55432-22-9Relevant articles and documents
N-substituted benzimidazole acrylonitriles as in vitro tubulin polymerization inhibitors: Synthesis, biological activity and computational analysis
Perin,Hok,Be?,Persoons,Vanstreels,Daelemans,Vianello,Hranjec
, (2020/12/02)
We present the design, synthesis and biological activity of novel N-substituted benzimidazole based acrylonitriles as potential tubulin polymerization inhibitors. Their synthesis was achieved using classical linear organic and microwave assisted techniques, starting from aromatic aldehydes and N-substituted-2-cyanomethylbenzimidazoles. All newly prepared compounds were tested for their antiproliferative activity in vitro on eight human cancer cell lines and one reference non-cancerous assay. N,N-dimethylamino substituted acrylonitriles 30 and 41, bearing N-isobutyl and cyano substituents placed on the benzimidazole nuclei, showed strong and selective antiproliferative activity in the submicromolar range of inhibitory concentrations (IC50 0.2–0.6 μM), while being significantly less toxic than reference systems docetaxel and staurosporine, thus promoting them as lead compounds. Mechanism of action studies demonstrated that two most active compounds inhibited tubulin polymerization. Computational analysis confirmed the suitability of the employed benzimidazole-acrylonitrile skeleton for the binding within the colchicine binding site in tubulin, thus rationalizing the observed antitumor activities, and demonstrated that E-isomers are active substances. It also provided structural determinants affecting both the binding position and the matching affinities, identifying the attached NMe2 group as the most dominant in promoting the binding, which allows ligands to optimize favourable cation???π and hydrogen bonding interactions with Lys352.
4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: Potent and selective p70S6 kinase inhibitors
Bandarage, Upul,Hare, Brian,Parsons, Jonathan,Pham, Ly,Marhefka, Craig,Bemis, Guy,Tang, Qing,Moody, Cameron Stuver,Rodems, Steve,Shah, Sundeep,Adams, Chris,Bravo, Jose,Charonnet, Emmanuelle,Savic, Vladimir,Come, Jon H.,Green, Jeremy
scheme or table, p. 5191 - 5194 (2010/03/24)
We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (Ki 100-fold selectivity against PKA, ROCK and GSK3.
Aromatic Nucleophilic Substitution Reactions of 1,2-Dinitrobenzene with Aliphatic Primary Amines in n-Hexane; Catalysis by Non-nucleophilic Bases
Chiacchiera, Stella M.,Singh, Joaquin O.,Anunziata, Jorge D.,Silber, Juana J.
, p. 987 - 994 (2007/10/02)
The kinetics of the reactions of 1,2-dinitrobenzene with n-butyl-, s-butyl-, isobutyl-, n-propyl-, and isopropyl-amine in n-hexane at various temperatures have been investigated.The second-order rate coefficients for these reactions increase linearly with the amine concentrations.The values of the ratio of the rate constant for the catalysed process to the rate constant of the uncatalysed step 3RNH2/k2> are dependent on temperature, so that it is possible to minimize the catalysed or uncatalysed processes simply by temperature variation.Kinetic studies in the presence of non-nucleophilic bases confirmed the proposal that all these reactions are base-catalysed even for the cases where k3RNH2/k2 is less than 50.The role that electron donor-acceptor complex formation between reactants may play in the mechanism of these reactions is discussed.The influence of electronic and steric effects in the amine structure on the catalytic rate constant has been analysed.It has been shown that the catalysed step is disfavoured by electron-donating substituents and that it is inhibited by steric hindrance.The studies with the addition of the bulky bases TEA and TBA confirmed these conclusions.
