Abstract
Background: Carcer is one of the most common diseases that endanger human health and even lives in the world today. As it reported, lung, breast and colon cancers are most common in the developing and under developed countries. Fortunately, several therapeutic regimes have been successfully approached for fighting cancer nowadays. Osimertinib (AZD9291), approved in 2015 by the FDA, as the third-generation inhibitors were designed to conquer the severe drug resistance for nonsmall-cell lung cancer. However, the emergence of new drug resistance of AZD9291 called for more potent new drugs. In order to design more potent new molecular entities, introduction of a new skeleton, such as 1,3-thiazole, to modified AZD9291 might gain better results. Herein, we reported the synthesis and biological evaluation of eighteen thiazole-2-carboxamide derivatives in this paper.
Methods: All synthesized target compounds were evaluated for their growth inhibitory activity against two human tumor cell lines in vitro via using CCK-8 assay. Based on the in vitro potency in the assays, a lead compound was selected for in vivo studies of toxicity and chemotherapeutic efficacy.
Results: The reported functionalized thiazole-2-carboxamide derivatives displayed potency against both of the two cell lines at low μM concentrations. Compound 6f displayed significant antiproliferative activity against both human lung cancer cell line and breast cancer cell line with IC50 values 0.48 µM and 3.66 µM, respectively. And compound 6f showed potent in vivo efficacy with tumor inhibition of 84.3% at a dosage of 10 mg/Kg.
Conclusion: A series of novel thiazole-2-carboxamide derivatives were designed and synthesized. Several synthesized thiazole-2-carboxamide derivatives showed potent efficacy against both human lung cancer cell line and breast cancer cell line in vitro. And a lead compound 6f was proved to be well tolerated and potent in vivo efficacy compared to the positive control AZD9291.
Keywords: Thiazole, carboxamide, lung cancer, breast cancer, antitumor, osimertinib.
Graphical Abstract
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