Design and Synthesis of New Quinoxaline-thiazolidine-2,4-dione-isoxazole Conjugates as EGFR Targeting Agents

A method was proposed for the synthesis of quinoxaline-thiazolidine-2,4-dione-isoxazole conjugates. Anticancer activity of the prepared compounds was evaluated against three human cancer cell lines, including MCF-7 (breast), HepG2 (liver), and HCT-116 (colorectal). The outcomes of the tested compounds (Z)-3-{[3-(4-methoxyphenyl)isoxazol-5-yl]methyl}-5-(quinoxalin-2-ylmethylene)thiazolidine-2,4-dione, (Z)-3-{[3-(3,5-dimethoxyphenyl)isoxazol-5-yl]methyl}-5-(quinoxalin-2-ylmethylene)thiazolidine-2,4-dione and (Z)-5-(quinoxalin-2-ylmethylene)-3-{[3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl]methyl}thiazolidine-2,4-dione have shown more potent activity as compared to the standard drug erlotinib. Furthermore, (Z)-3-{[3-(4-methoxyphenyl)isoxazol-5-yl]methyl}-5-(quinoxalin-2-ylmethylene)thiazolidine-2,4-dione, (Z)-3-{[3-(3,5-dimethoxyphenyl)isoxazol-5-yl]methyl}-5-(quinoxalin-2-ylmethylene)thiazolidine-2,4-dione and (Z)-5-(quinoxalin-2-ylmethylene)-3-{[3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl]methyl}thiazolidine-2,4-dione were tested for tyrosine kinase EGFR inhibitory action using erlotinib as the reference drug. All compounds demonstrate higher tyrosine kinase EGFR inhibitory potency than the reference erlotinib. The potent (Z)-3-{[3-(4-methoxyphenyl)isoxazol-5-yl]methyl}-5-(quinoxalin-2-ylmethylene)thiazolidine-2,4-dione, (Z)-3-{[3-(3,5-dimethoxyphenyl)isoxazol-5-yl]methyl}-5-(quinoxalin-2-ylmethylene)thiazolidine-2,4-dione and (Z)-5-(quinoxalin-2-ylmethylene)-3-{[3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl]methyl}thiazolidine-2,4-dione were subjected to in silico pharmacokinetic assessment by SWISS, ADME and pkCSM.