Experiment stands corrected: accurate prediction of the aqueous pKa values of sulfonamide drugs using equilibrium bond lengths

Abstract

We show here for the first time that strongly correlated linear relationships exist between equilibrium bond lengths of the sulfonamide group and aqueous pK_a values. Models are constructed for three variants of the SO₂NHR group: primary benzene sulfonamide derivatives (e.g. diuretic drugs furosemide and hydrochlorothiazide), N-phenyl substituted 4-amino-N-phenylbenzenesulfonamide analogues (e.g. the sulfa antibiotic sulfadiazine) and phenylsulfonylureas (e.g. insulin secretagogue, glimepiride). In the context of these compounds, we present solutions to some of the more complex challenges in pK_a prediction: (i) prediction for multiprotic compounds, (ii) predicting macroscopic values for compounds that tautomerize, and (iii) quantum chemical pK_a prediction for compounds with more than 50 atoms. Using bond lengths as a powerful descriptor of ionization feasibility, we also identify that literature values for drug compounds celecoxib, glimepiride and glipizide are inaccurate. Our newly measured experimental values match our initial predictions to within 0.26 pK_a units, whereas previous values were found to deviate by up to 1.68 pK_a units. For glimepiride, our corrected value denotes a percentage of ionization at intracellular pH, which is only now in excellent agreement with its known therapeutic efficacy. We propose that linear relationships between bond lengths and pK_a should emerge for any set of congeners, thus providing a powerful method of pK_a prediction in instances where pK_a data exist for close congeners, thereby obviating the need for thermodynamic cycles.