Green synthesis and in vitro anticancer evaluation of 1,2-disubstituted benzimidazole derivatives

The benzimidazole core, a fundamental scaffold in medicinal chemistry, has been key in the advancement of this health field, leading to the development of numerous commercially available drugs, including those to treat cancer, which constitutes the most pressing health problem, being the main cause of death globally, whose current chemotherapeutic treatments, although some effective, have serious side effects, highlighting the need to discover safer and more potent drugs. In this context, a series of 1-benzyl-2-aryl benzimidazole derivatives ( 21 ‐– 29 ) were synthesized using a selective and affordable method under mild reaction conditions and green chemistry criteria. A hydroxylated Schiff base ( 23 ) is also included, evidence of the possible reaction mechanism for synthesizing the different BZM derivatives. All compounds were characterized using spectroscopic techniques and single-crystal X-ray analysis. The latter, including Hirshfeld surface analysis, allowed the study of the main non-covalent interactions that stabilize molecular packing and supramolecular arrangements. A preliminarily evaluated by in vitro assays against a panel of six human cancer cell lines and healthy cells using tamoxifen as a reference drug. The results showed that all the compounds demonstrate bioactivity, highlighting the halogenated structures 1-(4-chlorobenzyl)-2-(4-chlorophenyl)-1 H -benzo[ d ]imidazole ( 26 ), 1-(4-bromobenzyl)-2-(4-bromophenyl)-1 H -benzo[ d ]imidazole ( 27 ) and 1-(4-methoxybenzyl)-2-(4-methoxyphenyl)-1 H -bebioavailability nzo[ d ]imidazole ( 29 ) exhibited the highest biological activity, mainly against the cancer lines leukemia (K562), colon cancer (HCT-15), breast cancer (MCF-7) and lung cancer (SKLU-1). A brief ADME analysis evaluated that the obtained compounds have pharmacodynamic and pharmacokinetic parameters to be potentially administered enterally. • A series of benzimidazole (BZM) derivatives ( 21 - 29 ) and a Schiff base 23 were synthesized selectively employing green chemistry criteria by a straightforward strategy with very good yield. • X-ray diffraction and Hirshfeld surface studies of 27 support the structural analysis of electronic and steric effects influencing the noncovalent interactions and supramolecular arrangements of BZM derivatives (highlight modified). • In vitro evaluations were performed against six cell lines of different types of human cancer, including healthy cells and tamoxifen as references. • Complementary in silico ADME analyses allowed the estimation of physicochemical parameters of BZM derivatives, including pharmacokinetic and pharmacodynamic profiles for possible enteric absorption.