Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction

In our continuing efforts to develop novel c-Met inhibitors as potential Anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four Cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 Cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC₅₀ = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC₅₀ values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the Anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and Apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.