Abstract A method for the synthesis of 3,4-diaryl-5-morpholinoisoxazoles was developed, featuring the optimization of reaction conditions to introduce a morpholine moiety at the 5-position of 5-chloroisoxazoles. The representative compound 9 was prepared and evaluated in vitro , demonstrating moderate water solubility along with cytotoxic activity against selected cell lines. This modification strategy provides a viable approach for further structural diversification of combretastatin A4 analogues within the isoxazole series, enabling the expansion of a library of heterocyclic derivatives with improved physicochemical properties.