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

Ridho Asra; Aigul Malmakova; Alan M Jones

doi:10.26434/chemrxiv-2024-32xrs

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

Ridho Asra, Aigul Malmakova, Alan M Jones^*

^*Corresponding author for this work

Pharmacy

Research output: Working paper/Preprint › Preprint

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.

Original language	English
Publisher	ChemRxiv
Pages	1-22
Number of pages	22
DOIs	https://doi.org/10.26434/chemrxiv-2024-32xrs
Publication status	Published - 22 Apr 2024

Bibliographical note

Acknowledgments and Funding
R.A. gratefully acknowledges the PhD scholarship of The Center for Education Funding Services (BPI); Ministry of Education, Culture, Research, and Technology; and the Indonesia Endowment Fund for Education (LPDP), Ministry of Finance, The Republic of Indonesia. A.E.M. gratefully acknowledge the Bolashak Scholarship Program of the Ministry of Science and Higher Education, the Republic of Kazakhstan.

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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.",

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

Abstract

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