Ring-chain tautomerism of simplified analogues of isoniazid-NAD(P) adducts:: an experimental and theoretical study

Simplified analogues of oxidized and reduced isoniazid-NAD(P) adducts were prepared to study their behaviour with regard to ring-chain tautomeric isomerism in solution. In DMSO, the oxidized analogues (pyridinium salts) and the corresponding 1,2-dihydropyridine-reduced compounds were found to exist exclusively in the ring (cyclic hemiamidal) form. In contrast, the 1,4-dihydropyridine-reduced analogues were present in the ring and/or chain forms depending on the nature of the aromatic substituent. The 1,4-dihydropyridines (Ar = Ph, 3Cl-Py) are, in solution, preferentially in the keto-amide chain form, whereas the pyridine analogue (Ar = Py), which is the closest model of the isoniazidNAD(P) adduct, exists as ring (major) and chain (minor) tautomers in equilibrium. The ratio of the tautomeric forms involved in the equilibrium of this system is also influenced by the polarity of the solvent with a shift towards the ring tautomer when the polarity of the solvent is increased. Complementary computational studies were performed by using quantum chemical calculations (B3LYP/6-31G**) and frontier molecular orbital analysis, which allowed the key structural factors involved in the ring-chain tautomerism equilibrium to be discussed. ((c) Wiley-VCH Verlag GmbH & Co.