Benzimidazole derivatives related to 2,3-acrylonitriles, benzimidazo[1,2- a]quinolines and fluorenes: Synthesis, antitumor evaluation in vitro and crystal structure determination

Abstract

A synthesis and biological evaluation of new benzimidazole derivatives, related to 2,3-disubstituted acrylonitriles, benzimidazo[1,2- a]quinoline-6-carbonitriles and heteroaromatic fluorenes was described. The molecular and crystal structures of three compounds 4, 16 and 17 reveal that non-fused fluoro derivative, 4, deviates from planarity by 13.11(2)°, while fused methyl, 16, and fluoro, 17, derivatives are planar within 4° exhibiting a planar aromatic surface capable to intercalate into double-stranded DNA. Compound 4 exists as E-isomer. The crystal structures confirmed that hydrogen bonding patterns are characterized dominantly by the weak C–H⋯N(F) bonds, except in the case of 4 where the presence of ethanol molecule of crystallization resulted in the N–H⋯O and O–H⋯N hydrogen bonds formation. In the crystal structures of 16 and 17 cyano group participates in hydrogen bonding formation, while in 4 this is not the case. All compounds, except 16 and 14 exerted pronounced antiproliferative activity on five tumor cell lines, whereby 2-benzimidazolyl-3- N-methylpyrolyl-acrylonitrile 13 and its fused analogue 23 exerted the highest activity on all cell lines (IC 50 = 0.8–30 μM) and showed a special selectivity toward HeLa cells. There is no major difference in the biological activity between non-fused and fused analogues. Similarly, all compounds showed significant interaction with ct-DNA, supporting the fact that their antitumor activity could partially be the consequence of DNA-binding. The cyano moiety is important for the activity, but not the selectivity of tested compounds.