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...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-02, Vol.23 (3), p.663-668
Main Authors: Ferrari, Stefania, Ingrami, Marco, Soragni, Fabrizia, Wade, Rebecca C., Costi, M. Paola
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Antibacterial compound
Anticancer compound
Carboxylic Acids - chemical synthesis
Carboxylic Acids - chemistry
Carboxylic Acids - pharmacology
Deconstruction approach
derivatization
Drug Discovery
Enzyme Activation - drug effects
Enzyme inhibition
Escherichia coli
Escherichia coli - drug effects
Humans
Ligands
scaffolds
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Sulfonamides
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Thymidylate synthase
Thymidylate Synthase - antagonists & inhibitors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.11.117