2-aminobenzimidazole Derivatives Research Articles

Novel Sulfone 2-Aminobenzimidazole Derivatives and Their Coordination Compounds: Contribution of the Ethyl and Phenyl Substituents on Non-Covalent Molecular Interactions; Biological Antiproliferative Activity

New sulfone 2-aminobenzimidazole derivatives were designed and synthesized. Their nickel(II), copper(II), zinc(II), cadmium(II) and mercury(II) compounds were obtained and fully characterized by spectroscopic and analytical techniques. Single crystal X-ray structural analysis was performed in order to study the relevant intra and inter non-covalent interactions, mainly H···π, lone pair···π, and π···π, highlighting the difference between the terminal ethyl and phenyl groups in such interactions. Dimeric and trimeric supramolecular syntons were found for some of these compounds. Additionally, their antiproliferative activity was investigated, finding that the copper(II) compounds with the sulfone phenyl derivative were the most active.

Synthesis, Characterization, ADME Study and Antimicrobial Evaluation of New 1,2,3-triazole Derivatives of 2-phenyl benzimidazole.

Novel 2-amino benzimidazole derivatives containing amide, azide and 1,2,3-triazole moieties have been synthesized. Compound 3 was synthesized by reaction of o-phenylenediamine with p-aminobenzoic acid. Compound 3 was converted into amide by treatment with chloroacetyl chloride to get compound 4. Compound 4 and sodium azide were combined to create compound which has an azide group. Compound 5 was converted into 1,2,3-triazole derivatives by treatment with acetylene derivatives. FTIR, 1H-NMR, and Mass spectra have been used to confirm the chemical structures of various substances. By using a technique called well diffusion agar, the final products were examined in vitro to predict activity against two kinds of gram-positive bacteria and two kinds of gram-negative bacteria as well as the antifungal activity against Candida albicans fungus. All the final products exhibited moderate to potent activity compared to Trimethoprim and Fluconazole as reference antibacterial and antifungal drugs respectively. Swiss ADME was also used to undertake ADME tests to determine the bioavailability, drug-likeness and topological polar surface area of the synthesized molecule. The results showed that every chemical tested was absorbed orally and followed the Lipinski rule.

Derivatives of 2-aminobenzimidazole potentiate ASIC open state with slow kinetics of activation and desensitization.

The pharmacology of acid-sensitive ion channels (ASICs) is diverse, but potent and selective modulators, for instance for ASIC2a, are still lacking. In the present work we studied the effect of five 2-aminobenzimidazole derivatives on native ASICs in rat brain neurons and recombinant receptors expressed in CHO cells using the whole-cell patch clamp method. 2-aminobenzimidazole selectively potentiated ASIC3. Compound Ru-1355 strongly enhanced responses of ASIC2a and caused moderate potentiation of native ASICs and heteromeric ASIC1a/ASIC2a. The most active compound, Ru-1199, caused the strongest potentiation of ASIC2a, but also potentiated native ASICs, ASIC1a and ASIC3. The potentiating effects depended on the pH and was most pronounced with intermediate acidifications. In the presence of high concentrations of Ru-1355 and Ru-1199, the ASIC2a responses were biphasic, the initial transient currents were followed by slow component. These slow additional currents were weakly sensitive to the acid-sensitive ion channels pore blocker diminazene. We also found that sustained currents mediated by ASIC2a and ASIC3 are less sensitive to diminazene than the peak currents. Different sensitivities of peak and sustained components to the pore-blocking drug suggest that they are mediated by different open states. We propose that the main mechanism of action of 2-aminobenzimidazole derivatives is potentiation of the open state with slow kinetics of activation and desensitization.

Novel fragment-derived colchicine-site binders as microtubule-destabilizing agents

Microtubules (MTs) are dynamic filaments of the cytoskeleton, which are formed by the polymerization of their building block tubulin. Perturbation of MT dynamics by MT-targeting agents (MTAs) leads to cell cycle arrest or cell death, a strategy that is pursued in chemotherapy. We recently performed a combined computational and crystallographic fragment screening approach and identified several tubulin-binding fragments. Here, we sought to capitalize on this study with the aim to demonstrate that low affinity tubulin-binding fragments can indeed be used as valuable starting points for the development of active, lead-like antitubulin small molecules. To this end, we report on a new, rationally designed series of 2-aminobenzimidazole derivatives that destabilize MTs by binding tubulin at the colchicine-binding site (CBS). We applied a fragment growing strategy by combining X-ray crystallography and computer-aided drug design. Preliminary structure-activity-relationship studies afforded compound 18 that inhibits HeLa cell viability with a submicromolar activity (IC50 of 0.9 μM). X-ray crystallography confirmed the compound pose in the CBS, while immunostaining experiments suggested a molecular mechanism of action alike classical CBS ligands with antimitotic and antitumor activity associated with MTs destabilization. This promising outcome underpins that our previously performed combined computational and crystallographic fragment screening approach provides promising starting points for developing new MTAs binding to the CBS of tubulin and, eventually, to further tubulin pockets.

