Rationally Designed Phenyl- and Phenanthryl-Based Imidazole Hybrids for the Treatment of Breast Cancer—A Structure–Activity Relationship Study

A series of 11 compounds of phenyl–imidazole–pyrrole and 9 compounds of phenanthryl–imidazole–pyrrole were synthesized and evaluated against breast cancer cell lines differing in the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)-2, viz., BT-474 (ER+, PR+, and HER2+), T-47D and MCF-7 (ER+, PR+, and HER2−), and MDA-MB-468 and MDA-MB-231 (ER−, PR−, and HER2−). The analysis of the results indicated that the most active compounds were 5d and 5k from the phenyl–imidazole–pyrrole series and 6b and 6i from the phenanthryl–imidazole–pyrrole series (IC50 < 50 µM). Molecular docking (MD) and molecular dynamics simulation (MDS) studies demonstrated that the active compounds exhibited high binding affinity to the 7NH5 (a co-crystal structure of Akt1 and its specific inhibitor) protein, which is overexpressed in many breast cancer types. The active compounds 6b and 6i reduced the viability of MDA-MB-231 and MCF-7 cells by inducing cell death mechanisms. Both compounds halted the proliferation by arresting cells in the G0/G1 phase of the cell cycle. The results are similar to those of traditional Cisplatin. Intraperitoneal administration of 6i retarded the development of EAC tumors and increased the survival of mice compared with tumor-bearing control and 5-fluorouracil (5FU)-treated positive control mice.