Efficient Synthesis, Anticancer Evaluation, and Molecular Docking Studies of New Triazole‐aryl‐Ester Hybrids of β‐Himachalene as Potent Inducers of Apoptosis

ABSTRACT A novel series of aromatic ester‐1.4‐disubstituted‐1,2,3‐triazole hybrids containing himachalene was efficiently synthesized by a regioselective copper‐catalyzed azide‐alkyne cycloaddition between an azidomethyl‐himachalene derivative and various propargylated esters. These compounds were characterized by NMR and HRMS analyses. The Hemisynthesized products were studied for their in vitro cytotoxicity against four cancer cell lines (HT‐1080, A‐549, MCF‐7, and MDA‐MB‐231). Most of the tested compounds showed moderate to significant activities with IC 50 values ranging from 8.06 to 47 µM on all cancer cell lines. Notably, compound 6d, with a 4‐methoxy substituent, was the most potent against HT‐1080 and MCF‐7 cells. The mechanism of action study revealed that compound 6d induced apoptosis through caspase‐3/7 activation and cell cycle arrest at G0/G1. These results were confirmed by in silico molecular docking investigations, which demonstrated that compound 6d had a strong binding affinity toward caspase‐3/7 (‐8.6 kcal/mol), much higher than the co‐crystallized ligand. Key hydrogen bonds with ARG207 and SER205, π‐cation interaction with ARG207, π – π stacking with HIS121 and TYR204, and hydrophobic interactions with MET61 and PHE128 were all present in its well‐balanced interaction profile. These interactions give the ligand a molecular basis for its increased biological activity and aid in its stable position inside the active site.