Synthesis of Metal Complexes of Phenelzine Derivatives

Phenelzine, a non-selective monoamine oxidase inhibitor (MAOI), is widely used for treating major depressive disorder and anxiety due to its ability to increase monoamine neurotransmitter levels by irreversibly inhibiting monoamine oxidase enzymes (MAO-A and MAO-B). However, its clinical utility is constrained by adverse effects, including hepatotoxicity, hypertensive crises from dietary tyramine interactions. This abstract reviews recent advancements in the development of phenelzine derivatives, focusing on their chemical synthesis, pharmacological profiles, and potential to address these limitations. Structurally, phenelzine serves as a scaffold for modifications primarily at the hydrazine moiety and phenyl ring. Derivatives incorporating electron-donating (e.g., methoxy, methyl) or electronwithdrawing (e.g., fluoro, chloro) substituents on the phenyl ring have been synthesized to modulate MAOA and MAO-B selectivity. Some analogs demonstrate enhanced MAO-A inhibition, crucial for antidepressant effects, while minimizing MAO-B activity to reduce off-target effects. Additionally, prodrug strategies have been explored to improve bioavailability and mitigate first-pass metabolism, enhancing therapeutic efficacy. Computational approaches, including molecular docking and structureactivity relationship studies, have guided the design of derivatives with optimized binding affinities and reduced toxicity. Despite these advances, challenges remain, as many derivatives retain irreversible inhibition, perpetuating risks of drug-food interactions. Preclinical evaluations indicate some compounds exhibit lower hepatotoxicity, yet clinical translation is hindered by safety and efficacy concerns. Analytical techniques, such as NMR, IR spectroscopy, and mass spectrometry, have been instrumental in characterizing these derivatives, confirming their structural integrity and purity. This work underscores the potential of phenelzine derivatives to deliver safer, more selective MAOIs for psychiatric disorders. Future researchshould focus on developing reversible inhibitors, leveraging high-throughput screening, and conducting robust clinical trials to validate therapeutic benefits, ultimately bridging the gap between chemical innovation and clinical application.