Design, synthesis, and biological evaluation of novel triazoloquinazolinone derivatives as SHP2 protein inhibitors.

A novel series of triazoloquinazolinone derivatives were designed, synthesised, and evaluated for their biological activities against the SHP2 protein. Moreover, some compounds were evaluated against A375 cells. The results revealed that target compounds possessed moderate to excellent inhibitory activity against SHP2 protein, whereas compounds , , , , and have strong antiproliferative activity on A375 cells. The compound showed remarkable cytotoxicity against A375 cells and a strong inhibitory effect against SHP2 protein when compared with . The structure-activity relationships (SARs) indicated that electron-donating groups (EDGs) on phenyl rings are beneficial for improving the antitumor activity; compounds with a hydroxyl substituent at the 2-position of phenyl ring exhibited superior activities than compounds with a substituent at the 4-position. In addition, compound displayed improved physicochemical properties as well as metabolic stability compared to . Our efforts identified as a promising SHP2 protein inhibitor, warranting its further investigation.