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acetohydroxamic acid [keywords]
- Synthesis, structure-activity relationship analysis and kinetics study of reductive derivatives of flavonoids as Helicobacter pylori urease inhibitors. [JOURNAL ARTICLE]
- Eur J Med Chem 2013 Mar 16.:685-695.
In a continuing study for discovering urease inhibitors based on flavonoids, nineteen reductive derivatives of flavonoids were synthesized and evaluated against Helicobacter pylori urease. Analysis of structure-activity relationship disclosed that 4-deoxy analogues are more potent than other reductive products. Out of them, 4',7,8-trihydroxyl-2-isoflavene (13) was found to be the most active with IC50 of 0.85 μM, being over 20-fold more potent than the commercial available urease inhibitor, acetohydroxamic acid (AHA). Kinetics study revealed that 13 is a competitive inhibitor of H. pylori urease with a Ki value of 0.641 μM, which is well matched with the results of molecular docking. Biological evaluation and mechanism study of 13 suggest that it is a good candidate for discovering novel anti-gastritis and anti-gastric ulcer agent.
- Biotransformation of Acetamide to Acetohydroxamic Acid at Bench Scale Using Acyl Transferase Activity of Amidase of Geobacillus pallidus BTP-5x MTCC 9225. [Journal Article]
- Indian J Microbiol 2012 Mar; 52(1):76-82.
The bioprocess employing acyl transferase activity of intracellular amidase of BTP-5x MTCC 9225 was harnessed for the synthesis of pharmaceutically important acetohydroxamic acid. BTP-5x exhibited highest acyl transferase activity with acetamide: hydroxylamine in ratio of 1:5 in 0.1 M NaHPO/NaHPO buffer (pH 7.5) at 65°C. In one liter fed-batch reaction containing 1:5 ratio of two substrates total of eight feedings of 0.05 M/20 min of acetamide were made and it was found that maximum acetohydroxamic production was achieved at 3:5 ratios of substrate and cosubstrate. In 1 l bench scale batch reaction containing 0.3 M acetamide, 0.5 M hydroxylamine in 0.1 M NaHPO/NaHPO buffer (pH 7.5, 50°C, 400 rpm) and 0.5 mg/ml (dry cell weight) of whole cells of BTP-5x (as biocatalyst) resulted in an yield of 0.28 M of acetohydroxamic acid after 20 min reaction time at 50°C. The acetamide bioconversion rate was 90-95% (mol mol) and 51 g powder containing 40% (w/w) acetohydroxamic acid was recovered after lyophilization.
- Conformational analysis of a secondary hydroxamic acid in aqueous solution by NOE spectroscopy. [Journal Article]
- Magn Reson Chem 2013 Feb; 51(2):72-5.
Hydroxamic acids are metal-binding compounds used by micro-organisms and possess applications in medicine and industry. Hydroxamic acids favor two conformations, E and Z; metal binding is limited to the Z conformation. The Z conformation may be identifiable by NOE spectroscopy, but analysis is complicated by the potential for long-range coupling as well as for relayed NOEs due to conformational switching. In this report, we re-examine the reported conformational preference of N-methyl acetohydroxamic acid (NMHA) in D(2)O using NOE spectroscopy. We find that the favored conformation of NMHA in aqueous solution is the E conformation, contrary to an earlier report. NOE build-up curves are proposed as a valuable tool to probe conformational behavior in similar systems.
- Synthesis, structures and urease inhibition studies of Schiff base metal complexes derived from 3,5-dibromosalicylaldehyde. [Journal Article, Research Support, Non-U.S. Gov't]
- Eur J Med Chem 2012 Dec.:323-31.
Eleven mononuclear copper(II), nickel(II), zinc(II) and cobalt(II) complexes of Schiff base ligands derived from 3,5-dibromosalicylaldehyde/3,5-dichlorosalicylaldehyde were synthesized and determined by single crystal X-ray analysis. The crystal structures of complexes 1, 2, 4, 5, 6, 8 and 11 present the square-planar coordination geometry at the metal center and complexes 7, 9 and 10 show the distorted tetrahedral geometry. While one copper center in 3 has a square-planar geometry, the other copper is slightly distorted square-planar. The inhibitory activities of all the obtained complexes were tested in vitro against jack bean urease. It was found that Schiff base copper(II) complexes 1, 3, 5, 8 and 11 showed strong urease inhibitory activities (IC(50) = 1.51-3.52 μM) compared with acetohydroxamic acid (IC(50) = 62.52 μM), which was a positive reference. Their structure-activity relationships were further discussed.
