Exploring 1,2,3-triazole-Schiff’s base hybrids as innovative EGFR inhibitors for the treatment of breast cancer: In vitro and in silico study

Abstract

EGFR inhibitors are a class of targeted therapies utilized in the management of certain tumor kinds such as NSCLC and breast cancer. Series of 1,2,3-triazole-Schiff’s base hybrids were designed, synthesized, and estimated for their antitumor effect toward breast cancer cells, MCF-7 and MDA-MB-231. The safety and selectivity of the new compounds were tested using normal cell (WI-38). Analogs 4a, 4b, and 5f demonstrated significant antitumor effects toward both MCF-7 and MDA-MB-231 with IC₅₀ range of 5.61–18.01 µM in comparison to Doxorubicin (6.72 µM). Moreover, they proved considerable selectivity toward the tested cancer cells (SI values of 4.36–5.33). The superior compounds were investigated for EGFR inhibition where compounds 4b and 5f showed the highest EGFR inhibition effect with IC₅₀ equal 0.16 and 0.15 µM, respectively utilizing Gefitinib as reference (IC₅₀ = 0.081 µM). Further mechanistic studies for hybrid 5f in MDA-MB-231 cells, exhibited cell cycle arrest at G2/M phase by 29.85 % that was accompanied by the elevation of apoptosis percent by 48-fold more than the control. The apoptosis studies indicated that hybrid 5f was able to upregulate Bax (9.43 folds) while downregulate Bcl-2 (0.27) with substantial remarkable elevation of Bax/Bcl-2 ratio (35:1). Furthermore, it upregulated both caspases 8 and 9 by 2.93 and 6.54-fold, respectively. Molecular modeling studies showed the good binding affinity of compounds 4b and 5f with EGFR kinase active site explaining their potent biological effects. Drug likeness and ADMET features of compounds 4b and 5f demonstrated that they represent promising drug like candidates against breast cancer.