title: Design, synthesis, and biological evaluation of imidazolyl derivatives of 4,7-disubstituted coumarins as aromatase inhibitors selective over 17-α-hydroxylase/C17-20 lyase.
abstract: The design, synthesis, and biological evaluation of a series of new aromatase (AR, CYP19) inhibitors bearing an imidazole ring linked to a 7-substituted coumarin scaffold at position 4 (or 3) are reported. Many compounds exhibited an aromatase inhibitory potency in the nanomolar range along with a high selectivity over 17-α-hydroxylase/C17-20 lyase (CYP17). The most potent AR inhibitor was the 7-(3,4-difluorophenoxy)-4-imidazolylmethyl coumarin 24 endowed with an IC(50) = 47 nM. Docking simulations on a selected number of coumarin derivatives allowed the identification of the most important interactions driving the binding and clearly indicated the allowed and disallowed regions for appropriate structural modifications of coumarins and closely related heterocyclic molecular scaffolds.
authors.affiliation: Dipartimento Farmaco-Chimico, Università degli Studi di Bari Aldo Moro, via Orabona 4, I-70125 Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanachi
authors.forename: Angelo D
authors.initials: AD
authors.lastname: Favia
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pisani
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: Christina
authors.initials: C
authors.lastname: Zimmer
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008861:Microsomes / Q000201:enzymology; D008958:Models, Molecular; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011485:Protein Binding; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C558735:7-(3,4-difluorophenoxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one; D047072:Aromatase Inhibitors; D003374:Coumarins; D007093:Imidazoles; D008024:Ligands; D013254:Steroid 17-alpha-Hydroxylase