Synthesis and Evaluation of Compounds Containing 4-arylpiperazinyl Moieties Linked to a 2-(pyridin-3-yl)-1H-benzimidazole as p38 MAP Kinase Inhibitors

A series of novel ethyl 1-(2-(4-(2-amino-5-(ethoxycarbonyl) phenyl) piperazin-1-yl) ethyl)-2-(2-(substituted) pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylate analogues were synthesized and screened as p38 MAP kinase inhibitors. The 4-chlorophenoxy substitution in the 2nd position of the pyridyl moiety (5i) gave effective inhibition of p38 with IC50 17μM. Moreover, the synthesized benzimidazole derivatives possess a significant antiproliferative activity against blood-leukemia (CCRF-CEM), colon (HCT-116) and breast (MDA-MB-468) cancer cell lines. Based on the report, we discussed structure-activity relationship (SAR) study of synthesized benzimidazole derivatives. Molecular modelling performed for the identification of most active compounds by using three dimensional crystal structures of MAPK p38, provide a disclosed binding template of these inhibitors in the active site of their respective enzyme.