Electrochemical Synthesis of the in human S-oxide metabolites of phenothiazine containing Anti-Psychotic Medications

The tractable preparation of phase-I drug metabolites is a critical step to understand the first-pass behaviour of novel chemical entities in drug discovery. In this study we have developed a structure electroactivity relationship (SeAR) informed electrochemical reaction of the parent 2-chlorophenothiazine and anti-psychotic, chlorpromazine. The ability to dial-in under current controlled conditions the formation of S-oxide and novel S,S-dioxide metabolites has been achieved for the first time on a multimilligram scale using a direct batch electrode platform. A potential rationale for the electrochemical formation of these metabolites in situ is proposed using molecular docking to a cytochrome P450 enzyme.