Design, synthesis, biological evaluation, and in silico studies of novel N-substituted-2-(3,4,5-trimethoxyphenyl)-1H-benzodimidazole-6-carboxamides as promising anticancer agents

Novel benzimidazole-based derivatives were synthesized and their cytotoxic activities were evaluated against two human cancer cells, SW480 and A549, and the normal human MRC-5 cells, using the MTT assay. N-(2,4-Dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole-6-carboxamide (5o) showed excellent cytotoxicity with IC50 values of 0.15 ± 0.01 and 3.68 ± 0.59 μM against A549 and SW480. Compound 5o had 38.5-, 62.9- and 3.1-fold superior cytotoxicity than cisplatin (IC50 = 5.77 ± 1.60 μM), etoposide (IC50 = 9.44 ± 1.98 μM), and doxorubicin (IC50 = 0.46 ± 0.02 μM), respectively against A549 cells. Moreover, 5o exhibited high selectivity towards A549 (SI = 794.6) and SW480 (SI = 32.4) cancer cells compared with the normal MRC-5. Further studies revealed the ability of 5o to induce apoptosis and arrest the cell cycle at the S phase in A549 cells. Molecular docking studies revealed 5o was well accommodated within the pocket of topoisomerase IIα-DNA, as a possible target. Molecular dynamics simulation studies confirmed the stability of the 5o-IIα-DNA complex. Compound 5o was predicted to have appropriate drug-likeness and pharmacokinetic properties.Novel benzimidazole-based derivatives were synthesized and their cytotoxic activities were evaluated against two human cancer cells, SW480 and A549, and the normal human MRC-5 cells, using the MTT assay. N-(2,4-Dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole-6-carboxamide (5o) showed excellent cytotoxicity with IC50 values of 0.15 ± 0.01 and 3.68 ± 0.59 μM against A549 and SW480. Compound 5o had 38.5-, 62.9- and 3.1-fold superior cytotoxicity than cisplatin (IC50 = 5.77 ± 1.60 μM), etoposide (IC50 = 9.44 ± 1.98 μM), and doxorubicin (IC50 = 0.46 ± 0.02 μM), respectively against A549 cells. Moreover, 5o exhibited high selectivity towards A549 (SI = 794.6) and SW480 (SI = 32.4) cancer cells compared with the normal MRC-5. Further studies revealed the ability of 5o to induce apoptosis and arrest the cell cycle at the S phase in A549 cells. Molecular docking studies revealed 5o was well accommodated within the pocket of topoisomerase IIα-DNA, as a possible target. Molecular dynamics simulation studies confirmed the stability of the 5o-IIα-DNA complex. Compound 5o was predicted to have appropriate drug-likeness and pharmacokinetic properties.