, S., Witt, G., Ellinger, B., Kuzikov, M., Gribbon, P., Reinshagen, J., Wolf, M., Behrens, B., Hannaert, V., Michels, P. A. M., Nerini, E., Pozzi, C., ... Costi, M. P. (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), 5666-5683. https://doi.org/10.1021/acsomega.7b00473

@article{efd58085b44e417cb79b1350ef9c8318,

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

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.",

keywords = "Journal article, Crystal structure , Medicinal chemistry , Molecular structure , Parasite , Structure-activity relationship",

author = "Pasquale Linciano and Alice Dawson and Ina P{\"o}hner and Costa, {David M.} and S{\'a}, {Monica S.} and {Cordeiro Da Silva}, Anabela and Rosaria Luciani and Sheraz Gul and Gesa Witt and Bernhard Ellinger and Maria Kuzikov and Philip Gribbon and Jeanette Reinshagen and Markus Wolf and Birte Behrens and V{\'e}ronique Hannaert and Michels, {Paul A. M.} and Erika Nerini and Cecilia Pozzi and {di Pisa}, Flavio and Giacomo Landi and Nuno Santarem and Stefania Ferrari and Puneet Saxena and Sandra Lazzari and Giuseppe Cannazza and Freitas-Junior, {Lucio H.} and Moraes, {Carolina B.} and Pascoalino, {Bruno S.} and Alc{\^a}ntara, {Laura M.} and Bertolacini, {Claudia P.} and Vanessa Fontana and Ulrike Wittig and Wolfgang M{\"u}ller and Wade, {Rebecca C.} and Hunter, {William N.} and Stefano Mangani and Luca Costantino and Costi, {Maria P.}",

note = "This project has received funding from the European Union{\textquoteright}s Seventh Framework Programme for Research, Technological Development, and Demonstration under grant agreement no.603240 (NMTrypI-New Medicines for Trypanosomatidic Infections). We acknowledge, in addition, the financial support of the European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (grant no. 283570) to W.N.H., MIUR-PRIN2012 N°2012 74BNKN_003 to M.P.C. and the Wellcome Trust (grant nos. 801897, 094090) to W.N.H. I.P. and R.C.W. gratefully acknowledge the support of the Klaus Tschira Foundation",

year = "2017",

month = sep,

day = "30",

doi = "10.1021/acsomega.7b00473",

language = "English",

volume = "2",

pages = "5666--5683",

journal = "ACS Omega",

issn = "2470-1343",

publisher = "American Chemical Society",

number = "9",

}

Linciano, P, Dawson, A, Pöhner, I, Costa, DM, Sá, MS, Cordeiro Da Silva, A, Luciani, R, Gul, S, Witt, G, Ellinger, B, Kuzikov, M, Gribbon, P, Reinshagen, J, Wolf, M, Behrens, B, Hannaert, V, Michels, PAM, Nerini, E, Pozzi, C, di Pisa, F, Landi, G, Santarem, N, Ferrari, S, Saxena, P, Lazzari, S, Cannazza, G, Freitas-Junior, LH, Moraes, CB, Pascoalino, BS, Alcântara, LM, Bertolacini, CP, Fontana, V, Wittig, U, Müller, W, Wade, RC, Hunter, WN, Mangani, S, Costantino, L & Costi, MP 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, vol. 2, no. 9, pp. 5666-5683. https://doi.org/10.1021/acsomega.7b00473

TY - JOUR

T1 - Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery

AU - Linciano, Pasquale

AU - Dawson, Alice

AU - Pöhner, Ina

AU - Costa, David M.

AU - Sá, Monica S.

AU - Cordeiro Da Silva, Anabela

AU - Luciani, Rosaria

AU - Gul, Sheraz

AU - Witt, Gesa

AU - Ellinger, Bernhard

AU - Kuzikov, Maria

AU - Gribbon, Philip

AU - Reinshagen, Jeanette

AU - Wolf, Markus

AU - Behrens, Birte

AU - Hannaert, Véronique

AU - Michels, Paul A. M.

AU - Nerini, Erika

AU - Pozzi, Cecilia

AU - di Pisa, Flavio

AU - Landi, Giacomo

AU - Santarem, Nuno

AU - Ferrari, Stefania

AU - Saxena, Puneet

AU - Lazzari, Sandra

AU - Cannazza, Giuseppe

AU - Freitas-Junior, Lucio H.

AU - Moraes, Carolina B.

AU - Pascoalino, Bruno S.

AU - Alcântara, Laura M.

AU - Bertolacini, Claudia P.

AU - Fontana, Vanessa

AU - Wittig, Ulrike

AU - Müller, Wolfgang

AU - Wade, Rebecca C.

AU - Hunter, William N.

AU - Mangani, Stefano

AU - Costantino, Luca

AU - Costi, Maria P.

N1 - This project has received funding from the European Union’s Seventh Framework Programme for Research, Technological Development, and Demonstration under grant agreement no.603240 (NMTrypI-New Medicines for Trypanosomatidic Infections). We acknowledge, in addition, the financial support of the European Community’s Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (grant no. 283570) to W.N.H., MIUR-PRIN2012 N°2012 74BNKN_003 to M.P.C. and the Wellcome Trust (grant nos. 801897, 094090) to W.N.H. I.P. and R.C.W. gratefully acknowledge the support of the Klaus Tschira Foundation

PY - 2017/9/30

Y1 - 2017/9/30

N2 - 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.

AB - 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.

KW - Journal article

KW - Crystal structure

KW - Medicinal chemistry

KW - Molecular structure

KW - Parasite

KW - Structure-activity relationship

U2 - 10.1021/acsomega.7b00473

DO - 10.1021/acsomega.7b00473

M3 - Article

C2 - 28983525

SN - 2470-1343

VL - 2

SP - 5666

EP - 5683

JO - ACS Omega

JF - ACS Omega

IS - 9

ER -

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

Abstract

Keywords

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State-of-the-Art Facilities for Structural Biology at the University of Dundee

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Hunter, Bill

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