Electrochemical Synthesis of the In Human S-oxide Metabolites of Phenothiazine-Containing Antipsychotic Medications.

The tractable preparation of Phase I drug metabolites is a critical step to understand the first-pass behaviour of novel chemical entities (NCEs) in drug discovery. In this study, we have developed a structure-electroactivity relationship (SeAR)-informed electrochemical reaction of the parent 2-chlorophenothiazine and the antipsychotic medication, chlorpromazine. With 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 multi-milligram 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.

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine.

In this article, we introduce a proof-of-concept strategy, Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM), to expedite the discovery of drug metabolites. The use of a bioactive natural product, piperine, that has a well-curated metabolite profile but an unpredictable computational metabolism (Biotransformer v3.0) was selected. We developed an electrochemical reaction to oxidize piperine into a range of metabolites, which were detected by LC-MS. A series of chemically plausible metabolites were predicted based on ion fragmentation patterns. These metabolites were docked into the active site of CYP3A4 using Autodock4.2. From the clustered low-energy profile of piperine in the active site, it can be inferred that the most likely metabolic position of piperine (based on intermolecular distances to the Fe-oxo active site) is the benzo[d][1,3]dioxole motif. The metabolic profile was confirmed by comparison with the literature, and the electrochemical reaction delivered plausible metabolites, vide infra, thus, demonstrating the power of the hyphenated technique of tandem electrochemical detection and computational evaluation of binding poses. Taken together, we outline a novel approach where diverse data sources are combined to predict and confirm a metabolic outcome for a bioactive structure.

Conductive Polypropylene Additive Manufacturing Feedstock: Application to Aqueous Electroanalysis and Unlocking Nonaqueous Electrochemistry and Electrosynthesis.

Additive manufacturing electrochemistry is an ever-expanding field; however, it is limited to aqueous environments due to the conductive filaments currently available. Herein, the production of a conductive poly(propylene) filament, which unlocks the door to organic electrochemistry and electrosynthesis, is reported. A filament with 40 wt % carbon black possessed enhanced thermal stability, excellent low-temperature flexibility, and high conductivity. The filament produced highly reproducible additive manufactured electrodes that were electrochemically characterized, showing a k0 of 2.00 ± 0.04 × 10-3 cm s-1. This material was then applied to three separate electrochemical applications. First, the electroanalytical sensing of colchicine within environmental waters, where a limit of detection of 10 nM was achieved before being applied to tap, bottled, and river water. Second, the electrodes were stable in organic solvents for 100 cyclic voltammograms and 15 days. Finally, these were applied toward an electrosynthetic reaction of chlorpromazine, where the electrodes were stable for 24-h experiments, outperforming a glassy carbon electrode, and were able to be reused while maintaining a good electrochemical performance. This material can revolutionize the field of additive manufacturing electrochemistry and expand research into a variety of new fields.

Green electrosynthesis of drug metabolites.

In this concise review, the field of electrosynthesis (ES) as a green methodology for understanding drug metabolites linked to toxicology is exemplified. ES describes the synthesis of chemical compounds in an electrochemical cell. Compared to a conventional chemical reaction, ES operates under green conditions (the electron is the reagent) and has several industrial applications, including the synthesis of drug metabolites for toxicology testing. Understanding which circulating drug metabolites are formed in the body is a crucial stage in the development of new medicines and gives insight into any potential toxic pathologies resulting from the metabolites formed. Current methods to prepare drug metabolites directly from the drug molecule often involve time-consuming multistep syntheses. Throughout this review, the application of green ES to (i) identify drug metabolites, (ii) enable their efficient synthesis, and (iii) investigate the toxicity of the metabolites generated are highlighted.