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Kinetics and mechanism of oxidation of the anti-tubercular prodrug isoniazid and its analog by iridium(IV) as models for biological redox systems

Dong, Jingran; Ren, Yanli ; Sun, Sufang; Yang, Jiao ; Nan, Chunixa; Shi, Hongmei ; Xu, Jianzhong; Duan, Jie; Shi, Tiesheng and Elding, Lars Ivar LU (2017) In Dalton Transactions 2017(46). p.8377-8386
Abstract (Swedish)
A complex reaction mechanism of oxidation of the anti-tubercular prodrug isoniazid (isonicotinic hydrazide, INH) by [IrCl6]2− as a model for redox processes of such drugs in biological systems has been studied in aqueous solution as a function of pH between 0 and 8.5. Similar experiments have been performed with its isomer nicotinic hydrazide (NH). All reactions are overall second-order, first-order in [IrCl6]2− and hydrazide, and the observed second-order rate constants k′ have been determined as a function of pH. Spectrophotometric titrations indicate a stoichiometry of [Ir(IV)]:[hydrazide] = 4:1. HPLC analysis shows that the oxidation product of INH is isonicotinic acid. The derived reaction mechanism, based on rate law, time-resolved... (More)
A complex reaction mechanism of oxidation of the anti-tubercular prodrug isoniazid (isonicotinic hydrazide, INH) by [IrCl6]2− as a model for redox processes of such drugs in biological systems has been studied in aqueous solution as a function of pH between 0 and 8.5. Similar experiments have been performed with its isomer nicotinic hydrazide (NH). All reactions are overall second-order, first-order in [IrCl6]2− and hydrazide, and the observed second-order rate constants k′ have been determined as a function of pH. Spectrophotometric titrations indicate a stoichiometry of [Ir(IV)]:[hydrazide] = 4:1. HPLC analysis shows that the oxidation product of INH is isonicotinic acid. The derived reaction mechanism, based on rate law, time-resolved spectra and stoichiometry, involves parallel attacks by [IrCl6]2− on all four protolytic species of INH and NH as rate-determining steps, depending on pH. These steps are proposed to generate two types of hydrazyl free radicals. These radicals react further in three rapid consecutive processes, leading to the final oxidation products. Rate constants for the rate-determining steps have been determined for all protolytic species I–IV of INH and NH. They are used to calculate reactivity–pH diagrams. These diagrams demonstrate that for both systems, species IV is ca. 105 times more reactive in the redox process than the predominant species III at the physiological pH of 7.4. Thus, species IV will be the main reactant, in spite of the fact that its concentration at this pH is extremely low, a fact that has not been considered in previous work. The results indicate that pH changes might be an important factor in the activation process of INH in biological systems also, and that in such systems this process most likely is more complicated than previously assumed. (Less)
Abstract
A complex reaction mechanism of oxidation of the anti-tubercular prodrug isoniazid (isonicotinic hydrazide, INH) by [IrCl6]2− as a model for redox processes of such drugs in biological systems has been studied in aqueous solution as a function of pH between 0 and 8.5. Similar experiments have been performed with its isomer nicotinic hydrazide (NH). All reactions are overall second-order, first-order in [IrCl6]2− and hydrazide, and the observed second-order rate constants k′ have been determined as a function of pH. Spectrophotometric titrations indicate a stoichiometry of [Ir(IV)]:[hydrazide] = 4:1. HPLC analysis shows that the oxidation product of INH is isonicotinic acid. The derived reaction mechanism, based on rate law, time-resolved... (More)
