Indazole, Pyrazole, and Oxazole Derivatives Targeting Nitric Oxide Synthases and Carbonic Anhydrases.

Abstract

Nitric oxide (NO) is an essential endogenous mediator with a physiological role in the central nervous system as neurotransmitter and neuromodulator. A growing number of studies have demonstrated that abnormal nitrergic signaling is a crucial event in the development of neurodegeneration. In particular, the uncontrolled production of NO by neuronal nitric oxide synthase (nNOS) is observed in several neurodegenerative diseases. Moreover, it is well recognized that specific isoforms of human carbonic anhydrase (hCA) physiologically modulate crucial pathways of signal processing and that low expression of CA affects cognition, leading to mental retardation, Alzheimer's disease, and aging-related cognitive impairments. In light of this, dual agents that are able to target both NOS (inhibition) and CA (activation) could be useful drug candidates for the treatment of Alzheimer's disease, aging, and other neurodegenerative diseases. In the present work, we show the design, synthesis, and in vitro biological evaluation of new nitrogen-based heterocyclic compounds. Among the tested molecules, 2-amino-3-(4-hydroxyphenyl)-N-(1H-indazol-5-yl)propanamide hydrochloride (10 b) was revealed to be a potent dual agent, able to act as a selective nNOS inhibitor and activator of the hCA I isoform.

• Authors: Cristina Maccallini, Mauro Di Matteo, Daniela Vullo, Alessandra Ammazzalorso, Simone Carradori, Barbara De Filippis, Marialuigia Fantacuzzi, Letizia Giampietro, Assunta Pandolfi, Claudiu T Supuran, Rosa Amoroso
• Journal: ChemMedChem (ChemMedChem) Vol. 11 Issue 16 Pg. 1695-9 (08 19 2016) ISSN: 1860-7187 [Electronic] Germany
• PMID: 27377568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Enzyme Inhibitors
• Indazoles
• Oxazoles
• Pyrazoles
• Nitric Oxide Synthase Type I
• Carbonic Anhydrase I

Topics

• Carbonic Anhydrase I (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Indazoles (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Nitric Oxide Synthase Type I (antagonists & inhibitors, metabolism)
• Oxazoles (chemical synthesis, chemistry, pharmacology)
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship