N-Alkyl-2-(2-undecyl-1H-benzimidazol-1-yl)acetamides as An-tiproliferative Agents for Invasive Breast Cancer. Design, Syn-thesis, In Vitro Activity, and Computational Studies

One of the most dangerous types of breast cancer that can spread from its original location to neighboring tissues is invasive breast cancer. Cathepsins, a group of proteolytic enzymes, has been thoroughly investigated in relation to cancer progression and has been shown to be crucial for the invasion and metastasis of breast cancer cells. A series of new N-alkyl-2-(2-undecyl-1H-benzimidazol-1-yl) acetamides were prepared from 2-(2-undecyl-1H-benzimidazol-1-yl)ethanhydrazide via azide coupling method with a variety of amines. The new compounds were designed to inhibit proliferation of breast cancer cells based on inhibition of the selectively and highly expressed cathepsin K. The compounds were tested for their antiproliferative activity on four cancer cell lines, namely, A549, MDA-MB231, MCF-7, U87, and HEK293 to elucidate their preferential activity on invasive breast cancer cells. The results showed that most compounds exerted enhanced activity against MDA-MD231 compared to other cell lines. Compounds 7h, 7i, 7a, and 7j showed the highest inhibition with IC50s of 17, 27, 38, and 67 μg/ml respectively. Compounds 7a, and 7j showed the highest selectivity to MDA-MD231 in terms of degree of inhibition. Molecular docking supported the cathepsin K mediated activity where compound 7i, the most potent compound, showed the best docking score of -7.126 with a low RMSD to the co-crystallized ligand pose. Molecular dynamics (MD) simulations demonstrated that 7i maintained stability within the binding pocket with minimal fluctuations. The postulated lipo-philicity impact on activity was evaluated through LLE calculations, where values for the most active compounds demonstrated that optimal potency was frequently associated with moderate lipophilicity, as seen in compound 7i (LLE = 2.69). Thus, the developed compounds are promising antiproliferative agents for invasive breast cancer where a cathepsin inhibition pathway is implicated.