Design, synthesis and biological evaluation of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents

• A series of benzimidazolyl chalcone derivatives was synthesized and characterized.
• Derivatives were evaluated for their antitumour activities and SAR.
• A1 and A7 indicated strong antitumour activity both in vivo and vitro.
• A1 and A7 were considerably safe in vivo.
• These compounds possible inhibited the p53-MDM2 binding.

A series of novel benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives were designed and synthesized. The biological activities of these derivatives were then evaluated as potential antitumour agents. These compounds were assayed for growth-inhibitory activity against HCT116, MCF-7 and HepG2 cell lines in vitro. The IC50 values of compounds A1 and A7 against the cancer cells were 0.06–3.64 μM and 0.04–9.80 μM, respectively. Their antiproliferative activities were significantly better than that of 5-Fluorouracil (IC50: 56.96–174.50 μM) and were close to that of Paclitaxel (IC50: 0.026–1.53 μM). The activity of these derivatives was over 100 times more effective than other reported structures of chalcone analogues (licochalcone A). A preliminary mechanistic study suggested that these compounds inhibit p53-MDM2 binding. Compounds A1, A7 and A9 effectively inhibited tumour growth in BALB/c mice with colon carcinoma HCT116 cells. The group administered 200 mg/kg of compound A7 showed a 74.6% tumour growth inhibition with no signs of toxicity at high doses that was similar to the inhibition achieved with the 12.5 mg/kg irinotecan positive control (70.2%). Therefore, this class of benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives represents a promising lead structure for the development of possible p53-MDM2 inhibitors as new antitumour agents.

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