Substituted Benzimidazole Derivatives Research Articles

New insight into the bioactivity of substituted benzimidazole derivatives: Repurposing from anti-HIV activity to cell migration inhibition targeting hnRNP M

Drug repurposing is a distinguished approach for drug development that saves a great deal of time and money. Based on our previous successful repurposing of a compound BMMP from anti-HIV-1 therapy to anti-cancer metastatic activity, we adopted the same techniques for repurposing benzimidazole derivatives considering MM-1 as a lead compound. An extensive structure–activity relationship (SAR) study afforded three promising compounds, MM-1d, MM-1h, and MM-1j, which inhibited cell migration in a similar fashion to BMMP. These compounds suppressed CD44 mRNA expression, whereas only MM-1h further suppressed mRNA expression of the epithelial-mesenchymal transition (EMT) marker zeb 1. Using benzimidazole instead of methyl pyrimidine as in BMMP resulted in better affinity for heterogeneous nuclear ribonucleoprotein (hnRNP) M protein and higher anti-cell migration activity. In conclusion, our study identified new agents that surpass the affinity of BMMP for hnRNP M and have anti-EMT activity, which makes them worthy of future attention and optimization.

Design, Synthesis, Pharmacological Screening and Molecular Docking Study of New Substituted Benzimidazole Derivatives

Design, Synthesis, Pharmacological Screening and Molecular Docking Study of New Substituted Benzimidazole Derivatives

Development of bioactive 2-substituted benzimidazole derivatives using an MnOx/HT nanocomposite catalyst.

Benzimidazole is a vital moiety found in a wide range of naturally and pharmacologically active molecules. We prepared a proficient and facile manganese oxide-supported magnesium and aluminium-based nanocomposite catalytic framework using the deposition-precipitation method and characterised it with XRD, XPS, SEM, TEM, and TGA techniques. Following that, the catalyst was used in the green synthesis of highly functional 2-substituted benzimidazole derivatives in an ethanol-water solvent system at room temperature using various assorted benzaldehydes and o-phenylenediamine as substituents. The synthesised catalyst operates efficiently and is applicable to a wide range of electron-withdrawing and electron-donating substrates, resulting in good to excellent yields. The advantages of this process include the use of a greener solvent, high yield, high conversions, no use of additives or bases, a good TOF, and a shorter reaction time.

Photochemically induced chloromethylation/cyclization of benzimidazole derivatives with CCl4/CHCl3.

Herein, it is reported that a series of trichloromethyl/dichloromethyl substituted benzimidazole derivatives have been synthesized by dechlorination of CCl4/CHCl3 to form polychloromethyl radicals and cyclization with an unactivated olefin under a purple LED lamp. The protocol features a wide substrate scope, high atom economy, and excellent regioselectivity, and is easy to scale up.

Facile one pot synthesis of 2-substituted benzimidazole derivatives under mild conditions by using engineered MgO@DFNS as heterogeneous catalyst.

Benzimidazole derivatives are considered as important heterocyclic motifs that show a wide range of pharmaceutical applications. In view of their wide-ranging bioactivities, it is imperative to direct research on the sustainable catalytic synthesis of benzimidazole. Therefore, herein, we report a novel approach for the synthesis of benzimidazole and its derivatives with engineered MgO supported on dendritic fibrous nano silica (MgO@DFNS) as a sustainable heterogeneous catalyst. The catalyst MgO@DFNS was thoroughly characterized to understand its physio-chemical properties using XRD, FE-SEM, XPS, FT-IR, zeta potential, HR-TEM, TGA, TPR and TPD. The obtained results suggested that the catalyst MgO@DFNS prepared well and have the desired characteristics in it. After the successful characterisation of the prepared catalyst MgO@DFNS, it was applied in the synthesis of benzimidazole derivatives via condensation of o-phenylenediamine, and various aromatic and aliphatic aldehydes under ambient temperature. The catalyst produced a clean reaction profile with excellent yields in a shorter time under the umbrella of green chemistry. The effect of reaction parameters such as the effect of time, catalyst dosage, loading of MgO, effect of solvents and effect of different homo and heterogeneous catalyst were also tested. Furthermore, to understand the scope of the catalyst different substituted diamines and substituted aldehydes were reacted and obtained desired products in good to efficient yield. In addition, a recyclability study was also conducted and it was observed that the catalyst could be recycled for up to six cycles without noticeable changes in the morphology and activity. We believe that the present methodology gave several advantages such as an eco-friendly method, easy work-up, good selectivity, high yields and quick recovery of catalyst. MgO@DFNS is highly stable for several cycles without significant loss of its activity, which possibly demonstrates its applicability at the industrial scale.

