Design, Spectral Insights, and Enhanced Antioxidant Potential of Novel Phenothiazine Derivatives -1

INTRODUCTION: Phenothiazine derivatives represent an important class of heterocyclic compounds known for a wide range of pharmacological activities. Their antioxidant potential has drawn considerable interest for therapeutic applications against oxidative stress-related disorders. This study focused on synthesizing a new series of phenothiazine derivatives and evaluating their antioxidant activity. METHODS: A series of phenothiazine derivatives [5a-5h] was synthesized by conjugating phenothiazine with various aryl amines via an acetyl linker using standard organic synthesis techniques. The structures of the synthesized compounds were confirmed using spectroscopic techniques, including FT-IR, ^1H NMR, ^13C NMR, and mass spectrometry (MS). Antioxidant activity was assessed using two in vitro assays: the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method and the low-density lipoprotein (LDL) oxidation inhibition assay. RESULTS: All synthesized compounds were successfully characterized by the aforementioned spectroscopic techniques. The antioxidant assays revealed that most of the derivatives exhibited notable antioxidant activity. Among them, Compound 5e, bearing a 4-amino-2-methoxyphenol moiety, demonstrated the highest activity, surpassing the standard antioxidants Vitamin C and butylated hydroxyanisole (BHA). Conversely, compound 5h showed comparatively lower activity. DISCUSSION: The findings indicate that structural variations, particularly the presence of electrondonating groups on the phenothiazine ring, significantly influence antioxidant potential. The superior performance of Compound 5e highlights the importance of specific substituent patterns in enhancing biological activity. However, further investigation into pharmacokinetics and in vivo efficacy is necessary to support potential therapeutic use. CONCLUSION: The study successfully synthesized and characterized a novel series of phenothiazine derivatives, several of which exhibited potent antioxidant properties. Structure- activity relationship (SAR) analysis suggested that electron-donating substituents enhance activity, pointing to promising future applications in treating oxidative stress-related conditions.