New hydrazide derivatives of <i>N</i>‐amino‐11‐azaartemisinin as promising epidermal growth factor receptor inhibitors for therapeutic development in triple‐negative breast cancer

Triple-negative breast cancer (TNBC) treatments, such as DNA-damaging agents like carboplatin, pose considerable human toxicity and may contribute to cancer relapse. Artemisinin derivatives offer a less toxic alternative; however, their specific role in TNBC management remains to be established. To address this gap, computational models were employed to design and evaluate artemisinin-based prototypes as potential TNBC therapeutics, aiming to provide safer and more effective treatment options for this aggressive cancer subtype. Among the series of hydrazide derivatives of azaartemisinin (10a-l) reported herein, compound 10j emerged as the most promising, exhibiting notable cytotoxicity with IC₅₀ values of 1.74 and 1.64 µM against MDA-MB-231 and MDA-MB-468 cells, respectively. The clinically useful drug doxorubicin provided IC₅₀ values of 0.29 and 0.29 µM against MDA-MB-231 and MDA-MB-468 cells, while artemisinin provided IC₅₀ values of 107.30 and 116.60 µM, respectively. Furthermore, putative interactions between the synthesized compounds and the epidermal growth factor receptor (EGFR) were identified using molecular docking studies, suggesting a possible mechanism for their anticancer effect. Additionally, to determine the thermodynamic parameters of the interactions between artemisinin, azaartemisinin, and biomolecules, isothermal titration calorimetry experiments were performed. The binding constant value on the order of 10⁴ indicates a comparatively stronger binding affinity of azaartemisinin with human serum albumin (HSA) compared to artemisinin with HSA. These findings support the potential of azaartemisinin derivatives as promising EGFR inhibitors for therapeutic development in TNBC, offering a new avenue for less toxic and more effective cancer treatments.