Anti-Angiogenetic and Anti-Lymphangiogenic Effects of a Novel 2-Aminobenzimidazole Derivative, MFB.

Background and PurposeBenzimidazoles have attracted much attention over the last few decades due to their broad-spectrum pharmacological properties. Increasing evidence is showing the potential use of benzimidazoles as anti-angiogenic agents, although the mechanisms that impact angiogenesis remain to be fully defined. In this study, we aim to investigate the anti-angiogenic mechanisms of MFB, a novel 2-aminobenzimidazole derivative, to develop a novel angiogenesis inhibitor.Experimental ApproachMTT, BrdU, migration and invasion assays, and immunoblotting were employed to examine MFB’s effects on vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration, invasion, as well as signaling molecules activation. The anti-angiogenic effects of MFB were analyzed by tube formation, aorta ring sprouting, and matrigel plug assays. We also used a mouse model of lung metastasis to determine the MFB’s anti-metastatic effects.Key ResultsMFB suppressed cell proliferation, migration, invasion, and endothelial tube formation of VEGF-A-stimulated human umbilical vascular endothelial cells (HUVECs) or VEGF-C-stimulated lymphatic endothelial cells (LECs). MFB suppressed VEGF-A and VEGF-C signaling in HUVECs or LECs. In addition, MFB reduced VEGF-A- or tumor cells-induced neovascularization in vivo. MFB also diminished B16F10 melanoma lung metastasis. The molecular docking results further showed that MFB may bind to VEGFR-2 rather than VEGF-A with high affinity.Conclusions and ImplicationsThese observations indicated that MFB may target VEGF/VEGFR signaling to suppress angiogenesis and lymphangiogenesis. It also supports the role of MFB as a potential lead in developing novel agents for the treatment of angiogenesis- or lymphangiogenesis-associated diseases and cancer.

New C2- and N3-Modified Thieno[2,3-d]Pyrimidine Conjugates with Cytotoxicity in the Nanomolar Range.

The aim of the current study was to develop and explore a series of new cytotoxic agents based on the conjugation between the thieno[2,3-d]pyrimidine moiety and a second pharmacophore at the C2 or N3 position. As the thieno[2,3-d]pyrimidine core is a bioisostere of the 4-anilinoquinazoline, various new thienopyrimidine derivatives were synthesized by modifying the structure of the clinically used anticancer quinazoline EGFR inhibitors of the first generation - gefitinib, and second-generation - dacomitinib and canertinib. It was reported that some thieno[2,3-d]pyrimidine derivatives showed improved EGFR inhibitory activity. On the other hand, the benzimidazole heterocycle is present as a pharmacophore unit in the structure of many clinically used chemotherapeutic agents. Some 2-aminobenzimidazole derivatives, possessing anticancer activity, demonstrated EGFR inhibition and the benzimidazole derivative EGF816 is currently in the second phase of clinical trials. The objectives of the study were the design of a novel series thieno[2,3-d]pyrimidines, synthesis of the compounds and investigation of their effects towards human cancer HT-29, MDA-MB-231, HeLa, HepG2 and to normal human Lep3 cell lines. (American Type Culture Collection, ATCC, Rockville, MD, USA). The synthetic protocol implemented cyclocondensation of 2-amino-thiophenes and nitriles in an inert medium, aza- Michael addition to benzimidazole derivatives and nucleophylic substitution at the N3 place. MTS test was used in order to establish the cytotoxicity of the tested compounds. SAR analysis and in silico assessment of the inhibitory potential towards human oncogenic V599EB-Raf were performed using Molinspiration tool and Molecular Operating environment software. The MTS test data showed that almost all studied thieno[2,3-d]pyirimidines (9-13, 21-22 and 25) manifest high inhibitory effect on cell proliferation at nanomolar concentrations, whereas compounds 9 (IC50 = 130 nM) and 10 (IC50 = 261 nM) containing amino acid moiety, and 21 (IC50 = 108 nM) possessing two thienopyrimidine moieties attached to a 1,3-disubstituted benzimidazole linker, revealed many times lower toxicity against Lep3 cells compared to the cancer cells. Thienopyrimidines 11-13 possessed high selectivity against HeLa cells. Compound 13 showed high inhibitory activity against MDA-MB-231 and HepG2, with IC50 1.44 nM and 1.11 nM respectively. To outline the possible biological target of the studied coumpounds, their potential to interact with human oncogenic V599EB-Raf was explored by a docking study. As a result, it was suggested that the benzimidazolyl and glycyl fragments could enhance the binding ability of the new compounds by increasing the number of hydrogen bond acceptors and by stabilizing the inactive form of the enzyme. The thienopyrimidines tested in vitro for human cancer HT-29, MDA-MB-231, HeLa, HepG2 and normal human Lep3 cell lines demonstrated cytotoxicity in the nanomolar range. It was established that compounds 9, 10 and 21 showed many times lower toxicity against normal Lep3 cells that can provide a high selectivity towards all four cancer cell lines at small concentrations. Based on the analysis of the structure-activity relationship, the observed trends in the cytotoxicity could be related to the lipophilicity and the topological polar surface area of the tested compounds. The docking study on the potential of the new thieno[2,3-d]pyrimidine-4-ones to interact with mutant V599EB-Raf showed that the compounds might be able to stabilize the enzyme in its inactive form.

