Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2

Abstract

We used classical linear and microwave-assisted synthesis methods to prepare novel N-substituted, benzimidazole-derived acrylonitriles with antiproliferative activity against several cancer cells in vitro. The most potent systems showed pronounced activity against all tested hematological cancer cell lines, with favorable selectivity towards normal cells. The selection of lead compounds was also tested in vitro for tubulin polymerization inhibition as a possible mechanism of biological action. A combination of docking and molecular dynamics simulations confirmed the suitability of the employed organic skeleton for the design of antitumor drugs and demonstrated that their biological activity relies on binding to the colchicine binding site in tubulin. In addition, it also underlined that higher tubulin affinities are linked with (i) bulkier alkyl and aryl moieties on the benzimidazole nitrogen and (ii) electron-donating substituents on the phenyl group that allow deeper entrance into the hydrophobic pocket within the tubulin’s β-subunit, consisting of Leu255, Leu248, Met259, Ala354, and Ile378 residues.

Indole-Acrylonitrile Derivatives as Potential Antitumor and Antimicrobial Agents—Synthesis, In Vitro and In Silico Studies

“…For a more beneficial effect, the additional pendant aromatic ring should be 2-naphthyl or para -substituted phenyl. Especially advantageous was the introduction of a dimethylamine moiety, which was consistent with literature data [ 45 , 46 ].…”

“…Recently, it has been reported that the introduction of an alkyl or aryl group at position N 1 of benzimidazole-derived acrylonitriles can result in promising antiproliferative agents [ 45 , 46 ]. Therefore, to explore the structure–activity relationships of the synthesized 2-(1 H -indol-2-yl)-3-acrylonitriles in more detail, we turned our attention to their N -substituted analogs.…”

“…In order to rationalize the experimentally assessed antiproliferative properties of the synthesized compounds against cancer cell lines, computational analysis was undertaken. As mentioned above, heteroaryl-acrylonitriles can exhibit antiproliferative effects by inhibiting tubulin polymerization due to their ability to bind to the colchicine-binding site [ 45 , 46 , 47 , 48 ]. Although some synthetic compounds that bind to the colchicine site have been evaluated in clinical trials [ 69 ], none have been approved for cancer therapy to date.…”

“…Otherwise, several studies have shown the anticancer potential of heteroaryl-acrylonitriles [ 34 ]. For example, some acrylonitriles bearing N -substituted benzimidazole II ( Figure 1 ) [ 45 , 46 ], benzotriazole III ( Figure 1 ) [ 47 ], or triazolo [4,5- b ]pyridine IV ( Figure 1 ) [ 48 ] fragment are able to exert antiproliferative effects against tumor cell lines by interacting with tubulin in the colchicine-binding site. Other heteroaryl-acrylonitrile-based compounds such as 3-aryl-2-(benzimidazol-2-yl)acrylonitriles V ( Figure 1 ) have shown significant interaction with ct-DNA, supporting the fact that their antitumor properties could be the consequence of DNA binding [ 49 ].…”

Discovery of novel tubulin polymerization inhibitors by utilizing 3D-QSAR, molecular docking and molecular dynamics simulation

“…Finally, the obtained trajectory results were further analyzed using the ptraj module of the Amber package. 34…”