- The use of cyclic nitroxide radicals as HNO scavengers. [Journal Article, Research Support, Non-U.S. Gov't]
- J Inorg Biochem 2013 Jan.:155-61.
Reduction of cyclic stable nitroxides (RNO) by HNO to the respective hydroxylamines (RNO-H) has been demonstrated using EPR spectrometry. HNO shows low reactivity toward piperidine, pyrrolidine and nitronyl nitroxides with rate constants below 1.4 × 10(5)M(-1)s(-1) at pH 7.0, despite the high driving force for these reactions. The rate constants can be predicted assuming that the reactions take place via a concerted proton-electron transfer pathway and significantly low self-exchange rate constants for HNO/NO and RNO-H/RNO. NO does not react with piperidine and pyrrolidine nitroxides, but does add to HNO forming the highly oxidizing and moderately reducing hyponitrite radicals. In this work, the radicals are produced by pulse radiolysis and the rate constants of their reactions with 2,2,6,6,-tetramethylpiperidine-1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (TEMPOL) and 3-carbamoyl-PROXYL have been determined at pH 6.8 to be (2.4 ± 0.2)× 10(6), (9.8 ± 0.2)× 10(5), (5.9 ± 0.5)× 10(5)M(-1)s(-1), respectively. This low reactivity implies that NO competes efficiently with these nitroxides for the hyponitrite radical. The ability of TEMPOL and 2-(4-carboxyphenyl)-4,4,5,5,-tetramethyl-imidazoline-1-oxyl-3-oxide (C-PTIO) to oxidize HNO and their different reactivity toward NO are used to quantify HNO formed via acetohydroxamic acid oxidation. The extent of TEMPOL or C-PTIO reduction was similar to the yield of HNO formed upon oxidation by ()OH under anoxia, but not by the metmyoglobin and H(2)O(2) reaction system where both nitroxides catalytically facilitate H(2)O(2) depletion and nitrite accumulation. In this system the conversion of C-PTIO into 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl (C-PTI) is a minor reaction, which does not provide any mechanistic insight.
- Oxidation of N-hydroxy-l-arginine by hypochlorous acid to form nitroxyl (HNO). [Journal Article, Research Support, U.S. Gov't, Non-P.H.S.]
- J Inorg Biochem 2013 Jan.:148-54.
Recent research has shown that nitroxyl (HNO) has important and unique biological activity, especially as a potential alternative to current treatments of cardiac failure. HNO is a reactive molecule that undergoes efficient dimerization and subsequent dehydration to form nitrous oxide (N(2)O), making its detection in solution or biologically relevant preparations difficult. Due to this limitation, HNO has not yet been observed in vivo, though several pathways for its endogenous generation have been postulated. Here, we investigate the oxidation of N-hydroxy-l-arginine (NOHA) by hypochlorous acid (HOCl), which is generated in vivo from hydrogen peroxide and chloride by the heme enzyme, myeloperoxidase. NOHA is an intermediate in the enzymatic production of nitric oxide (NO) by NO synthases, and has been shown previously to be chemically oxidized to either HNO or NO, depending on the oxidant employed. Using membrane inlet mass spectrometry and standard N(2)O analysis by gas chromatography, we find that NOHA is oxidized by excess HOCl to form HNO-derived N(2)O. In addition, we also observe the analogous production of HNO from the HOCl oxidation of hydroxylamine, hydroxyurea, and (to a lesser extent) acetohydroxamic acid.
- Characterization of cobalt(III) hydroxamic acid complexes based on a tris(2-pyridylmethyl)amine scaffold: reactivity toward cysteine methyl ester. [Journal Article, Research Support, Non-U.S. Gov't]
- Inorg Chem 2012 Sep 3; 51(17):9350-6.