A complex reaction mechanism of oxidation of the anti-tubercular prodrug isoniazid (isonicotinic hydrazide, INH) by [IrCl6]2− as a model for redox processes of such drugs in biological systems has been studied in aqueous solution as a function of pH between 0 and 8.5. Similar experiments have been performed with its isomer nicotinic hydrazide (NH). All reactions are overall second-order, first-order in [IrCl6]2− and hydrazide, and the observed second-order rate constants k′ have been determined as a function of pH. Spectrophotometric titrations indicate a stoichiometry of [Ir(IV)]:[hydrazide] = 4:1. HPLC analysis shows that the oxidation product of INH is isonicotinic acid. The derived reaction mechanism, based on rate law, time-resolved spectra and stoichiometry, involves parallel attacks by [IrCl6]2− on all four protolytic species of INH and NH as rate-determining steps, depending on pH. These steps are proposed to generate two types of hydrazyl free radicals. These radicals react further in three rapid consecutive processes, leading to the final oxidation products. Rate constants for the rate-determining steps have been determined for all protolytic species I–IV of INH and NH. They are used to calculate reactivity–pH diagrams. These diagrams demonstrate that for both systems, species IV is ca. 105 times more reactive in the redox process than the predominant species III at the physiological pH of 7.4. Thus, species IV will be the main reactant, in spite of the fact that its concentration at this pH is extremely low, a fact that has not been considered in previous work. The results indicate that pH changes might be an important factor in the activation process of INH in biological systems also, and that in such systems this process most likely is more complicated than previously assumed (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Anti-tubercular drugs, Isoniazid, Iridium(IV), Redox kinetics, Reaction mechanism, pH dependence, Nicotinic hydrazide, Biological redox, Physiological pH
in
Dalton Transactions
volume
2017
issue
46
pages
10 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:85021901370
  • wos:000404860300009
ISSN
1477-9234
DOI
10.1039/c7dt00885f
language
English
LU publication?
yes
id
b1b0c215-e661-44d0-87d5-6268233dfd81
date added to LUP
2017-06-17 12:57:47
date last changed
2017-09-18 11:41:49
@article{b1b0c215-e661-44d0-87d5-6268233dfd81,
  abstract     = {A complex reaction mechanism of oxidation of the anti-tubercular prodrug isoniazid (isonicotinic hydrazide, INH) by [IrCl6]2− as a model for redox processes of such drugs in biological systems has been studied in aqueous solution as a function of pH between 0 and 8.5. Similar experiments have been performed with its isomer nicotinic hydrazide (NH). All reactions are overall second-order, first-order in [IrCl6]2− and hydrazide, and the observed second-order rate constants k′ have been determined as a function of pH. Spectrophotometric titrations indicate a stoichiometry of [Ir(IV)]:[hydrazide] = 4:1. HPLC analysis shows that the oxidation product of INH is isonicotinic acid. The derived reaction mechanism, based on rate law, time-resolved spectra and stoichiometry, involves parallel attacks by [IrCl6]2− on all four protolytic species of INH and NH as rate-determining steps, depending on pH. These steps are proposed to generate two types of hydrazyl free radicals. These radicals react further in three rapid consecutive processes, leading to the final oxidation products. Rate constants for the rate-determining steps have been determined for all protolytic species I–IV of INH and NH. They are used to calculate reactivity–pH diagrams. These diagrams demonstrate that for both systems, species IV is ca. 105 times more reactive in the redox process than the predominant species III at the physiological pH of 7.4. Thus, species IV will be the main reactant, in spite of the fact that its concentration at this pH is extremely low, a fact that has not been considered in previous work. The results indicate that pH changes might be an important factor in the activation process of INH in biological systems also, and that in such systems this process most likely is more complicated than previously assumed},
  author       = {Dong, Jingran and Ren, Yanli  and Sun, Sufang and Yang, Jiao  and Nan, Chunixa and Shi, Hongmei  and Xu, Jianzhong and Duan, Jie and Shi, Tiesheng and Elding, Lars Ivar},
  issn         = {1477-9234},
  keyword      = {Anti-tubercular drugs,Isoniazid,Iridium(IV),Redox kinetics,Reaction mechanism,pH dependence,Nicotinic hydrazide,Biological redox,Physiological pH},
  language     = {eng},
  month        = {07},
  number       = {46},
  pages        = {8377--8386},
  publisher    = {Royal Society of Chemistry},
  series       = {Dalton Transactions},
  title        = {Kinetics and mechanism of oxidation of the anti-tubercular prodrug isoniazid and its analog by iridium(IV) as models for biological redox systems},
  url          = {http://dx.doi.org/10.1039/c7dt00885f},
  volume       = {2017},
  year         = {2017},
}