Computational exploration of the effect of molecular medium on the tautomerization of azo prodrug of 5-aminosalicylic acid.

The characterization of potential tautomerization of pharmaceutical materials has significant importance. Sulfasalazine (SSZ) is a prodrug that bears 5-aminosalicylic acid and pyridylamino-sulfonyl-phenyl moieties bridged by the azo group. SSZ may be present in various tautomeric forms, where dual tautomerization may occur; namely, amide↔imide and azo↔hydrazone tautomerization through the pyridylamino-sulfonyl-phenyl and salicylic acid moieties, respectively. In this report, we describe the prospects of the effect of molecular medium on the tautomerization of SSZ using selected computational methods. Two approaches were deliberated; namely, the explicit intermolecular hydrogen bonding (HB) through complexation with dimethylformamide (DMF) and implicit solvent effects. Using the DFT/ωB97XD/6-31G+(d) calculations, we conducted geometry optimization calculations of all possible tautomers of SSZ and their corresponding HB complexes with DMF with stoichiometric ratios (SSZ:DMF) of 1:1 and 1:2. The stability of the SSZ tautomeric forms and their corresponding H-Bonded DMF complexes were examined employing the ADMP molecular dynamics approach. Obtained results demonstrate that the amide and azo tautomers are favored over imide and hydrazone in the gas phase with E of 8.3 and 12.8 kcal/mol, respectively. However, these preferences were significantly affected by the implicit solvation effect of water with ΔE of 0.5 and 3.1 kcal mol, respectively. Obtained results demonstrate as well that DMF can bind to various sites of SSZ tautomers through intermolecular HBs with length in the range of 1.76-2.39 Å. This in turn demonstrates that intramolecular and intermolecular HB could not only play a significant role in directing the favored tautomeric forms of SSZ, but also distorting the planarity of the molecular comprising the azo and phenyl groups of the SSZ molecule. The ADMP-MD results verified that these complexes and the corresponding intra- and intermolecular HBs are stable over a timeframe of 100 femtosecond. The NBO analysis of the optimized geometries revealed that SSZ:DMF complexes can be stabilized by strong intermolecular HB, as indicated by the second perturbation energy of interaction (E(2)). Moreover, these results showed that the intermolecular HB of SSZ:DMF complexes has a notable effect on reducing the strength of intramolecular HB of certain tautomeric forms of SSZ and hence promotes the preference of SSZ toward a specific tautomeric form.