The conformational and tautomeric equilibrium of 5a,6-anhydrotetracycline in aqueous solution at pH 7

Abstract

The conformational and tautomeric equilibrium in tetracyclines has been considered to be important for the action mode of this class of antibiotics. In the present study the structures and thermodynamic properties for the distinct isomers of the 5a,6-anhydrotetracycline (AHTC) derivative were calculated in gas phase and aqueous solutions for the LH − ionized species, which is predominant at pH 7. Ab initio HF and MP2 levels of theory were used in gas phase and SCRF, IPCM and PCM continuum models in aqueous solution. The solvent effect was also analyzed through the Monte Carlo simulation. In the gas phase the folded (FLD) form was found to be predominant at the HF and MP2 levels. At the HF level, the inclusion of polarization functions on the heteroatoms (N and O) was found to be important to the stability order. The HF/3-21G and HF/6-31G results showed the extended conformer (EXT) as the most favorable in gas phase. This is the same result obtained at the semiempirical AM1 level. In aqueous solution, the equilibrium is shifted to the twisted (TWS) form when the PCM and Monte Carlo solvation energies are considered. In gas phase and water solution the tautomer ionized at O 11 was found to be preferred. In general the results obtained show that the conformational and tautomeric equilibrium are solvent-dependent, with the stability order in water solution determined by the overall effect of the solvent, being not localized on a specific molecular moiety.