Study on the Host-Guest Interactions Between Tetramethyl Cucurbit[6]uril and Benzimidazole Derivatives

In this paper,^(1)H NMR spectroscopy,isothermal titration calorimetry,X-ray crystallography and other characterization methods were used to investigate the interaction modes of tetramethyl cucurbit[6]uril(TMeQ[6])and three benzimidazole derivatives in an aqueous solution-solid state.The results showed that the aromatic ring moieties in the three derivatives all entered the cavity of TMeQ[6]and their substituents were located at the port of TMeQ[6],forming 1:1 host-guest inclusion complexes.The crystal structures showed that the aromatic part of the benzimidazole derivatives interacted with the cavity of TMeQ[6]via hydrogen bond interactions and the N atoms on the benzimidazole ring formed hydrogen bonds with the carbonyl oxygen of TMeQ[6].The ion-dipole interactions between[ZnCl_(4)]^(2-)and TMeQ[6]formed supramolecular self-assembly entities.

Synthesis,biological evaluation and SAR studies of benzimidazole derivatives as H_1-antihistamine agents

A series of benzimidazole derivatives have been designed, synthesized and evaluated for H1 antihistamine activity. Six compounds have showed potent antihistamine H1 activity. The primary SAR analysis indicated that benzyl or benzylidinyl substituted on the exo-nitrogen atom and C2 of the benzimidazole were significant. Further experiments indicated that compound 17d displayed excellent activity to reduce mast cell degranulation, moderate anti-PAF activity and decreased potency on hERG compared to astennizole. Hence compound 17d could serve as anti-allergic agent for further development.

Binding Mechanism and Molecular Design of Benzimidazole/Benzothiazole Derivatives as Potent Abl T3151 Mutant Inhibitors

Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.

Quantitative Structure-Activity Relationship Study of a Benzimidazole-Derived Series Inhibiting Mycobacterium tuberculosis H37Rv

This work was carried out on a series of twenty-two (22) benzimidazole derivatives with inhibitory activities against Mycobacterium tuberculosis H37Rv by applying the Quantitative Structure-Activity Relationship (QSAR) method. The molecules were optimized at the level DFT/B3LYP/6-31 + G (d, p), to obtain the molecular descriptors. We used three statistical learning tools namely, the linear multiple regression (LMR) method, the nonlinear regression (NLMR) and the artificial neural network (ANN) method. These methods allowed us to obtain three (3) quantitative models from the quantum descriptors that are, chemical potential (μ), polarizability (α), bond length l (C = N), and lipophilicity. These models showed good statistical performance. Among these, the ANN has a significantly better predictive ability R2 = 0.9995;RMSE = 0.0149;F = 31879.0548. The external validation tests verify all the criteria of Tropsha et al. and Roy et al. Also, the internal validation tests show that the model has a very satisfactory internal predictive character and can be considered as robust. Moreover, the applicability range of this model determined from the levers shows that a prediction of the pMIC of the new benzimidazole derivatives is acceptable when its lever value is lower than 1.

Benzimidazole and its derivatives as cancer therapeutics:The potential role from traditional to precision medicine

Cancer is the second leading cause of mortality globally which remains a continuing threat to human health today.Drug insensitivity and resistance are critical hurdles in cancer treatment;therefore,the development of new entities targeting malignant cells is considered a high priority.Targeted therapy is the cornerstone of precision medicine.The synthesis of benzimidazole has garnered the attention of medicinal chemists and biologists due to its remarkable medicinal and pharmacological properties.Benzimidazole has a heterocyclic pharmacophore,which is an essential scaffold in drug and pharmaceutical development.Multiple studies have demonstrated the bioactivities of benzimidazole and its derivatives as potential anticancer therapeutics,either through targeting specific molecules or non-gene-specific strategies.This review provides an update on the mechanism of actions of various benzimidazole derivatives and the structure-activity relationship from conventional anticancer to precision healthcare and from bench to clinics.

Synthesis and Crystal Structure of a Luminescent Compound 5-(1H-benzoimidazol-2-yl)-3H-[1,2,3]triazole-4-carboxylic Acid

The title compound, 5-（1H-benzoimidazol-2-yl）-3H-[1,2,3]triazole-4-carboxylic acid （CIoH.7Ns.O2.C3H7NO, M,..= 302.30）, has been synthesized and characterized by FT-IR and ES1-MS, ~H-NMR spectroscopy and X-ray single-crystal diffraction. Crystal structure of the title compound was grown from DMF by slow diffusion at room temperature. Crystal data： orthorhombic structure, space group Pna2＋ with a = 6.9635（3）, b = 19.4398（7）, c = 30.6165（12） A, V = 4144.5（3） A3, Z = 12, Dc = 1.454 g/cm3,/l（MoKa） = 0.108 mm-1, and F（000） = 1896. The structure was refined to R = 0.0450 and wR = 0.0975 for 3578 observed reflections with 1 〉 2σ（I）. The interm01ecular hydrogen bonds and π-π stacking further stabilize the structure.

