c-Mesenchymal epithelial transition factor (c-Met), a member of receptor tyrosine kinases (RTKs) is normally activated by binding to its natural ligand hepatocyte growth factor (HGF). Under normal physiology, the HGF/c-Met signaling facilitates numerous complex cellular processes, including those involved in proliferation, motility, migration and invasion. However, abnormalities in the pathway lead to tumor growth, angiogenesis, metastasis and resistance to some cancer therapies. The aberrant HGF/c-Met axis has been found in several human solid tumors and hematologic malignancies. Thus, c-Met kinase holds special importance for targeted therapeutic interventions in different cancers. Herein, we report the discovery and optimization of benzimidazole based c-Met kinase inhibitors. In computational studies, 3DQSAR analyses and molecular docking were carried out to gain insight into the structural basis of the inhibitory properties of small molecules c-Met kinase inhibitors. Based on the interpretation of obtained contour maps and binding mode analysis of reported Class I c-Met kinase inhibitors, key structural features have been identified for the designing of benzimidazole based c-Met kinase inhibitors. A series of sulfonyl linked benzimidazole derivatives were synthesized and characterized by <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, and Mass (ESI-MS). The synthesized benzimidazole derivatives were evaluated in c-Met kinase enzyme inhibition and cell-based assays. The compounds 10c and 11e were found as the most potent compounds in cell and enzyme-based assays. Ligand-based drug design studies and synthesis provided 1-substituted benzimidazole derivatives as c-Met kinase inhibitors and anti-cancer agents.

Discovery of benzimidazole based inhibitors of c-Met kinase: Design, synthesis and biological evaluation

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