title: Conformational analysis of phthalein derivatives acting as thymidylate synthase inhibitors by means of 1H NMR and quantum chemical calculations.
abstract: The conformations of a set of phthalein derivatives with bacterial thymidylate synthase (TS) inhibitory activity were investigated by 1H NMR spectra, performed at both room and low temperature, and by quantum chemical calculations. Since the crystal structure of the binary complex of phenolphthalein with the enzyme is known, we set out to study the conformation of various of its analogues in solution in order to observe the effects of the substituents on the phenolic rings, of the alpha-naphthol derivative and of the rigid analogue, fluorescein, and compare the results with the X-ray crystal structure studies. A relationship between the chemical shift of the proton on C4 (H4) of the phthalidic ring and the averaged angle formed by the phthalidic and the aromatic ring planes was found in which the most perpendicular conformations have the lowest H4 chemical shift values. At room temperature, the rotational freedom of all the studied compounds was similar, while at lower temperature the naphthol derivative assumed a partially blocked conformation. Finally, a qualitative relationship between the inhibitory properties of the compounds and their conformations is discussed.
authors.affiliation: Dipartimento di Chimica, Universita di Modena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ghelli
authors.forename: G
authors.initials: G
authors.lastname: Rastelli
authors.forename: D
authors.initials: D
authors.lastname: Barlocco
authors.forename: M
authors.initials: M
authors.lastname: Rinaldi
authors.forename: D
authors.initials: D
authors.lastname: Tondi
authors.forename: P
authors.initials: P
authors.lastname: Pecorari
authors.forename: M P
authors.initials: MP
authors.lastname: Costi
mesh_terms: D004396:Coloring Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011487:Protein Conformation; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D004396:Coloring Agents; D013940:Thymidylate Synthase