- Redox mediation in the peroxidase-catalyzed oxidation of aminopyrine: Possible implications for drug-drug interactions
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Many drugs, industrial pollutants, and other xenobiotics are known to be oxidized by peroxidases to potentially harmful free-radical intermediates. We have examined the possibility that certain compounds, acting as efficient peroxidase substrates, may stimulate the formation of reactive free radicals by acting as mediators of electron transfer reactions (redox mediators). To explore this hypothesis, we have investigated the interaction of two well- known peroxidase substrates, chlorpromazine and aminopyrine. As shown by ESR and UV-visible spectroscopy, chlorpromazine radical was able to oxidize aminopyrine to aminopyrine cation radical. The rate constant for this rapid, pH-dependent, reaction was estimated to be 1 x 107 M-1 s-1 at pH 4.5. Transient-state and steady-state kinetic studies both showed that rate constants for chlorpromazine oxidation to its cation radical by horseradish peroxidase (HRP) were about 100-fold greater than for the corresponding HRP- catalyzed oxidation of aminopyrine to its cation radical. When both aminopyrine and chlorpromazine were present with HRP and H2O2, aminopyrine cation radical formation was stimulated 100-fold. Concomitantly, the accumulation of chlorpromazine cation radical was completely inhibited in the presence of aminopyrine. Similar results were obtained when lactoperoxidase, myeloperoxidase, or the myeloperoxidase mimic HOCl were substituted for HRP. These data suggest that chlorpromazine can act as a redox mediator for peroxidase-catalyzed oxidation of aminopyrine and other chemicals. We suggest that some peroxidase substrates, acting as redox mediators, may stimulate the production of toxic free-radical intermediates from various drugs and other xenobiotics. As such, this may have implications for a number of adverse effects caused by these xenobiotic chemicals.
- Goodwin, Douglas C.,Grover, Thomas A.,Aust, Steven D.
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- Microwave assisted Biology-Oriented Drug Synthesis (BIODS) of new N,N′-disubstituted benzylamine analogous of 4-aminoantipyrine against leishmaniasis – In vitro assay and in silico-predicted molecular interactions with key metabolic targets
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Biology-Oriented Drug Synthesis (BIODS) deals with the simple chemical transformations on the commercially available drugs in order to enhance their new and diversified pharmacological profile. It opens new avenues for the rapid development of drug candidates for neglected tropical diseases (NTDs). Leishmaniasis is one of the NTDs which spread by the bite of sandflies (plebotomine). It ranges from cutaneous self-healing leishmaniasis to life threatening visceral leishmaniasis, known as kala-azar. The current treatment options include the use of pentamidine, miltefosine, and amphotericin B drugs. Unfortunately, all currently available drugs are associated with adverse effects, such as severe nephron- and cardiotoxicity, pancreatitis, and hepatotoxicity. This warrants the development of new drugs against leishmaniasis. Moreover, emergence of resistance against the current medications further worsens the conditions. With this objective, new N, N′-disubstituted benzylamine derivatives of ampyrone (4-aminoantipyrine) were synthesized by using ultrasonication, and microwave assistance. All derivatives were found to be new, except 1, 4, and 11. All the compounds were evaluated for their anti-leishmanial activity, and cellular cytotoxicity. Among them, compounds 4, 5, 8, and 9 showed a significant anti-leishmanial activity in vitro, in comparison to standard drug, miltefosine (IC50 = 25.78 ± 0.2 μM). These compounds were also docked against various metabolic enzymes to predict their interactions and mechanism of action, and were found to act via targeting important enzymes of various metabolic pathways.
