Synthesis of novel 1,2,5-trisubstituted benzimidazoles as potential antitumor agents

Novel methyl 1-(5-tert-butyl-1H-pyrazol-3-yl)-2-(aryl)-1H-benzo[d]imidazole-5-carboxylates 11 were synthesized by following a four-step strategy involving a nucleophilic aromatic displacement (SNAr) and a solvent free approach as key steps for the formation of the desired products. Structure of intermediates and products were confirmed by X-ray diffraction as well as the tautomeric rearrangement suffered by the pyrazole moiety during the curse of the final cyclization process. Several of the obtained compounds were screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines. Products 11b and 11n exhibited the highest activity against a range of cancer cell lines with remarkable values in panels of Non-Small Cell Lung Cancer, Melanoma and Leukemia, with GI50 range of 1.15–7.33 μM and 0.167–7.59 μM, respectively, and suitable LC50 with values greater than 100 μM.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Novel trisubstituted benzimidazoles of potential antitumor activity were obtained. ► A (SNAr) and a solvent free approach were the key steps in this strategy. ► Tautomeric rearrangement of pyrazole ring in 11 was confirmed by X-ray diffraction. ► Products were screened by the US (NCI) against 60 different human tumor cell lines. ► Products 11b,n showed the highest activity for NSCLC, Melanoma and Leukemia panels.