Design, Synthesis and Biological Evaluation of 2-Aminobenzimidazole Derivatives as DPP4 Inhibitors

Background: The objective of the research was to examine the DPPIV inhibitor activity of synthetic derivatives of 2-aminobenzimidazole derivatives by the in-vivo method. Methods: Molecular docking was performed using homology model of receptors to identify the binding sites for the inhibitory activity of diabetes by means of- CDocker energy using the Discovery Studio (DS) 4.5 Novel 2-amino benzimidazole derivatives were synthesized from orthophenylene diamine with cyanogens bromide. The synthesized compounds were identified by IR,1HNMR,13CNMR, and MASS spectroscopic techniques. The products were analyzed for their DPPIV inhibitory effects on Wistar Albino rat. Results: The results revealed that benzimidazole with para-aminobenzoic acid possesses best DPPIV inhibitor activity. 2- amino benzimidazole incorporated with aromatic compounds were synthesized and assessed for their DPP-IV inhibitor activity. Conclusion: 2- amino benzimidazole with para-aminobenzoic acid can be used as a lead compound for the development of a new class of DPP-IV inhibitor.

Design, synthesis and evaluation of 2-aminobenzimidazole derivatives: strong candidate for PPAR gamma agonists.

Design, synthesis and evaluation of 2-aminobenzimidazole derivatives: strong candidate for PPAR gamma agonists.

2-aminobenzimidazole derivative with surface activity as corrosion inhibitor of carbon steel in HCl: Experimental and theoretical study

The 2-aminobenzimidazole (ABI) derivative with surface activity, namely, 2-(n-hexylamino)-4-(3-N,N-dimethylaminopropyl)amino-6-(2-aminobenzimidazol)-1,3,5-s-triazine (BDCT) was synthesized and its effect on the corrosion of carbon steel in 1 M HCl solution was compared with ABI through weight loss method, electrochemical measurement, and scanning electron microscopy (SEM). The adsorption performances were studied by surface tension method, quantum chemical calculation and molecular dynamics simulation. The results revealed that BDCT acted as a mixed type inhibitor, and its inhibition efficiency showed an improvement of about 40% over ABI.

IN SILICO DESIGN, SYNTHESIS AND EVALUATION OF IN VITRO GLUCOSE UPTAKE, GENE EXPRESSION, AND α-GLUCOSIDASE INHIBITORY ACTIVITY OF NOVEL 2-AMINOBENZIMIDAZOLE DERIVATIVES

Objective: The present study was aimed to design and evaluate the antidiabetic potential of novel 2-aminobenzimidazole derivatives by in silico method.
 Materials and Methods: Various in silico tools such as Chemsketch, Molinspiration, Prediction of activity spectra for substances, OpenBabel, Discovery Studio was used in the designing and evaluation of the biological activity. The retrieved hits were further filtered by absorption, distribution, metabolism, and excretion descriptors. The designed molecules having required physicochemical properties, drug-likeness, and obeying Lipinski’s rule of five were selected for the synthesis. The synthesized compounds were subjected to determination of yield, melting point and characterized by infrared, 1HNMR, 13CNMR, and mass spectroscopic methods. The selected derivatives were subjected to in vitro glucose uptake, 50% lethal dose (LD50) determination, gene expression analysis, and α-glucosidase inhibitory assay.
 Results: Totally, 32 novel analogs of 2-aminobenzimidazole were designed and 17 compounds were selected for docking analysis; and finally, five derivatives (3a, 3c, 3e, 3f, and 3h) were selected for synthesis. Among them, the compounds 3a and 3f were selected for in vitro glucose uptake analysis. Finally, the compound 3f was selected for LD50 determination, gene expression analysis, and α-glucosidase inhibitory assay. The selected derivative 3f showed a significant α-glucosidase inhibitory activity compared with the standard drug acarbose.
 Conclusion: These results are useful for further investigation in the future, and hopefully, these studies could discover a new specific leads in antidiabetic category as α-glucosidase inhibitor.

