Medicinal‐Chemistry‐Driven Approach to 2‐Substituted Benzoxazole–Estradiol Chimeras: Synthesis, Anticancer Activity, and Early ADME Profile

Abstract

The efficient synthesis of novel estradiol‐based A‐ring‐fused oxazole derivatives, which can be considered as benzoxazole‐steroid domain‐integrated hybrids containing a common benzene structural motif, is described. The target compounds were prepared from steroidal 2‐aminophenol precursors by heterocycle formation or functional group interconversion (FGI) strategies. According to 2D projection‐based t‐distributed stochastic neighbor embedding (t‐SNE), the novel molecules were proved to represent a new chemical space among steroid drugs. They were characterized based on critical physicochemical parameters using in silico and experimental data. The performance of the compounds to inhibit cell proliferation was tested on four human cancer cell lines and non‐cancerous cells. Further examinations were performed to reveal IC50 and lipophilic ligand efficiency (LLE) values, cancer cell selectivity, and apoptosis‐triggering features. Pharmacological tests and LLE metric revealed that some derivatives, especially the 2‐(4‐ethylpiperazin‐1‐yl)oxazole derivative exhibit strong anticancer activity and trigger the apoptosis of cancer cells with relatively low promiscuity risk similarly to the structurally most closely‐related and intensively studied anticancer agent, 2‐methoxy‐estradiol.