Electrochemical Oxidative Coupling Synthesis of New Drug-Like Molecules Based on the Anti-Tuberculosis Drug Isoniazid: A Comprehensive Mechanistic Study

In this study, electrochemical late-stage sulfonylation of isoniazid ( ISO ), a common antibiotic drug for the treatment of tuberculosis, was performed. Late-stage functionalization (LSF) enables rapid structural modifications of drugs, which can lead to compounds with distinct biological and clinical features. The late-stage functionalization of ISO has led to the synthesis of unique drug-like molecules consisting of two sulfone and sulfonamide moieties. These syntheses have been conveniently carried out galvanostatically (60 mA for 130 min) via oxidation of ISO in the presence of arylsulfinic acids in an undivided cell equipped with a graphite anode and a stainless steel cathode in a water (0.2 M phosphate buffer, pH = 2.0)/acetonitrile (50/50 v/v) mixture. The electrochemical oxidation of ISO has been investigated over a wide pH range and it has been found that at all pHs, this drug exhibits irreversible behavior. The results also show that the potential as well as the mechanism of ISO oxidation is pH dependent and changes with pH change. Electrochemical studies also indicate that the first step in late-stage functionalization of ISO , is the sulfonylation of oxidized ISO by arylsulfinate ions. The next steps depend on the type of substitution on the aryl ring. When the arylsulfinic acid is unsubstituted or substituted with a methyl group, the reaction product is a benzenesulfonohydrazide derivative with yields of 88 and 84%, respectively. But when the arylsulfinic acid is substituted with a fluorine atom, the reaction product is a derivative of isonicotinohydrazide with the yield of 94%. This method does not use catalysts or toxic reagents, and products are synthesized with high yield and purity in a one-pot at room temperature and pressure.