Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin
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AutorNieto, Carla I.; Cabildo, María Pilar; Cornago, María Pilar; Sanz, Dionisia; Claramount, Rosa M.; Torralba, María del Carmen; Torres, María Rosario; Elguero, José; García, José A.; López Ramírez, Ana; Acuña Castroviejo, Darío
NOS inhibitorsPyrazolesTautomerismFluorine derivativesCurcuminCrystallographyMultinuclear NMR
Nieto, C.I.; et al. Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin. Molecules, 20(9): 15643-15665 (2015). 
PatrocinadorThis work has been financed by Ministerio de Ciencia e Innovación (CTQ2010-16122) and Ministerio de Economía y Competitividad of Spain (CTQ2014-56833-R, RD12/0043/0005, and PI13-00981) and Comunidad Autónoma de Madrid (Project MADRISOLAR2, ref. S2009/PPQ-1533). One of us (C. I. Nieto) is indebted to UNED for a predoctoral fellowship (FPI “Grupos de Investigación” UNED).
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, 13C, 19F and 15N) 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.