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A new series of isoxazolyl and thiazolyl urea derivatives was synthesized, fully characterized and evaluated in vitro as anticancer agents. The chemistry involves a facile protocol for the preparation of urea derivatives 12–22 through the reaction of isocyanates (p‐tolylsulfonyl isocyanate, p‐tolyl isocyanate, benzoyl isocyanate and ethylisocyanate) 8–11 with the corresponding aminoisoxazoles and aminothiazoles 2, 3, 6 and 7. The cytotoxicity of the synthesized compounds 12–22 were evaluated using human lung adenocarcinoma cell line (A549), cervical cancer cell line (HeLa), and breast cancer cell line (MCF7). All novel compounds (except compounds 12, 17, and 18) were potential cytotoxic against lung cancer as it displayed IC_50s less than the reference drug (5‐Fluro uracil (5FU)). All tested compounds (except 15 and 19) showed strong inhibition of breast cancer cell line even much better than the 5FU. The …