A Novel One-pot Protocol for the Cu-Catalyzed Synthesis of Nine 2-Aminobenzimidazole Derivatives from o-Phenylenediamine and Trichloroacetonitrile

The synthesis of a variety of 2-aminobenzimidazoles via a one pot reaction of ophenylenediamine and trichloroacetonitrile catalyzed by copper (II) acetate in THF at room temperature, with good yields is described. Use of simple and readily available starting materials, good to high yields, free ligand, and no column chromatography are important features of this protocol.

Microwave Assisted Synthesis of Pyrazolo[1,5-a]pyrimidine, Triazolo[1,5-a]pyrimidine, Pyrimido[1,2-a]benzimdazole, Triazolo[5,1-c][1,2,4]triazine and Imidazo[2,1-c][1,2,4]triazine

Background: This paper describes the synthesis of novel fused heterocycles, from the reaction 2-cyano-N-cyclohexyl-3-acrylamide derivatives 5a-f with nitrogen nucleophilic reagents, which carried out under microwave irradiation. Reactivity of 3 towards diazonium amines salts to afford hydrazones undergo cyclization to give amino pyrazole and the fused heterocyclic compounds incorporating cyclohexyl moiety. The synthesized compounds excellently utilized microwave irradiation in short time and high yield. Methods: Synthesis of Fused heterocycles derivatives from 2-cyano-N-cyclohexyl acetamide utilizing Microwave irradaition. Results: Regioselective facile synthesis of innovative heterocycles from the reaction of 2-cyano-Ncyclohexyl acetamide (3) with appropriate aldehydes to afford the corresponding acrylamide derivatives 5a-f under microwave irradiation. Acrylamides 5 reacts with hydrazine derivatives affording the corresponding pyrazole derivatives 7a and 7b, furthermore the treatment of acrylamides 5 with 2-amino benzimidazole, amino pyrazole, and aminotriazole derivatives to gives corresponding pyrimido[1,2-a]benzimdazole 10, pyrazolo[1,5-a]pyrimidine 12 and triazolo[1,5-a]pyrimidine 14; respectively in good yield. Reactivity of 3 towards diazonium amines salts afforded hydrazones derivatives, which undergo cyclization to give the corresponding derivatives 19a and the fused pyrazolo[5,1-c][1,2,4]triazine 22, triazolo[5,1-c][1,2,4]triazine 24 and imidazo[2,1-c][1,2,4]triazine 28 incorporating cyclohexyl moiety. Conculsion: In this investigation, we have synthesized innovative pyrimido[1,2-a]benzimdazole, and triazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyrimidine, 2-amino benzimidazole, amino pyrazole, aminotriazole, fused pyrazolo[5,1-c][1,2,4]triazine, triazolo[5,1-c][1,2,4]triazine and imidazo[2,1- c][1,2,4]triazine derivatives incorporating cyclohexyl moiety utilizing microwave irradiation. The compounds were obtained under microwave reaction in excellent yield in a short reaction time.

Using 2-aminobenzimidazole derivatives to inhibit Mycobacterium smegmatis biofilm formation.

Biofilm formation by mycobacteria can lead to enhanced antibiotic tolerance. Herein, we report on the identification of a series of 2-aminobenzimidazole (2-ABI) derivatives that potently inhibit biofilm formation by Mycobacterium smegmatis.

Iodine-mediated direct synthesis of multifunctional 2-aminobenzimidazoles from N-substituted o-diaminoarenes and isothiocyanates

Multifunctional 2-aminobenzimidazoles were directly synthesized through sequential addition of N-substituted o-diaminoarenes to isothiocyanates, formation of carbodiimides via I2-mediated oxidative desulfurization, and intramolecular cycloaddition. This efficient and eco-friendly synthetic process provides a facile access to diverse 2-aminobenzimidazole derivatives from readily accessible substrates under mild reaction conditions in a scalable fashion.

