In vitro and in silico analysis of synthesized N-benzyl indole-derived hydrazones as potential anti-triple negative breast cancer agents†

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer, and it is characterized by a high recurrence rate and the rapid development of drug resistance across various subtypes. Currently, there is no targeted therapy, which is specifically approved for the treatment of TNBC. In this study, we synthesized a series of N-benzyl indole-3-carboxaldehyde-based hydrazones and subjected them to in vitro anticancer studies on MCF-10A and MDA-MB-231 breast cancer (BC) cell lines. Our in vitro results suggested that all the compounds exhibited significant anti-TNBC activity, especially on MDA-MB-231 cells. Compound 5b showed excellent activity on MDA-MB-231 (IC₅₀ = 17.2 ± 0.4 nM). Furthermore, molecular docking analysis revealed that this compound had a higher binding affinity towards the target EGFR (epidermal growth factor receptor) with a docking score of −10.523 kcal mol⁻¹. The molecular dynamics simulation of complex 5b:3W2S showed stable binding over a period of 100 ns. A detailed multi-linear regression (MLR) QSAR denoted the importance of key molecular descriptors, such as com_accminus_2A, fringNlipo6A, and sp³Cplus_AbSA. These analyses indicate that the synthesized compounds deserve further studies for developing novel and more potent candidates against triple-negative breast cancer.