- Choudhary, Muhammad Iqbal,Rizvi, Fazila,Shaikh, Muniza,Siddiqui, Hina,Yousuf, Sammer,Zafar, Humaira
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- General catalytic methylation of amines with formic acid under mild reaction conditions
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A general catalytic protocol for the methylation of amines has been developed applying, for the first time, formic acid as the C1 building block and silanes as reducing agents. A broad range of aromatic and aliphatic, both primary and secondary, amines has been converted to the corresponding tertiary amines including [N-13C]-labelled drugs in good to excellent yields under mild conditions. Methylation made easy: A general catalytic protocol for the methylation of amines has been developed applying, for the first time, formic acid as the C1 building block and silanes as reducing agents. A broad range of aromatic and aliphatic, both primary and secondary, amines has been converted to the corresponding tertiary amines, including [N-13C]-labelled drugs, in good to excellent yields at mild conditions (see scheme; dppp=(1,3-bis(diphenylphosphino)propane)).
- Sorribes, Ivan,Junge, Kathrin,Beller, Matthias
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supporting information
p. 7879 - 7883
(2014/07/07)
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- Pyrazolone methylamino piperidine derivatives as novel CCR3 antagonists
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The discovery and optimization of a novel class of potent CCR3 antagonists is described. Details of synthesis and SAR are given together with some ADME properties of selected compounds. An optimal balance between activities, physicochemical properties, and in vitro metabolic stability was reached by the proper choice of substituents.
- Pegurier, Cecile,Collart, Philippe,Danhaive, Pierre,Defays, Sabine,Gillard, Michel,Gilson, Frederic,Kogej, Thierry,Pasau, Patrick,Van Houtvin, Nathalie,Van Thuyne, Marc,van Keulen, BerendJan
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p. 4228 - 4231
(2008/02/09)
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- Oxidation of Aminopyrine by Hypochlorite to a Reactive Dication: Possible Implications for Aminopyrine-Induced Agranulocytosis
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Aminopyrine is associated with a high incidence of agranulocytosis. It is known to be oxidized by peroxidases and hypochlorous acid to a blue cation radical. It has been proposed that the mechanism by which hypochlorous acid oxidizes aminopyrine to a cation radical involves N-chlorination followed by loss of a chlorine radical. Another possible mechanism is loss of HCl to form an iminium ion and subsequent reaction with another molecule of aminopyrine and a hydrogen ion to form two radical cations. This mechanism would lead to incorporation of a hydrogen from water; however, using a deuterated analog, we found no hydrogen incorporation, thus providing strong evidence against this mechanism. Using a stopped-flow diode array spectrophotometer to study the reaction between aminopyrine and hypochlorous acid, an intermediate with a λmax at ca. 420 nm was observed in the formation of the cation radical. We propose that this represents a dication formed by the loss of chloride ion from N-chloroaminopyrine. This intermediate is very reactive, with a half-life of approximately 15 ms, and in addition to being the precursor of the cation radical, it also appears to react with two molecules of water to form several other products that were observed and are consistent with the proposed dication intermediate. Similar stable products were formed when aminopyrine was oxidized by the combination of myeloperoxidase, hydrogen peroxide, and chloride or activated neutrophils. The reactive dication formed by neutrophil-derived hypochlorous acid could be responsible for aminopyrine-induced agranulocytosis.
- Uetrecht, Jack P.,Ma, Hing Man,MacKnight, Earl,McClelland, Robert
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p. 226 - 233
(2007/10/03)
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- Aminopyrine and Antipyrine Free Radical-cations: Pulse Radiolysis Studies of One-electron Transfer Reactions
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Absolute rate constants for the reaction of a variety of electrophilic free radicals with the pyrazoline derivatives aminopyrine and antipyrine have been measured by pulse radiolysis.In the case of aminopyrine the resulting radical cation is a particularly stable species ε325 5.35*103 dm3 mol-1 cm-1).Both compounds are readily oxidised to their respective radical-cations with the one-electron oxidation potential of antipyrine (E0 1.1-1.6 V) being higher than that of aminopyrine (E0 0.26-0.5 V).Studies of the reaction of the radical-cations with reducing agents suggest that aminopyrine in particular may prove to be a useful reference compound in studies of free radical one-electron oxidations.
- Forni, Luigi G.,Mora-Arellano, Victor O.,Packer, John E.,Willson, Robin L.
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p. 1579 - 1584
(2007/10/02)
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