Design, Synthesis, and Biological Evaluation of Benzimidazole‐Pyrazole Hybrids as Aromatase Inhibitors for Breast Cancer Therapy

ABSTRACT Current aromatase inhibitors (AIs) are limited by poor bioavailability and high toxicity, underscoring the need for the development of new therapeutics. In the present study, a series of 12 benzimidazole‐pyrazole hybrids was designed, synthesized, and structurally characterized using infrared spectroscopy, mass spectrometry, nuclear magnetic resonance spectroscopy, and elemental analysis. Their anti‐breast cancer potential was evaluated against the MCF‐7 cell line using the MTT assay. Notably, compounds 5g and 5i exhibited the highest cytotoxicity, reflected by the lowest IC 50 values, while showing minimal toxicity toward the normal cell line, NIH3T3. Aromatase inhibitory activity, assessed using the fluorometric assay, further identified compound 5g as the most potent inhibitor. Complementary molecular docking studies demonstrated that compounds 5g and 5i form favorable interactions with the aromatase enzyme, showing higher binding affinity compared to letrozole, providing mechanistic insight into their inhibitory activity. ADMET analysis further confirmed the drug‐likeness and pharmacokinetic suitability of the synthesized derivatives. Collectively, these results establish compound 5g as a promising lead for aromatase inhibition, necessitating further in vivo evaluation.