2. Academic Validation
  3. Design of 2-Aminobenzothiazole Derivatives Targeting Trypanosomatid PTR1 by a Multidisciplinary Fragment Hybridization Approach

Design of 2-Aminobenzothiazole Derivatives Targeting Trypanosomatid PTR1 by a Multidisciplinary Fragment Hybridization Approach

  • J Med Chem. 2025 Oct 9;68(19):20595-20618. doi: 10.1021/acs.jmedchem.5c01799.
Joanna Panecka-Hofman 1 2,  Pasquale Linciano 3 4,  Ina Pöhner 1 5,  Edyta Dyguda-Kazimierowicz 6,  Wiktoria Jedwabny 6,  Giacomo Landi 7,  Nuno Santarem 8,  Gesa Witt 9,  Bernhard Ellinger 9,  Maria Kuzikov 9,  Rosaria Luciani 3,  Stefania Ferrari 3,  Daniele Aiello 3,  Stefano Mangani 7,  Cecilia Pozzi 7 10,  Anabela Cordeiro-da-Silva 8,  Sheraz Gul 9,  Maria Paola Costi 3,  Rebecca C Wade 1 11 12
Affiliations

Affiliations

  • 1 Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), D-69118 Heidelberg, Germany.
  • 2 Biophysics Division, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-093 Warsaw, Poland.
  • 3 Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy.
  • 4 Department of Drug Science, University of Pavia, 27100 Pavia, Italy.
  • 5 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • 6 Faculty of Chemistry, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
  • 7 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy.
  • 8 Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute for Molecular and Cell Biology, 4150-180 Porto, Portugal.
  • 9 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, D-22525 Hamburg, Germany.
  • 10 Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), 50019 Sesto Fiorentino, Florence, Italy.
  • 11 Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, and Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, D-69120 Heidelberg, Germany.
  • 12 Faculties of Engineering Sciences and Biosciences, Heidelberg University, D-69120 Heidelberg, Germany.
PMID: 41026998 DOI: 10.1021/acs.jmedchem.5c01799
Abstract

Pteridine reductase 1 (PTR1) is a folate pathway enzyme essential for pathogenic trypanosomatids and a promising drug target for diseases such as sleeping sickness and leishmaniasis. Previous studies have shown that the 2-aminobenzothiazole moiety targets the PTR1 biopterin pocket, while 3,4-dichlorophenyl-containing compounds, such as I bind a different region of the Trypanosoma brucei PTR1 (TbPTR1) pocket. This study combines both moieties via various linkers, creating two compound series screened in silico against TbPTR1 and Leishmania major PTR1 (LmPTR1). In the first series, five compounds were synthesized, and 1a and 1b emerged as potent TbPTR1 inhibitors, with 1b also being active against LmPTR1 and moderately effective against Leishmania infantum. Furthermore, structure-activity relationship analysis, supported by quantum calculations and crystallography, revealed meta-halogenation to be more favorable than para, although single halogenation reduced antiparasite effects. Our fragment hybridization approach led to less toxic, more effective compounds than I.

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