Retraction statement: ‘Microwave Assisted Synthesis of Trifluoro Substituted 2‐Aminobenzimidazole Derivatives via Iodoactic Acid Mediated One‐pot Condensation’ by R. Sriram, R. Sapthagiri, L. Ilavarasan and A. Ravi

Retraction statement: ‘Microwave Assisted Synthesis of Trifluoro Substituted 2‐Aminobenzimidazole Derivatives <i>via</i> Iodoactic Acid Mediated One‐pot Condensation’ by R. Sriram, R. Sapthagiri, L. Ilavarasan and A. Ravi

The Discovery of 2‐Aminobenzimidazoles That Sensitize Mycobacterium smegmatis and M. tuberculosis to β‐Lactam Antibiotics in a Pattern Distinct from β‐Lactamase Inhibitors

A library of 2-aminobenzimidazole derivatives was screened for the ability to suppress β-lactam resistance in Mycobacterium smegmatis. Several non-bactericidal compounds were identified that reversed intrinsic resistance to β-lactam antibiotics in a manner distinct from β-lactamase inhibitors. Activity also translates to M. tuberculosis, with a lead compound from this study potently suppressing carbenicillin resistance in multiple M. tuberculosis strains (including multidrug-resistant strains). Preliminary mechanistic studies revealed that the lead compounds act through a mechanism distinct from that of traditional β-lactamase inhibitors.

Synthesis, characterization and biological studies of copper(II) complexes with 2-aminobenzimidazole derivatives

Novel series of four copper(II) complexes with 2-aminobenzimidazole derivatives (obtained from the Knoevenagel condensate of acetylacetone (obtained from acetylacetone and halogen substituted benzaldehydes) and 2-aminobenzimidazole) were synthesized. They were structurally characterized using elemental analysis, molar conductance, FAB mass, FT- IR, 1H &13C-NMR, UV–Vis., and EPR techniques. On the basis of analytical and spectral studies, the distorted square planar geometry was assigned for all the complexes. The antibacterial screening of the ligands and their copper complexes indicated that all the complexes showed higher anti microbial activities than the free ligands. Superoxide dismutase and antioxidant activities of the copper complexes have also been performed. In the electrochemical technique, the shift in ΔEp, E1/2 and Ipc values were explored for the interaction of the complexes with CT-DNA. During the electrolysis process, the present ligand system stabilizes unusual oxidation state of copper in the complexes. It is believed that the copper complexes with curcumin analogs may enhance chemotherapeutic behavior.

Heterocycle-based bifunctional organocatalysts in asymmetric synthesis

AbstractDifferent chiral bifunctional organocatalysts derived fromtrans-cyclohexane-1,2-diamine bearing different types of guanidine units able to form-hydrogen bonding activation have been designed. Conformational rigid 2-aminobenzimidazoles bearing a tertiary amino group have been used in enantioselective Michael type reactions of activated methylene compounds to nitroalkenes. The C2symmetric bis(2-aminobenzimidazole) derivatives the appropriate organocatalyst for the conjugate addition of 1,3-dicarbonyl compounds to maleimides as well as for the SN1 reaction of benzylic alcohols with carbon nucleophiles. 2-Aminobenzimidazoles bearing a primary amino group have shown excellent catalytic activity in the Michael reaction of aldehydes to maleimides and nitroalkenes. Diastereomeric 2-aminopyrimidines bearing a prolinamide unit have been incorporated in thetrans-cyclohexane-1,2-diamine scaffold and have been used for the inter- and intra-molecular direct aldol reaction under solvent-free conditions. For the Michael reaction of aldehydes with maleimides the primary amine 2-aminopyrimidine has shown excellent efficiency as organocatalyst. The bifunctional character of these organocatalysts has been demonstrated by means of DFT calculations.

Organocatalytic Asymmetric α-Chlorination of 1,3-Dicarbonyl Compounds Catalyzed by 2-Aminobenzimidazole Derivatives

Bifunctional chiral 2-aminobenzimidazole derivatives 1 and 2 catalyze the enantioselective stereodivergent α-chlorination of β-ketoesters and 1,3-diketone derivatives with up to 50% ee using N-chlorosuccinimide (NCS) or 2,3,4,4,5,6-hexachloro-2,5-cyclohexadien-1-one as electrophilic chlorine sources.

Novel Synthesis and Characterization of 2-Aminobenzimidazole Derivative

Novel Synthesis and Characterization of 2-Aminobenzimidazole Derivative