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

28 June 2024, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

Electrochemistry
metabolite
phenothiazine
chlorpromazine

Supplementary materials

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Description
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Supporting Information
Description
General Experimental Methods General Procedures Compound Characterization NMR and MS data HPLC data LCMS data IR data HPLC-LCMS data 2-Chlorophenothiazine Fractions Cyclic voltammetry data on analogues Molecular docking studies Biotransformer results
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