One-pot Synthesis of Substituted Benzimidazole Derivatives under Ultrasonic Irradiation Using ZnFe2O4 Reusable Catalyst

Herein, an efficient one-pot synthesis is described, of substituted benzimidazole derivatives (3a-j) from a condensation of various o-phenylenediamine (1a-j) aromatic aldehyde (2a-j) using ZnFe2O4 as a nano-catalyst under ultrasonic irradiation conditions. All forms of aldehydes with an electron releasing or electron –withdrawing substituent have a significant yield. The catalyst can easily be recovered after completion of the reaction and reused without affecting its activity. Prepared benzimidazole derivatives showed moderate to good anti-tuberculosis results.

BMPTFB]-ionic liquid as an efficient catalyst for the rapid, and eco-friendly synthesis of benzimidazole, 2-substituted benzimidazole, and benzothiazole derivatives at room temperature

We wish to report an easy, mild, and effective procedure for the synthesis of benzimidazole, 2-substituted benzimidazole, and benzothiazole derivatives by employing 1-butyl-1-methylpiperidinium tetrafluoroborate [BMPTFB]-ionic liquid as a catalyst in ethanol at room temperature. The reaction between 1,2-diamines and various aldehydes/some organic acids in presence of the catalyst allowed to result in the targeted product(s). The features of this protocol are short reaction time, ease of handling of the catalyst, mild reaction conditions, and moderate to high yield of the product.

An elegant approach for selective synthesis of 2-substituted benzimidazoles at room temperature using Ag nanoparticles as an activator: effect of solvent on the selectivity

An expedient, competent, and green protocol was developed for the selective synthesis of 2-substituted benzimidazole by the condensation of 1,2-diaminobenzene and various aldehydes, including aromatic, heteroaromatic, and aliphatic aldehydes, in methanol and water (1:1) as reaction media in the presence of Ag nanoparticles in a one pot operation at room temperature. The selectivity of the protocol for obtaining 2-substituted benzimidazole is highly dependent on the ratios of methanol and water used, as well as the reaction temperature. The present protocol exhibits several advantages, such as high yield, short reaction time, high selectivity, and no side reaction, and it works at room temperature, which makes this methodology green, providing a practical input to the existing procedures available for the synthesis of 2-substituted benzimidazole derivatives.

DESIGN, SYNTHESIS AND EVALUATION OF PYRAZOLE SUBSTITUTED BENZIMIDAZOLE AS AN ANTI-TUBERCULAR, ANTI-FUNGAL AND ANTI-MICROBIAL AGENT

Objective: A series of pyrazole substituted benzimidazole derivatives were subjected to in silico studies to identify a new lead for anti-tubercular, antimicrobial and antifungal activity. Methods: Docking studies was carried out against Mycobacterium tuberculosis InhA bound with ETH-NAD adduct-PDB ID: 2H9I and Crystal structure of S. aureus TyrRS in complex with SB-239629-PDB ID: 1JIJ. Results: Based on the binding interactions, binding energies, and ADMET predictions, the most active compounds were produced, consisting of a para-halo phenyl substitution at the pyrazole nucleus that was connected to benzimidazole. The synthesized compounds were evaluated for tuberculostatic activity using microplate Almar blue assay method, and anti-microbial and anti-fungal activity by disc diffusion method. Conclusion: Compound 5c with chloro substituted phenyl ring on the pyrazole showed moderate anti-tubercular, mild antifungal and anti-microbial activity. This compound may thus represent a novel, multi target molecule having a selective class of anti-tubercular, anti-fungal and anti-microbial activity.

