Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS): Synthesis and biological evaluation |
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Authors: | Rosa M. Claramunt, Concepci n L pez, Carlos P rez-Medina, Marta P rez-Torralba, Jos Elguero, Germaine Escames,Darí o Acu a-Castroviejo |
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Affiliation: | aDepartamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain;bInstituto de Química Médica, CSIC, Centro de Química Orgánica Manuel Lora-Tamayo, Juan de la Cierva 3, E-28006 Madrid, Spain;cCentro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avenida del Conocimiento s/n, E-18100 Armilla, Granada, Spain;dLaboratorio de Análisis Clínicos, Hospital Universitario San Cecilio, Avenida Dr. Olóriz s/n, 18012 Granada, Spain |
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Abstract: | In order to find new compounds with neuroprotective activity and NOS-I/NOS-II selectivity, we have designed, synthesized, and characterized 14 new NOS inhibitors with an indazole structure. The first group corresponds to 4,5,6,7-tetrahydroindazoles (4–8), the second to the N-methyl derivatives (9–12) of 7-nitro-1H-indazole (1) and 3-bromo-7-nitro-1H-indazole (2), and the latter to 4,5,6,7-tetrafluoroindazoles (13–17). Compound 13 (4,5,6,7-tetrafluoro-3-methyl-1H-indazole) inhibited NOS-I by 63% and NOS-II by 83%. Interestingly, compound 16 (4,5,6,7-tetrafluoro-3-perfluorophenyl-1H-indazole) inhibited NOS-II activity by 80%, but it did not affect to NOS-I activity. Structural comparison between these new indazoles further supports the importance of the aromatic indazole skeleton for NOS inhibition and indicate that bulky groups or N-methylation of 1 and 2 diminish their effect on NOS activity. The fluorination of the aromatic ring increased the inhibitory potency and NOS-II selectivity, suggesting that this is a promising strategy for NOS selective inhibitors. |
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Keywords: | Indazoles Fluorine pharmacophore NOS-I NOS-II |
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