~1H and ~(13)C NMR characterization of pyridinium-type isoniazid-NAD adducts as possible inhibitors of InhA reductase of Mycobacterium tuberculosis

摘要

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/~(13)C 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 ketonc 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.