Design, Synthesis and Pharmacological Evaluation of Novel Benzimidazole Derivatives as Anticancer Agents

Background: Cancer is undoubtedly a major challenge of modern era and is the second leading cause of death in the world. Lung cancer is the second most common cancer and the leading cause of cancer death among men and women. Non-Small Cell Lung Cancer (NSCLC) accounts for 84% of all lung cancer diagnosed. Benzimidazoles are important heterocyclic compounds possessing a variety of biological activities such as anticancer, antioxidant, anti-inflammatory, and analgesic, anti-viral, anti-bacterial, anti-fungal and hypoglycemic activities. Pyrazolines reported antitumor, immunosuppressive, antibacterial and anti tubercular agents. Biological activities of the benzimidazole derivatives depend on the functional group attached to the benzimidazole moiety. Objective: The present research focused on incorporating pyrazoline nucleus into benzimidazole nucleus to form a potent anticancer agent targeting lung cancer therapy. Method: The in silico novel pyrazoline substituted benzimidazole derivatives were designed. Docking was performed to know the binding interactions of the newer agents with the enzymes. The compounds were found to be active in docking studies synthesized and tested for anticancer activity. In vitro screening of the selected derivatives for anticancer activity by MTT assay method showed very good results. Cytotoxicity of compounds BZ1, BZ2, BZ10 and BZ16 studied against fibrosarcoma and lung cancer cell line. Results: The compound BZ1 showed highest activity against fibrosarcoma and lung cancer cell line. Conclusion: Further studies on these compounds to prove it as a lead compound in cancer therapy should be conducted.

Cytotoxic activity evaluation of naphthalene substituted benzimidazole derivatives

Cytotoxic activity evaluation of naphthalene substituted benzimidazole derivatives

2-Phenyl substituted Benzimidazole derivatives: Design, synthesis, and evaluation of their antiproliferative and antimicrobial activities

The inability to meet the desired outcomes of anticancer treatment and decrease in treatment success of bacterial and fungal infections accelerated research in these areas. Our research group has conducted numerous studies, especially on benzimidazole ring systems’ antiproliferative and antimicrobial activities. In this study, the antiproliferative activity of benzimidazole compounds was tested against A549, A498, HeLa, A375, and HepG2 cancer cell lines by MTT assay. All compounds exhibited good to potent antiproliferative activity against all tested cancer cell lines. Compounds 6-chloro-2-(4-fluorobenzyl)-1H-benzo[d]imidazole (30) and 6-chloro-2-phenethyl-1H-benzo[d]imidazole (46) were especially active against HeLa and A375 cancer cell lines with IC50 values in the range of 0.02–0.04 µM. In contrast, compounds 6-chloro-2-((p-tolyloxy)methyl)-1H-benzo[d]imidazole (67) and 5(6)-chloro-2-((4-hydroxyphenoxy)methyl)-1H-benzimidazole (68) were active against A549 and A498 cancer cell lines with an IC50 value of 0.08 µM. These compounds (30, 46, 67, and 68) were less toxic to normal human cells than the positive control compound methotrexate, which was screened to determine its toxicity against normal cell lines (HEK293). In the second part of the study, all compounds were tested to demonstrate their antimicrobial properties. All compounds exhibited moderate activity against all tested bacteria and fungi. However, some phenoxy methyl derivatives 5-chloro-2-((4-chlorophenoxy)methyl)-1H-benzo[d]imidazole (69) and 5,6-dichloro-2-((4-chlorophenoxy)methyl)-1H-benzo[d]imidazole and (74) were most active against Candida (<3.90 µg/mL). Molecular docking studies were carried out against certain proteins in order to identify potential targets of the antiproliferative effects of the synthesized compounds. The docking scores of the compounds were found to be significantly compatible with the antiproliferative activity results. Graphical abstract

Design, synthesis, characterization and pharmacological screening of some novel 2 substituted and 1(h)-substituted Benzimidazole derivatives

The most of drugs containing Benzimidazole ring is a prominent structural motif found in numerous therapeutically active compounds. Benzimidazole and its synthetic analogues have been found to exhibit industrial, agricultural and biological application such asantitubercular, anti-inflammatory, analgesic, anticancer, anticoagulant, as well as good antifungal and anti microbial activity.Recent advances in technology considers microwave irradiation energy as the most efficient means of heating reactions for chemical transformations that can be accomplished in a minutes. Microwave irradiation assists organic synthesis (MAOS) not only help in implementing green chemistry but also led to progress in organic synthesis. We report pharmacological screening of some novel 2 substituted and 1(h)-substituted Benzimidazole derivatives.

