by Claramunt, Rosa M, López, Concepción, Pérez-Medina, Carlos, Pérez-Torralba, Marta, Elguero, José, Escames, Germaine and Acuña-Castroviejo, Darío
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.
Reference:
Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS): synthesis and biological evaluation. (Claramunt, Rosa M, López, Concepción, Pérez-Medina, Carlos, Pérez-Torralba, Marta, Elguero, José, Escames, Germaine and Acuña-Castroviejo, Darío), In Bioorganic & medicinal chemistry, volume 17, 2009.
Bibtex Entry:
@article{Claramunt:2009goa,
author = {Claramunt, Rosa M and L{'o}pez, Concepci{'o}n and P{'e}rez-Medina, Carlos and P{'e}rez-Torralba, Marta and Elguero, Jos{'e} and Escames, Germaine and Acu{~n}a-Castroviejo, Dar{'i}o},
title = {{Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS): synthesis and biological evaluation.}},
journal = {Bioorganic {&} medicinal chemistry},
year = {2009},
volume = {17},
number = {17},
pages = {6180--6187},
month = sep,
affiliation = {Departamento de Qu{'i}mica Org{'a}nica y Bio-Org{'a}nica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain. rclaramunt@ccia.uned.es},
doi = {10.1016/j.bmc.2009.07.067},
pmid = {19679481},
language = {English},
rating = {0},
date-added = {2015-01-08T16:02:24GMT},
date-modified = {2020-07-09T13:27:51GMT},
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.},
url = {http://linkinghub.elsevier.com/retrieve/pii/S0968089609007251},
uri = {url{papers3://publication/doi/10.1016/j.bmc.2009.07.067}}
}