LAUSR

A series of novel 5-methylpyrazolo[1,5-a]pyrimidine derivatives (10a-10x) were designed, synthesized, and evaluated for their in vitro inhibitory activities against c-Met kinase and antiproliferative activities against the SH-SY5Y, MDA-MB-231, A549, and HepG2 cell lines. Most of the compounds remarkably inhibited c-Met kinase and showed moderate to good cytotoxicity and selectivity toward the four cancer cell lines. Among them, compounds 10b and 10f were the two most potent selective c-Met inhibitors with half-maximal inhibitory concentration (IC50) values of 5.17 ± 0.48 nM and 5.62 ± 0.78 nM, respectively, and suppression abilities comparable with the positive control cabozantinib. Cell proliferation assay further demonstrated that the two most promising compounds 10a and 10b also showed good cytotoxicity and selectivity toward MDA-MB-231 cells, with IC50 values of 26.67 ± 2.56 μM and 26.83 ± 2.41 μM, respectively. Compounds 10f and 10g showed cytotoxicity and selectivity toward A549 cells, with IC50 values of 20.20 ± 2.04 μM and 21.65 ± 1.58 μM, respectively. All antiproliferative activities were within the range of those of cabozantinib. Notably, these compounds presented relatively low hepatotoxicity compared with reference drugs. Moreover, the preliminary structure-activity relationship and docking studies revealed that replacement of a nitrogen-containing heterocycle on the R2 (block A) group might improve the c-Met kinase inhibitory and antiproliferative effects in MDA-MB-231 cells, whereas displacement by a substituted benzene ring, especially for the p-fluorophenyl or 4-fluoro-3-methoxyphenyl moiety, on the R2 group enhanced cytotoxicity toward A549 cells. Together, these results suggest that 10b and 10f are promising compounds and provide a basis for their development as new antitumor agents.