Complexation of sym-bis(benzimidazole)-2,2'-ethylene salts with cucurbit[6]uril derivatives:A potential axle molecule for pseudorotaxanes

Sym-bis（benzimidazole）-2,2＇-ethylene cations act as a new axle template for threading cucurbit[6]uril derivatives on,forming[2]pseudorotaxane and[3]pseudorotaxane.These new complexes have been studied using 1 H NMR,UV-vis absorption spectroscopy and X-ray analysis.Changes in the 1 H NMR spectra indicate that the two types of pseudorotaxane can be formed by varying the host concentration. UV-vis absorption titration experiments at different pH values demonstrate that interesting pK_a shifts of the bis-benzimidazole derivatives can be induced by the host-guest complexation.The associated constants were calculated to be 2.81×10^4 L/mol and 9.06×10^6 L/mol for the[2]pseudorotaxanes and ｜3]pseudorotaxanes,respectively.Furthermore,X-ray diffraction studies of the solid state structures provide unequivocal proof of the host concentration dependent pseudorotaxane,which is strongly in line with the evidences in solution.

Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension

Optimization efforts were devoted to discover novel PDE10 A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension(PAH)starting from the previously synthesized inhibitor A.As a result,a potent and highly selective PDE10 A inhibitor,14·3 HC1(half maximal inhibitory concentration,IC50=2.8 nmol/L and>3500-fold selectivity)exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of50%was identified with the aid of efficient methods of binding free energy predictions.Animal PAH studies showed that the improvement offered by 14·3 HCl[2.5 mg/kg,oral administration(p.o.)]was comparable to tadalafil(5.0 mg/kg,p.o.),verifying the feasibility of PDE10 A inhibitors for the antiPAH treatment.The crystal structure of the PDE10 A-14 complex illustrates their binding pattern,which provided a guideline for rational design of highly selective PDE10 A inhibitors.

Metal-Organic Gels Based on Carboxyl-Functionalized Benzimidazole and Their Stimuli Responsivenesses

Three multi-responsiveness supramolecular metal-organic gels(MOGs)have been prepared upon Ba(OAc)_(2),CdSO_(4)•8H_(2)O and Pb(NO_(3))_(2) with a simple ligand(G17)based on a carboxyl-functionalized benzimidazole derivative in alcoholic-water solutions.The MOGs display the formation of well-developed nanofibrillar networks composed of intertwined fibers which provide stability to gels structures through coordination,hydrogen bonding and π-π interactions characterized by using field emission scanning electron microscopy(FESEM),the fourier transform infrared(FT-IR)spectroscopy and powder X-ray diffraction(XRD)techniques.MOG-1 shows good stimuli responsiveness toward the changes in K_(2)CrO_(4),both MOG-2 and MOG-3 do good job toward the changes in Na_(2)S.Moreover,because these MOGs were formed easily by gelator with some heavy metal ion,such as Cd(Ⅱ)and Pb(Ⅱ),it might provide the basis for heavy metal ion capture and removal.

Synthesis of 2,5-disubstitued benzimidazole using SnCl_2-catalyzed reduction system at room temperature

Stannous chloride dihydrate is used as an efficient catalyst in reductive cyclization of 2-nitro-5- substituted aniline Schiff base leading to stable 2,5-disubstitued benzimidazole derivatives in excellent yields with good purity. It provides a novel method of synthesis of 2,5-disubstitued benzimidazole under reductive system at room temperature.

Novel smart supramolecular metallo-hydrogel that could selectively recognize and effectively remove Pb^(2+) in aqueous solution

A series of novel and simple ligands based on a biscarboxyl-functionalized benzimidazole derivative were synthesized.The experiments showed that the ligand L2 as a low molecular weight(LMW) hydrogelator could form stable metallo-hydrogels in the presence of up to 0.3 equiv.of lead ions.The metallo-hydrogels were characterized using powder X-ray diffraction,scanning electron microscopy(SEM),and Fourier transform infrared(FT-IR) spectroscopic techniques.When the molar ratio of L2:Pb2+ was in the range of 1:0.3 to 1:0.5 a translucent gel was produced.When the L2:Pb2+ molar ratio was higher than 1:0.5 the resulting gel tended to be opaque.The morphologies of these metallo-hydrogels were L2/Pb ratio dependent,ranging from worm-like to rod-shaped and nanofibrous.The FT-IR and X-ray diffraction(XRD) studies revealed that L2-Pb complexation was the main driving force for the formation of the metallo-hydrogels.In addition,these metallo-hydrogels exhibited outstanding thermostability and thermoreversibility,and displayed a reversible sol-gel transition induced by changes in pH and EDTA concentration.Importantly,ligand L2 showed an excellent capacity for the removal of Pb 2+ in aqueous solution through the formation of metallo-hydrogels.At a L2:Pb molar ratio of 1:0.5 and below,the concentration of residual Pb2+ was as low as 7.6×10-5 mol/L in aqueous solution,and the removal ratio was as high as 95.4%.These results demonstrate that multi-channel responsive smart metallo-hydrogels have the potential to be widely applied in materials science,and might provide the basis for lead pollution capture and removal.

Multi-stimuli responsive metal-organic gel of benzimidazol-based ligands with lead nitrate and their use in removal of dyes from waste-water

A novel smart metal-organic gel（MOG） formed from biscarboxyl-functionalized benzimidazole derivative（D11） in the presence of lead nitrate has been investigated.The critical gel concentration for the formation of MOG was just 0.36 wt%,which exhibits a super gelation capability of D11.The coordination of the metal to the ligand D11 was found to play a vital role in the construction of the supramolecular MOG.Microstructures determined by SEM observation demonstrated that the MOG was formed by intertwined fibrils.Interestingly,the MOG exhibits pH-induced,thermo-induced,and chemical-induced reversible gel-sol transition.Meanwhile,this supramolecular MOG shows desirable absorption ability of methyl orange dye molecules in aqueous solution.