Synthesis, Anticancer Activity, and Molecular Docking Studies of Novel Substituted Isoxazole Derivatives Tethered 4‐Nitroimidazole

Abstract A series of 4‐nitroimidazole‐piperazine conjugated 3,5‐disubstituted isoxazole analogs 9a‐o were synthesized using nitrile oxide/alkyne cycloadditions (NOAC) with good yields. The antiproliferative activities of these compounds were evaluated against breast cancer cell lines MCF‐7 and MDA‐MB‐231, as well as prostate cancer cell lines PC‐3 and DU‐145. Notably, compounds 9a , 9j , 9k , and 9o exhibited significant antiproliferative effects against MCF‐7 cells, with IC 50 values ranging from 0.052 to 0.012 µM, while no activity was observed against the MDA‐MB‐231 cell line. Additionally, compounds 9a , 9d , 9g , 9j , and 9k showed significant cytotoxicity against PC‐3 cells, with IC 50 values between 0.156 and 0.041 µM. Compounds 9a , 9j , 9k , and 9o also demonstrated antiproliferative activity against DU‐145 cells, with IC 50 values ranging from 1.18 to 0.356 µM. Molecular docking studies revealed that compound 9a exhibited strong binding interactions with human protein receptors ER, PR, and HER2, while compound 9j showed significant binding affinity with the androgen receptor CYPP450 17A1.