Computational study reveals substituted benzimidazole derivatives' binding selectivity to PI3Kδ and PI3Kγ.

Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. Class IA PI3K isoforms γ and δ share a highly homologous ATP binding site and are distinguished by only a few residues around the binding site. Subtype-selective inhibitors have been proven to have great advantages in tumor treatment. Preliminary studies have obtained PI3K inhibitors bearing a benzimidazole structural motif with a certain selectivity for PI3Kδ and PI3Kγ subtypes. On this basis, we investigated the selective inhibitory mechanism of PI3Kδ and PI3Kγ using four developed inhibitors via molecular docking, molecular dynamics, binding free energy calculations, and residue energy decomposition. This study could provide references for the further development of PI3K-isoform-selective inhibitors.

One‐step synthesis of novel N1‐substituted benzimidazole derivatives: Experimental and theoretical investigations

AbstractIn this work, we describe a simple and efficient route for the synthesis of novel N1‐substituted benzimidazole derivatives (8–14) by a rearrangement reaction of N1‐alkyl‐1,5‐benzodiazepine‐2‐thiones (1–7) in the presence of hydroxylamine hydrochloride in boiling ethanol. Good to excellent yields were achieved for a wide range of alkyl partners with both short‐chain and long‐chain substituents. The title products were identified using 1H and 13C‐NMR spectroscopic measurements and confirmed by single‐crystal X‐ray diffraction techniques for 8–10. In addition, we performed theoretical studies of 8–10 using Hirshfeld surface analysis, molecular docking studies and, along with experimental data. The predicted spectral data were obtained using density functional theory (DFT) at the B3LYP/6‐311++G(d,p) level of theory. Also, according to Monte Carlo simulations, the inhibition trend is 10 &gt; 8 &gt; 9 toward all metals in an acidic environment. Good inhibition performance is predicted for iron as compared to copper and aluminum metals.

Synthesis, Characterization and Pharmacological Screening of Some Novel 2- substituted and 1(H)-substituted Benzimidazole Derivatives as potent Anti-cancer agents

The most of drugs containing Benzimidazole ring is a prominent structural motif found in numerous therapeutically active compounds. Benzimidazole and its synthetic analogues have been found to exhibit industrial, agricultural and biological application such as antitubercular, anti-inflammatory, analgesic, anticancer, anticoagulant, as well as good antifungal and anti microbial activity. Recent advances in technology considers microwave irradiation energy as the most efficient means of heating reactions for chemical transformations that can be accomplished in a minutes. Microwave irradiation assists organic synthesis (MAOS) not only helps in implementing green chemistry but also led to progress in organic synthesis. We report pharmacological screening of some novel 2 substituted and 1(h)-substituted Benzimidazole derivatives.

Synthesis, characterization and anti HIV1 screening of some novel clubbed benzimidazole derivatives

A humble and a competent technique was improved in production of novel substituted benzimidazole derivatives by the condensation of various diamines with 2-amino-benzoic acid and many substituted benzoyl chloride reactions have demonstrated the benefits of classical reactions; convenient operation, and good yields. Finally, it has treated with phosphorous pentachloride and sodiumazide reaction to yield benzimidazole clubbed with tetrazole moiety compounds which were established by an Elemental analysis, IR, 1H NMR, 13C NMR and Mass spectra and screening of various biological studies also recorded.

Design, synthesis, kinetic, molecular dynamics, and hypoglycemic effect characterization of new and potential selective benzimidazole derivatives as Protein Tyrosine Phosphatase 1B inhibitors

Protein-tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling pathway and has been validated as a therapeutic target for type 2 diabetes. A wide variety of scaffolds have been included in the structure of PTP1B inhibitors, one of them is the benzimidazole nucleus. Here, we report the design and synthesis of a new series of di- and tri- substituted benzimidazole derivatives including their kinetic and structural characterization as PTP1B inhibitors and hypoglycemic activity. Results show that compounds 43, 44, 45, and 46 are complete mixed type inhibitors with a Ki of 12.6 μM for the most potent (46). SAR type analysis indicates that a chloro substituent at position 6(5), a β-naphthyloxy at position 5(6), and a p-benzoic acid attached to the linker 2-thioacetamido at position 2 of the benzimidazole nucleus, was the best combination for PTP1B inhibition and hypoglycemic activity. In addition, molecular dynamics studies suggest that these compounds could be potential selective inhibitors from other PTPs such as its closest homologous TCPTP, SHP-1, SHP-2 and CDC25B. Therefore, the compounds reported here are good hits that provide structural, kinetic, and biological information that can be used to develop novel and selective PTP1B inhibitors based on benzimidazole scaffold.

