# Design, Synthesis, Biological Evaluation and Molecular Docking Studies of New N-Heterocyclic Compounds as Aromatase Inhibitors

## TL;DR

This paper reports new N-heterocyclic compounds that inhibit aromatase, a key enzyme in breast cancer treatment, with some showing strong activity comparable to existing drugs.

## Contribution

The paper introduces new 1,3,4-thiadiazole and 1,2,4-triazole compounds with potent aromatase inhibitory activity and antiproliferative effects.

## Key findings

- 1,2,4-triazole derivatives 5b, 5c, 5e, 5f, and 5g showed high antiproliferative activity against MCF-7 cells.
- Compound 5c exhibited strong aromatase inhibition comparable to letrozole.
- Molecular docking and MD simulations confirmed compound 5c's interaction with the aromatase enzyme.

## Abstract

Background/Objectives: Breast cancer is the most common cancer and the second leading cause of cancer death in women. The aromatase enzyme plays a role in estrogen biosynthesis and is an important biological target for breast cancer treatment. For this purpose, some new 1,3,4-thiadiazole (4a–4j) and 1,2,4-triazole (5a–5j) structures were designed and synthesized based on the structures of the existing aromatase inhibitors letrozole and anastrozole. Methods: The antiproliferative activities of the compounds were tested against MCF-7 cancer cells. The NIH3T3 healthy cells were used to evaluate the selectivity of the compounds. The inhibitory activities of all compounds were tested against the aromatase enzyme. Results: The 1,2,4-triazole derivatives 5b, 5c, 5e, 5f and 5g exhibited the highest antiproliferative activity against MCF7 cells with IC50 values ranging from 3.142 to 10.415 μM. Similar to the antiproliferative activity results, triazole derivatives 5b, 5c, 5e, 5f and 5g exhibited comparable anti-aromatase activity to letrozole (IC50 = 0.031 μM) with IC50 values ranging from 0.064 to 2.224 μM and demonstrated the highest anti-aromatase activity within the series. The interactions of compound 5c, the most potent compound based on activity results, with the aromatase enzyme have been elucidated through molecular docking and MD simulation studies. Conclusions: According to experimental studies and molecular docking findings, compound 5c shows promise for further studies with its aromatase enzyme inhibitory potential.