Six Co(III) complexes based on unsubstituted or substituted TPA ligands (where TPA is tris(2-pyridylmethyl)amine) and acetohydroxamic acid (A), N-methyl-acetohydroxamic acid (B), or N-hydroxy-pyridinone (C) were prepared and characterized by mass spectrometry, elemental analysis, and electrochemistry: [Co(III)(TPA)(A-2H)](Cl) (1a), [Co(III)((4-Cl(2))TPA)(A-2H)](Cl) (2a), [Co(III)((6-Piva)TPA)(A-2H)](Cl) (3a), [Co(III)((4-Piva)TPA)(A-2H)](Cl) (4a) and [Co(III)(TPA)(B-H)](Cl)(2) (1b), and [Co(III)(TPA)(C-H)](Cl)(2) (1c). Complexes 1a-c and 3a were analyzed by (1)H NMR, using 2D ((1)H, (1)H) COSY and 2D ((1)H, (13)C) HMBC and HSQC, and shown to exist as a mixture of two geometric isomers based on whether the hydroxamic oxygen was trans to a pyridine nitrogen or to the tertiary amine nitrogen. Complex 3a exists as a single isomer that was crystallized. Its crystal structure revealed the presence of an H-bond between the pivaloylamide and the hydroximate oxygen. Complexes 1a, 2a, and 4a are irreversibly reduced beyond -900 mV versus SCE, while complexes 1b and 1c are reduced at less negative values of -330 and -190 mV, respectively. The H-bond in 3a increased the redox potential up to -720 mV. Reaction of complex 1a with L-cysteine methyl ester CysOMe was monitored by (1)H NMR and UV-vis at 2 mM and 0.2 mM in an aqueous buffered solution at pH 7.5. Complex 1a was successively converted into an intermediate [Co(III)(TPA)(CysOMe-H)](2+), 1d, by exchange of the hydroximate with the cysteinate ligand, and further into Co(III)(CysOMe-H)(3), 5. An authentic sample of 1d was prepared and thoroughly characterized. A detailed (1)H NMR analysis showed there was only one isomer, in which the thiolate was trans to the tertiary amine nitrogen.
- Growth-inhibiting, bactericidal, and urease inhibitory effects of Paeonia lactiflora root constituents and related compounds on antibiotic-susceptible and -resistant strains of Helicobacter pylori. [Journal Article, Research Support, Non-U.S. Gov't]
- J Agric Food Chem 2012 Sep 12; 60(36):9062-73.
An assessment was made of the growth-inhibiting, bactericidal, and urease inhibitory activities of paeonol (PA), benzoic acid (BA), methyl gallate (MG), and 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG) identified in Paeonia lactiflora root, structurally related compounds, and four antibiotics toward three reference strains and four clinical isolates of Helicobacter pylori using broth dilution bioassay and Western blot. BA and PA showed strong bactericidal effect at pH 4, while MG and PGG were effective at pH 7. These constituents exhibited strong growth-inhibiting and bactericidal activity toward the five strains resistant to amoxicillin (minimal inhibitory concentration (MIC) 12.5 mg/L), clarithromycin (64 mg/L), metronidazole (64 mg/L), or tetracycline (15 mg/L), indicating that these constituents and the antibiotics do not share a common mode of action. Structural characteristics, such as types of functional groups and carbon skeleton, and hydrophobicity appear to play a role in determining the anti- H. pylori activity. H. pylori urease inhibitory activity of PGG was comparable to that of acetohydroxamic acid, while MG was less potent at inhibiting urease than thiourea. The UreB band disappeared at 250 mg/L PGG on Western blot, while the UreA bands were faintly visible at 1000 mg/L PGG. These constituents showed no significant cytotoxicity. Global efforts to reduce the level of antibiotics justify further studies on P. lactiflora root-derived materials containing MG, PA, and PGG as potential antibacterial products or lead molecules for the prevention or eradication from humans from diseases caused by H. pylori .
- Synthesis, inhibitory activity and molecular docking studies of two Cu(II) complexes against Helicobacter pylori urease. [Journal Article, Research Support, Non-U.S. Gov't]
- J Enzyme Inhib Med Chem 2012 Aug; 27(4):528-32.
Two mononuclear copper(II) complexes, [Cu(C(15)H(16)NO(2))(2)] (1) and [Cu(C(6)H(9)N(2)O(4))(2)·3H(2)O] (2·3H(2)O), were synthesised and structurally characterised by single-crystal X-ray analysis. The copper(II) atom adopts a square-planar environment in complex 1, while the geometry in 2·3H(2)O could be described as the distorted square pyramidal. Complexes 1 and 2·3H(2)O were evaluated for their inhibitory activities against Helicobacter pylori (H. pylori) urease in vitro. They both were found to have strong inhibitory activities against H. pylori urease comparable to that of acetohydroxamic acid (AHA). A docking simulation was performed to position 2 into the H. pylori urease active site to determine the probable binding conformation.