Facile Synthesis of 1,2-Disubstituted Benzimidazoles as Potent Cytotoxic Agents

Benzimidazoles have a broad spectrum of biological and pharmacological properties, including anticancer activity. This study reports the facile synthesis and cytotoxic evaluation of twenty-eight 1,2-disub-stituted benzimidazoles (6a–β), based on condensation reactions between N-benzyl o-phenylenediamine and benzylamine. The reactions were solvent-free, with the use of Na₂S₂O₅ as an inexpensive and environmentally friendly oxidizing agent, and progressed rapidly. Cytotoxicity assessments using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were performed against the A549, HeLa, and MCF-7 cell lines for all synthesized compounds (6a–β). Among them, 6j, 6k, 6l, and 6n displayed good activities against the A549 and MCF-7 cell lines. These compounds possessed IC₅₀ values ranging from 2.55 to 4.50µM, corresponding to 1.4-fold to 2.4-fold stronger potencies than that of the positive control 5-fluorouracil (5-FU) (IC₅₀=6.08µM) against MCF-7 cells, while 6k (IC₅₀=3.22µM) was consistent with 5-FU on the A549 cell line (IC₅₀=3.77µM). Structure–activity relationship analyses revealed the 3-pyridinyl moiety at C-2 and the CH₃, OCH₃, or 1,3-dioxolyl groups on the benzene ring at the N-1 position of the benzimidazole heterocycle as key structural features effectuating the observed cytotoxicities.