Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin.
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.
Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, Universidad Nacional de Educación a Distancia, Paseo Senda del Rey, 9, Madrid 28040, Spain. carla.nieto@hotmail.com.
Carla I
CI
Nieto
Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, Universidad Nacional de Educación a Distancia, Paseo Senda del Rey, 9, Madrid 28040, Spain. pcabildo@ccia.uned.es.
María Pilar
MP
Cabildo
Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, Universidad Nacional de Educación a Distancia, Paseo Senda del Rey, 9, Madrid 28040, Spain. pcabildo@ccia.uned.es.
María Pilar
MP
Cornago
Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, Universidad Nacional de Educación a Distancia, Paseo Senda del Rey, 9, Madrid 28040, Spain. dsanz@ccia.uned.es.
Dionisia
D
Sanz
Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, Universidad Nacional de Educación a Distancia, Paseo Senda del Rey, 9, Madrid 28040, Spain.
Rosa M
RM
Claramunt
Departamento de Química Inorgánica I and CAI de Difracción de Rayos-X, Facultad de Ciencias Químicas, Universidad Complutense de Madrid (UCM), Madrid 28040, Spain. Torralba@ucm.es.
María Carmen
MC
Torralba
Departamento de Química Inorgánica I and CAI de Difracción de Rayos-X, Facultad de Ciencias Químicas, Universidad Complutense de Madrid (UCM), Madrid 28040, Spain. mrtorres@quim.ucm.es.
María Rosario
MR
Torres
Instituto de Química Médica, Centro de Química Orgánica "Manuel Lora-Tamayo", CSIC, Juan de la Cierva, 3, Madrid 28006, Spain. iqmbe17@iqm.csic.es.
José
J
Elguero
Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avda. del Conocimiento s/n, Armilla, 18100 Granada, Spain. jgsantos@ugr.es.
José A
JA
García
Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avda. del Conocimiento s/n, Armilla, 18100 Granada, Spain. al653@cam.ac.uk.
Ana
A
López
Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avda. del Conocimiento s/n, Armilla, 18100 Granada, Spain. dacuna@ugr.es.
Darío
D
Acuña-Castroviejo
D003474:Curcumin / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction / Q000379:methods
D004791:Enzyme Inhibitors; D011720:Pyrazoles; D005461:Fluorine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D003474:Curcumin
NOS inhibitors; crystallography; curcumin; fluorine derivatives; multinuclear NMR; pyrazoles; tautomerism