Nitrosocarbonyl release from O-substituted hydroxamic acids with pyrazolone leaving groups

Abstract

A new class of nitrosocarbonyl precursors, O-substituted hydroxamic acids with pyrazolone leaving groups (OHPY), is described.These compounds generate nitrosocarbonyl intermediates, which upon hydrolysis release nitroxyl (azanone, HNO) under physiologically relevant conditions. Pyrazolones have been used to confirm the generation of nitrosocarbonyls by competitive trapping to form isomeric N-substituted hydroxamic acids (NHPY) via an N-selective nitrosocarbonyl aldol reaction. The rate of nitrosocarbonyl release from OHPY donors is impacted by donor substituents, including the pyrazolone leaving group.

Development of N-Substituted Hydroxamic Acids with Pyrazolone Leaving Groups as Nitrosocarbonyl Precursors

“…We have recently used 1 H NMR spectroscopy to measure half-lives of donor decomposition by quantifying donor and pyrazolone byproduct as a function of time. , On the basis of the distinctive chemical shifts of the methyl groups of the NHPY donors and the pyrazolone byproducts, the decomposition of the donors and release of byproducts is easily monitored. Utilizing this assay, the half-lives of NHPY donors were determined under physiologically relevant conditions (Table ).…”

Mild Nitration of Pyrazolin‐5‐ones by a Combination of Fe(NO3)3 and NaNO2: Discovery of a New Readily Available Class of Fungicides, 4‐Nitropyrazolin‐5‐ones

“…One of the main ways in which the nitro group can be metabolized in living organisms is by reduction, which can lead to the formation of radical species, nitroso compounds (R−N=O), and hydroxylamines (RNHOH) . Therefore, 4‐nitropyrazolin‐5‐ones can be considered as compounds that may be metabolically, and structurally, related to HNO donors . The key structural feature of the mentioned compounds responsible for the demonstrated HNO‐donating activity is the easily cleavable C−N bond at the 4‐position of pyrazolin‐5‐one.…”

“…[97,103,104] Therefore, 4-nitropyrazolin-5-ones can be considered as compounds that may be metabolically, and structurally,r elated to HNO donors. [76,77] The key structuralf eature of the mentioned compounds responsible for the demonstrated HNO-donating activity is the easily cleavable CÀNb ond at the 4-position of pyrazolin-5-one. Ta king into account the relationship between the high antifungal activity of 4-nitropyrazolin-5-onesa nd the presence of the nitro group in the pyrazolin-5-one heterocycle,i nitial experiments on the chemical reactivityo ft he synthesized 4-nitropyrazolin-5-ones under reductive conditions were carried out.…”

“…[74,75] They also show nitroxyl (HNO)d onating properties. [76,77] Although some pyrazolin-5-ones with quite complicated structures have been reported to possess fungicidal activity, [64,[67][68][69][70][71] such properties are not intrinsic or typical of the pyrazolin-5-one scaffold. Instead, these compoundsa re widelyrecognized as anti-inflammatory and analgesic drugs.…”

“…These include anti‐inflammatory, analgesic, antitumor, antimicrobial, hypoglycemic, antitubercular, herbicidal, and fungicidal activities, as well as p38 inhibitory, HIV integrase inhibitory, and 4‐phosphodiesterase inhibitory activities . They also show nitroxyl (HNO) donating properties …”