Synthesis, biological evaluation, and molecular docking studies of novel 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives as potential tubulin polymerization inhibitors

Yan-Ting Wang; Ya-Juan Qin; Na Yang; Ya-Liang Zhang; Chang-Hong Liu; Hai-Liang Zhu

doi:10.1016/j.ejmech.2015.05.021

Synthesis, biological evaluation, and molecular docking studies of novel 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives as potential tubulin polymerization inhibitors

Eur J Med Chem. 2015 Jun 24:99:125-37. doi: 10.1016/j.ejmech.2015.05.021. Epub 2015 May 21.

Authors

Yan-Ting Wang¹, Ya-Juan Qin¹, Na Yang¹, Ya-Liang Zhang¹, Chang-Hong Liu¹, Hai-Liang Zhu²

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
² State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: zhuhl@nju.edu.cn.

PMID: 26070164
DOI: 10.1016/j.ejmech.2015.05.021

Abstract

A series of 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives were designed, synthesized and evaluated as potential tubulin polymerization inhibitors and for the cytotoxicity against anthropic cancer cell lines. Among the novel compounds, compound 11f was demonstrated the most potent tubulin polymerization inhibitory activity (IC50 = 1.5 μM) and antiproliferative activity against A549, HepG2 and MCF-7 (GI50 = 2.4, 3.8 and 5.1 μM, respectively), which was compared with the positive control colchicine and CA-4. We also evaluated that compound 11f could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Docking simulation and 3D-QSAR model in these studies provided more information that could be applied to design new molecules with more potent tubulin inhibitory activity.

Keywords: 3D-QSAR; Benzimidazole; Molecular docking; N-methylindole; Tubulin polymerization inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Benzene / chemical synthesis*
Benzene / chemistry
Benzene / metabolism
Benzene / pharmacology*
Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry
Benzimidazoles / metabolism
Benzimidazoles / pharmacology*
Cell Division / drug effects
Cell Line, Tumor
Chemistry Techniques, Synthetic
Drug Design*
Drug Screening Assays, Antitumor
Humans
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / metabolism
Indoles / pharmacology*
Molecular Docking Simulation*
Protein Multimerization / drug effects*
Protein Structure, Quaternary
Quantitative Structure-Activity Relationship
Tubulin / chemistry*
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / metabolism
Tubulin Modulators / pharmacology

Substances

Antineoplastic Agents
Benzimidazoles
Indoles
Tubulin
Tubulin Modulators
Benzene