Synthesis, characterization and in vitro, in vivo, in silico biological evaluations of substituted benzimidazole derivatives.

A series of substituted benzimidazole derivatives were synthesized by reacting O-phenylenediamine with various aromatic aldehydes or glycolic acid using various inexpensive reagents in aqueous media. Synthesized compounds were characterized and elucidated by IR, 1H NMR, ESI-MS spectra. Resultant compounds were screened for in vitro antimicrobial, cytotoxic, antioxidant, lipid peroxidation and cholinesterase inhibitory activities, in vivo analgesic and anti-inflammatory, and in silico anti-acetylcholinesterase and anti-butyrylcholinesterase activities. Among the synthesized compounds, compound 3b showed most promising central analgesic effect (46.15%) compared to morphine (48.08%), whereas compounds 6, 3c and 3a showed significant peripheral analgesic activity at two different dose levels (25mg/kg and 50mg/kg). Compounds 3b and 3a at the dose of 100mg/kg showed significant anti-inflammatory effects from the first hour and onward, whereas compounds 6 and 3b showed moderate cytotoxic activities. In addition, compound 3a showed significant antioxidant activity having IC50 value of 16.73µg/ml compared to 14.44µg/ml for the standard BHT. Compound 6, 3a and 3b exhibited mild to moderate cholinesterase inhibitory activity. In silico studies revealed that compound 3a and 3b might be suitable for cholinesterase inhibitory activity. A comprehensive computational and experimental data suggested compounds 3b and 3a as the best possible candidates for pharmacological activity. All the experimental data were statistically significant (p<0.01 level).

Synthesis and Pharmacological Evaluation of Novel Benzimidazole Derivatives as Antiulcer and H+ K+ ATPase Inhibitor

Aims: To Synthesis the novel substituted benzimidazole derivatives and screened Pharmacologically as antiulcer and H+ K+ ATPase inhibitor.&#x0D; Study Design: Study design as series of substituted benzimidazole derivatives prepared by three different reaction scheme and further evaluated pharmacologically in desired activity.&#x0D; Place and Duration of Study: In Patal Dhamal Wadwani College of Pharmacy Yavatmal, Maharashtra, India, between July 2014 to August 2017.&#x0D; Methodology: A series of new 2-[(substituted-pyrimidin-4-yl) sulfinyl]-1H-benzimidazole (54a-54i) were synthesized by the condensation of O-phenylenediamine, KOH and CS2 resulting potassium 1-H-benzimidazole 2-thiolate further treated with glacial acetic acid gives 1H-benzimidazole 2- thiol (2-mercaptobenzimidazole). 4-Chloro 2 Methyl, 6-Alkylpyrimidine- 4-ol prepared by ethanimidamide and alkyl acetoacetate gives 2-Methyl, 6-Alkylpyrimidine-4-ol by chlorination using thionyl chloride 4-Chloro 2 Methyl, 6-Alkylpyrimidine- 4-ol was obtained. further reacted with sodium oxide followed by m-chloroperbenzoic finally gives 2-[(substituted-pyrimidin-4-yl) sulfinyl]-1H-benzimidazole. Structural characterization of these synthesized compounds was confirmed by FT-IR, 1HNMR, and Mass spectral data. Later synthesized derivatives evaluated for their antiulcer and H+ K+ ATPase inhibitory activity by aspirin induced method and assays of H+/K+-ATPase activity respectively.&#x0D; Results: Compound 54c (74.03%), 54f (72.87%) and 54i (75.15%) shows highly significant antiulcer activity compared to standard drug and compound 54c (88.88 %), 54d (91.03 %), 54f (86.48%) and 54g (84.21%) shows highly significant antisecretory activity when compare to standard drug.&#x0D; Conclusion: Our research work provokes further to work for development of different derivatives of 2-(pyrimidinyl-sulfinyl) benzimidazole which have lesser side effect and better action than few of marketed drugs.