N-substituted benzimidazole acrylonitriles as in vitro tubulin polymerization inhibitors: Synthesis, biological activity and computational analysis

Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2

“…According to the obtained results, it is obvious that the most significant impact on the antiproliferative activity enhancement relates to the introduction of the N,N -diethylamino group at the para -position of the phenyl ring. In comparison to the previously published results [ 27 ], it can be concluded that the introduction of the N,N -diethylamino group instead of the N,N -dimethylamino group decreased the antiproliferative activity against Capan-1, HCT-116, NCI-H460, DND-41, and HL-60 cancer cells from a submicromolar to micromolar range of inhibitory concentrations.…”

“…By using uncatalyzed microwave-assisted amination in acetonitrile with an excess of desired amine, N -substituted precursors 3 – 8 bearing i -butyl, methyl, phenyl, and n -hexyl substituents were obtained in good reaction yields. Within the reduction of nitro-substituted compounds 3 – 8 with SnCl 2 ·2H 2 O in MeOH followed by cyclocondensation with 2-cyanoacetamide at high temperatures, corresponding N -substituted 2-(cyanomethyl)-benzimidazoles 17 – 25 as main precursors were obtained in moderate yields [ 27 ]. Targeted acrylonitrile derivatives 32 – 71 were synthesized in the condensation with the chosen unsubstituted and methoxy-, N,N -dimethyl-, and N,N -diethyl-substituted aromatic aldehydes 26 – 31 in absolute ethanol by using a few drops of piperidine as a weak base.…”

“…Computational analysis was performed to interpret the observed biological properties and to identify structural and electronic features responsible for the highest activity of 64, which should aid in the subsequent design of even more effective ligands based on the utilized organic skeleton. To do so, we considered a representative set of compounds, including 50 , 63 , 64 , 66 , 68 , and 69 , together with two model systems m1 and m2 , as well as colchicine, which was taken as a typical ligand for the colchicine binding site in tubulin ( Figure 5 ), in line with our previous results [ 27 ].…”

“…Recently, as a continuation of our previous efforts aimed at the design and discovery of novel benzimidazoles with promising antitumor activities, we prepared novel N -substituted, benzimidazole-derived acrylonitriles as potential tubulin polymerization inhibitors. N,N -dimethylamino-substituted acrylonitriles I and II ( Figure 2 ) with submicromolar inhibitory concentrations (IC 50 0.2–0.6 μM) were chosen as lead compounds, while their interference with the tubulin activity was confirmed by in vitro studies of the tubulin polymerization inhibition and the computational analysis [ 27 ].…”

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…In addition, the method was carried out in a decagram scale to furnish the polyfluorinated biaryl product with 80% yield from the coupling of 2,3,5,6-tetrafluoroanisole and ethylbenzene, which could be further converted to different products through hydrodefluorination by nucleophilic aromatic substitution of fluorine atoms. The acrylonitrile products 257 and 258 have shown potential anticancer activity against eight different cell lines (Scheme 81A) [341]. The direct cyanation of alkenes and (hetero)aromatic compounds are useful reactions that have been reported to be accomplished through copper-mediated activation of C(sp 2 )-H bonds [342][343][344].…”