In vitro Evaluation of Endocrine‐Related Adverse Effects of 5‐Fluoroindole Derived Melatonin Analogues with Antioxidant Activity

Melatonin (MLT) is a natural indolic hormone with well documented antioxidant properties, but it can also modulate the estrogen signaling pathway by inhibiting the aromatase enzyme and estrogen receptor modulating activity. This dual activity raises concerns about potential endocrine-related adverse effects when using MLT and its analogues as therapeutic agents in the prevention and treatment of oxidative stress related diseases. In this study, 34 novel 5-fluoroindole derivatives of MLT were synthesized and evaluated for their antioxidant, estrogen receptor modulatory, and aromatase inhibitory activities.Three compounds (4c, 5c, and 6c) demonstrated significant antioxidant activity, with compound 4c showing the highest efficacy in reducing intracellular reactive oxygen species (ROS) by 65 % in CHO-K1 cells and displaying DPPH radical scavenging comparable to the standard antioxidant, BHT. However, these same compounds also exhibited antiestrogenic effects in the E-Screen assay, with IC