1H and 13C NMR characterization of pyridinium-type isoniazid-NAD adducts as possible inhibitors of InhA reductase of Mycobacterium tuberculosis.
Oxidative activation of the antituberculous drug isoniazid (INH) in the presence of the NADH cofactor gives a pool of INH-NAD adducts proposed to be involved in the mechanism of action of this drug through inhibition of the reductase InhA. Among these adducts and besides dihydropyridine derivatives, two pyridinium-type isoniazid-NAD adducts were shown to be formed in solution and have been fully characterized by 1H/13C NMR and MS. One of them results from the oxidation of dihydropyridine-type INH-NAD adducts. The spectral data strongly support its existence under two epimeric structures. These epimers arise from a cyclization process between the carboxamide group and the ketone function with the creation of a new chiral center at C-7. The second pyridinium-type adduct was formed in acidic solution by dehydration of the cyclized dihydropyridine-type INH-NAD adducts and also exists as a cyclized structure. Both of these pyridinium-type compounds were inactive as inhibitors of InhA activity and can be considered as deactivated species.
Broussy
Sylvain
S
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse cedex 4, France.
Bernardes-Génisson
Vania
V
Coppel
Yannick
Y
Quémard
Annaïk
A
Bernadou
Jean
J
Meunier
Bernard
B
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009243:NAD / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D011726:Pyridinium Compounds; D009243:NAD; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; D007538:Isoniazid