Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin

• Published in: Molecules (Basel, Switzerland) Switzerland), 2015-08, Vol.20 (9), p.15643-15665
• Main Authors: Nieto, Carla I, Cabildo, María Pilar, Cornago, María Pilar, Sanz, Dionisia, Claramunt, Rosa M, Torralba, María Carmen, Torres, María Rosario, Elguero, José, García, José A, López, Ana, Acuña-Castroviejo, Darío
• Format: Article
• Language: English
• Subjects: crystallography; curcumin; Curcumin - chemistry; Electronic mail systems; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fluorine; Fluorine - chemistry; fluorine derivatives; Magnetic Resonance Spectroscopy; Molecular Structure; multinuclear NMR; Nitric oxide; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase Type I - antagonists & inhibitors; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type III - antagonists & inhibitors; NOS inhibitors; pyrazoles; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Structure-Activity Relationship; tautomerism; X-Ray Diffraction - methods
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules200915643

A series of new (E)-3(5)-[β-(aryl)-ethenyl]-5(3)-phenyl-1H-pyrazoles bearing fluorine atoms at different positions of the aryl group have been synthesized starting from the corresponding β-diketones. All compounds have been characterized by elemental analysis, DSC as well as NMR (¹H, (13)C, (19)F and (15)N) spectroscopy in solution and in solid state. Three structures have been solved by X-ray diffraction analysis, confirming the tautomeric forms detected by solid state NMR. The in vitro study of their inhibitory potency and selectivity on the activity of nNOS and eNOS (calcium-calmodulin dependent) as well as iNOS (calcium-calmodulin independent) isoenzymes is presented. A qualitative structure-activity analysis allowed the establishment of a correlation between the presence/ absence of different substituents with the inhibition data proving that fluorine groups enhance the biological activity. (E)-3(5)-[β-(3-Fluoro-4-hydroxyphenyl)-ethenyl]-5(3)-phenyl-1H-pyrazole (13), is the best inhibitor of iNOS, being also more selective towards the other two isoforms.