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Ligand-based discovery of N-(1,3-dioxo-1H,3H-benzo(de)isochromen-5-yl)-carboxamide and sulfonamide derivatives as thymidylate synthase A inhibitors

Phenolnaphthalein derivatives show potential for pharmacological activity as inhibitors of thymidylate synthase (TS) but difficulties in their synthesis and derivatization hinder their development. A deconstruction approach aimed at identifying a suitable new scaffold was proposed. A new scaffold wa...

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Bibliographic Details
Main Authors: Ferrari, Stefania (Author) , Ingrami, Marco (Author) , Soragni, Fabrizia (Author) , Wade, Rebecca C. (Author) , Costi, M. Paola (Author)
Format: Article (Journal)
Language:English
Published: 2013
In: Bioorganic & medicinal chemistry letters
Year: 2012, Volume: 23, Issue: 3, Pages: 663-668
ISSN:1464-3405
DOI:10.1016/j.bmcl.2012.11.117
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.bmcl.2012.11.117
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0960894X12015697
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Author Notes:Stefania Ferrari, Marco Ingrami, Fabrizia Soragni, Rebecca C. Wade, M. Paola Costi
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Summary:Phenolnaphthalein derivatives show potential for pharmacological activity as inhibitors of thymidylate synthase (TS) but difficulties in their synthesis and derivatization hinder their development. A deconstruction approach aimed at identifying a suitable new scaffold was proposed. A new scaffold was identified and two compound libraries based on this scaffold were designed. The carboxamide library (Library B) showed specific inhibition activity against Escherichia coli TS, whereas the sulfonamide library (Library C) showed a non-specific inhibition profile against hTS. N-(1,3-Dioxo-1H,3H-benzo[de]isochromen-5-yl)-sulfonamide derivatives, 1C and 9C, showed one order of magnitude improvement in inhibition constant against hTS with respect to the starting lead and represent potential compounds for further lead development.
Item Description:Available online 7 December 2012
Gesehen am 12.03.2021
Physical Description:Online Resource
ISSN:1464-3405
DOI:10.1016/j.bmcl.2012.11.117

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