title: 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.affiliation: Department of Pharmacy, University of Chieti "G. d'Annunzio", 66100, Chieti, Italy. cmaccallini@unich.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Maccallini
authors.affiliation: Department of Pharmacy, University of Chieti "G. d'Annunzio", 66100, Chieti, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Di Matteo
authors.affiliation: Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Via della Lastruccia 3, 50019, Sesto Fiorentino, Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Department of Pharmacy, University of Chieti "G. d'Annunzio", 66100, Chieti, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ammazzalorso
authors.affiliation: Department of Pharmacy, University of Chieti "G. d'Annunzio", 66100, Chieti, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Carradori
authors.affiliation: Department of Pharmacy, University of Chieti "G. d'Annunzio", 66100, Chieti, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: De Filippis
authors.affiliation: Department of Pharmacy, University of Chieti "G. d'Annunzio", 66100, Chieti, Italy.
authors.forename: Marialuigia
authors.initials: M
authors.lastname: Fantacuzzi
authors.affiliation: Department of Pharmacy, University of Chieti "G. d'Annunzio", 66100, Chieti, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Giampietro
authors.affiliation: Department of Medical, Oral and Biotecnological Sciences, University "G. d'Annunzio", Aging Research Center, "G. d'Annunzio" University Foundation, 66100, Chieti, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Pandolfi
authors.affiliation: Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Department of Pharmacy, University of Chieti "G. d'Annunzio", 66100, Chieti, Italy. ramoroso@unich.it.
authors.forename: Rosa
authors.initials: R
authors.lastname: Amoroso
mesh_terms: D024401:Carbonic Anhydrase I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D010080:Oxazoles; D011720:Pyrazoles; D052248:Nitric Oxide Synthase Type I; D024401:Carbonic Anhydrase I
keywords: activators; carbonic anhydrase; inhibitors; nitric oxide synthase; synthesis