title: Ligand-based discovery of N-(1,3-dioxo-1H,3H-benzo[de]isochromen-5-yl)-carboxamide and sulfonamide derivatives as thymidylate synthase A inhibitors.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41126 Modena, Italy. stefania.ferrari@unimore.it
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferrari
authors.forename: Marco
authors.initials: M
authors.lastname: Ingrami
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Soragni
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Wade
authors.forename: M Paola
authors.initials: MP
authors.lastname: Costi
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D002264:Carboxylic Acids; D008024:Ligands; D054852:Small Molecule Libraries; D013449:Sulfonamides; D013940:Thymidylate Synthase