Chemie des Isoniazids

Krüger-Thiemer, Ekkehard

doi:10.1007/978-3-662-30602-4_20

Cited by 7 publications

(7 citation statements)

References 192 publications

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“…Thus, other hydrazides were tested and it can be concluded from the results in Table 4 and from the beginning of this paragraph that acetic, benzoic, and nicotinic acid hydrazides had no effect on cell-free mycolic acid synthesis. These results are in agreement with the known structural requirements for INH, i.e., that both the isonicotinic structure and the hydrazide moiety are required to obtain significant inhibition of mycobacterial culture growth (9).…”

Section: Methodssupporting

confidence: 80%

Isoniazid inhibition of mycolic acid synthesis by cell extracts of sensitive and resistant strains of Mycobacterium aurum

Quémard

Lacave

Lanéelle

1991

Antimicrob Agents Chemother

112

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Isonicotinic acid hydrazide (isoniazid; INH) inhibition of mycolic acid synthesis was studied by using cell extracts from both INH-sensitive and -resistant strains of Mycobacterium aurum. The cell extract of the INHsensitive strain was inhibited by INH, while the preparation from the INH-resistant strain was not. This showed that the INH resistance of mycolic acid synthesis was not due to a difference in drug uptake or the level of peroxidase activity (similar in both extracts). As INH did not induce accumulation of any labeled intermediates, it is postulated that the drug acts either on production of labeled chain elongation precursors of mycolic acids or an early step of this elongation. The level of inhibition was not changed by addition of NAD or nicotinamide; thus, INH does not act on mycolic acid synthesis as an NAD antimetabolite. Benzoic or acetic acid hydrazides and known or postulated metabolites of INH (i.e., the corresponding acid, aldehyde, or alcohol) were not inhibitors of cell-free mycolic acid synthesis; the complete structure of INH was required, as already known for inhibition of mycobacterial culture growth. Extracts prepared from INH-treated cells showed reduced mycolic acid synthesis, and the inhibition level was not modified by either extensive dialysis or pyridoxal phosphate. This latter molecule efficiently antagonized INH action by reacting rapidly with INH, as shown by differential spectroscopy. Moreover, pyridoxal phosphate did not release inhibition of INH-treated extracts. It is proposed that INH may covalently react with an essential component of the mycolic acid synthesis system.

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Section: Methodssupporting

confidence: 80%

Isoniazid inhibition of mycolic acid synthesis by cell extracts of sensitive and resistant strains of Mycobacterium aurum

Quémard

Lacave

Lanéelle

1991

Antimicrob Agents Chemother

112

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“…An alternative hypothesis had been put forward by Krüger-Thiemer [69][70][71] and is depicted in Figure 5. It suggests that INH enters the mycobacterium by passive diffusion, facilitated by the hydrazide.…”

Section: The Active Form Of Isoniazid Including Stereo-chemical Aspectsmentioning

confidence: 97%

“…Hydrogen atoms are partly omitted for better viewing. Simulating the proposed meta-isomer of NAD(H) [69,72], where isonicotinic acid replaces nicotinic acid, we find a hydrogen bond (yellow) between its amide group and Tyr158 under MMFF94 force field standard conditions. Since Tyr158 is experimentally shown [82] to play an important role in natural substrate reduction, its temporary binding to a false substrate, namely the meta-isomer of NAD(H) (iso), could explain the partial loss of enzyme activity [35], just like mutants show when the para-hydroxyl group of Tyr158 is lost by introducing amino acids like phenylalanine and alanine [82].…”

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confidence: 98%

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Antitubercular Isoniazid and Drug Resistance of Mycobacterium tuberculosis — A Review

Scior

Morales

Eisele

et al. 2002

Archiv der Pharmazie

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Isoniazid is one of the most potent drugs available for tuberculosis treatment. As a pro-drug it requires activation, which is performed by catalase/peroxidase. The active principle, whose identity has not yet been determined unambiguously, then acts on at least one target molecule, the enoyl-acyl carrier protein, required for the synthesis of the vital mycolic acids present in the cell wall of the bacterium. Some other targets have been proposed in order to explain the unusual potency of isoniazid; however, the supporting data are still controversial. We thoroughly discuss the action of isoniazid, resistance mechanisms, and the possible active product, which includes an isonicotinic acid-NADH adduct as well as a meta-isomer of NADH. Both structures have been probed positively in a 3D modeling analysis.

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“…Also, since the estimate of the absorption rate constant depends upon the value of the elimination rate constant, the estimated value of the absorption rate constant may be in error too. It is the purpose of this communication to show that this difficulty may be overcome by methods of digital computation, although Kruger-Thiemer and Eriksen (2) recently reported that it could not. The problem with the data of Kruger-Thiemer and Eriksen (2) was that blood samples were not taken long enough following oral administration.…”

mentioning

confidence: 95%

Estimation of Rate Constants for Absorption and Elimination From Blood Concentration Data

Wagner

Metzler

1967

Journal of Pharmaceutical Sciences

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Chemie des Isoniazids

Cited by 7 publications

References 192 publications

Isoniazid inhibition of mycolic acid synthesis by cell extracts of sensitive and resistant strains of Mycobacterium aurum

Isoniazid inhibition of mycolic acid synthesis by cell extracts of sensitive and resistant strains of Mycobacterium aurum

Antitubercular Isoniazid and Drug Resistance of Mycobacterium tuberculosis — A Review

Estimation of Rate Constants for Absorption and Elimination From Blood Concentration Data

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