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Design of 2-aminobenzothiazole derivatives targeting trypanosomatid PTR1 by a multidisciplinary fragment hybridization approach

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-dichlor...

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Hauptverfasser: Panecka-Hofman, Joanna (VerfasserIn) , Linciano, Pasquale (VerfasserIn) , Pöhner, Ina (VerfasserIn) , Dyguda-Kazimierowicz, Edyta (VerfasserIn) , Jedwabny, Wiktoria (VerfasserIn) , Landi, Giacomo (VerfasserIn) , Santarem, Nuno (VerfasserIn) , Witt, Gesa (VerfasserIn) , Ellinger, Bernhard (VerfasserIn) , Kuzikov, Maria (VerfasserIn) , Luciani, Rosaria (VerfasserIn) , Ferrari, Stefania (VerfasserIn) , Aiello, Daniele (VerfasserIn) , Mangani, Stefano (VerfasserIn) , Pozzi, Cecilia (VerfasserIn) , Cordeiro-da-Silva, Anabela (VerfasserIn) , Gul, Sheraz (VerfasserIn) , Costi, Maria Paola (VerfasserIn) , Wade, Rebecca C. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: September 30, 2025
In: Journal of medicinal chemistry
Year: 2025, Jahrgang: 68, Heft: 19, Pages: 20595-20618
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.5c01799
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1021/acs.jmedchem.5c01799
Verlag, kostenfrei, Volltext: https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01799
Volltext
Verfasserangaben:Joanna Panecka-Hofman, Pasquale Linciano, Ina Pöhner, Edyta Dyguda-Kazimierowicz, Wiktoria Jedwabny, Giacomo Landi, Nuno Santarem, Gesa Witt, Bernhard Ellinger, Maria Kuzikov, Rosaria Luciani, Stefania Ferrari, Daniele Aiello, Stefano Mangani, Cecilia Pozzi, Anabela Cordeiro-da-Silva, Sheraz Gul, Maria Paola Costi, and Rebecca C. Wade
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 13.03.2026
Beschreibung:Online Resource
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.5c01799

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