These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
Preprints are manuscripts made publicly available before they have been submitted for formal peer review and publication. They might contain new research findings or data. Preprints can be a draft or final version of an author's research but must not have been accepted for publication at the time of submission.
submitted on 12.04.2019, 15:27 and posted on 15.04.2019, 16:28by Beth A. Caine, Maddalena Bronzato, Paul Popelier
We show here for the first time that strongly correlated linear relationships exist between equilibrium bond lengths of the sulfonamide group and aqueous pKa 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 secretogogue, glimepiride). In the context of these compounds, we present solutions to some of the more complex challenges in pKa prediction: (i) prediction for multiprotic compounds, (ii) predicting macroscopic values for compounds that tautomerize, and (iii) quantum chemical pKa 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 pKa units, whereas previous values were found to deviate by up to 1.68 pKa 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 pKa should emerge for any set of congeners, thus providing a powerful method of pKa prediction obviating the need for thermodynamic cycles.