Benzimidazole Derivatives Research Articles

Synthesis Antimicrobial Activity and Chemotherapeutic Potential some Novel Benzimidazole Derivatives

Benzimidazole derivates play vital role in biological field such as antimicrobial, antiviral, antidiabetic, and anticancer activity. Therapeutic significance of these clinically useful drugs in treatment of microbial infections encouraged the development of some more potent and significant compounds. With the purpose of finding new chemical entities with enhanced antimicrobial activity, a series comprises 2-substituted-5-nitro benzimidazole derivatives were synthesized. Investigation of antimicrobial activity of the compounds was done by disc diffusion method using Gram-positive (S. aureus, S. mutans and B. subtilis), Gram-negative (E. coli, S. typhi and P. aeruginosa) bacteria. Some derivatives showed remarkable activity comparable to that of standard against Gram-positive and Gram-negative bacteria.

Quantitative Structure Activity Relationship Analysis of Benzimidazole Derivatives as Aldose Reductase Inhibitors

Hyperglycemia is involved in the pathogenesis of diabetic neuropathy, retinopathy, nephropathy, and macro-vascular disease via multiple mechanisms, of which increased aldose reductase activity. Aldose reductase inhibitors, when administered from the onset of hyperglycemia, prevent the progression of polyol accumulation–linked complication. In this work, we report quantitative structure activity relationship analysis performed on the Triazino[4,3-α]benzimidazole acetic acid derivatives as aldose reductase inhibitors. The molecular modeling study was performed by using the software BioMed CAChe 6.0 and the regression analysis by SYSTAT 10.2. Various physicochemical parameters belonging to different classes viz. hydrophobic, steric and electronic etc. were calculated. QSAR models were generated using 17 compounds. The model showed a good correlative and predictive ability having convention coefficient (r2) of 0.846 and cross-validated correlation coefficient (q2) of 0.6866 by LOO external validation method. Based on the developed QSAR model, it may be concluded that aldose reductase inhibition activity of benzimidazole acetic acid derivatives is strongly influenced by the thermodynamic and electronic nature of the substituents. QSAR model shows that LOGP, LUMO energy, and steric energy are negatively affecting the biological activity. For a molecule to have higher aldose reductase activity, compound should be less lipophilic and should have more electronegative groups or atoms than electropositive groups or atoms present in the compound.

Solvent Dependent Selectivity in the Synthesis of 1,2‐Disubstituted and 2‐Substituted Benzimidazoles by Dehydrogenative Coupling Reactions with Ruthenium‐Polyoxoniobate Catalysts

Ruthenium‐polyoxoniobate complexes were found to be efficient catalysts for the selective synthesis of 2‐substituted benzimidazoles and 1,2‐disubstituted benzimidazoles by solvent switching. The current strategy enables the synthesis of 2‐substituted benzimidazoles in water as a green solvent. Switching to aprotic solvents resulted in the formation of 1,2‐disubstituted benzimidazoles as the major product. Control experiments showed the involvement of both acceptorless dehydrogenative and oxidative coupling pathways. The method was extended to synthesize various 2‐substituted and 1,2‐disubstituted benzimidazole derivatives, and the desired products were obtained in moderate to good yields.

Novel Benzimidazole Derivatives as Potent Inhibitors of Microsomal Prostaglandin E2 Synthase 1 for the Potential Treatment of Inflammation, Pain, and Fever.

Microsomal prostaglandin E2 synthase 1 (mPGES-1) is a promising target for treating inflammatory diseases and pain. This study introduces a novel series of benzimidazoles, with the most potent analogs exhibiting IC50 values of 0.27-7.0 nM in a cell-free assay for prostaglandin (PG)E2 production. Compound 44 (AGU654) demonstrated remarkable selectivity for mPGES-1 (IC50 = 2.9 nM) over COX-1, COX-2, 5-LOX, and FLAP, along with excellent bioavailability. Metabololipidomics analysis with activated human monocyte-derived macrophages and human whole blood revealed that AGU654 selectively suppresses PGE2 production triggered by bacterial exotoxins while sparing other prostaglandins. Furthermore, in vivo studies showed that AGU654 significantly alleviated fever, inflammation, and inflammatory pain in preclinical guinea pig models, suggesting that it could be an effective strategy for managing inflammatory diseases. In conclusion, these benzimidazole derivatives warrant further exploration into new and alternative analogs, potentially uncovering novel compounds with a favorable pharmacological profile possessing significant anti-inflammatory and analgesic properties.

One Pot Synthesis of New Benzimidazole Derivatives with Exceptionally High Luminescence Quantum Efficiency.

There are different approaches to the synthesis of benzimidazole. In this article, five new benzimidazole derivatives, BMPO, Me-BMPO, Di-MeBMPO, F-BMPO and Cl-BMPO where (BMPO=3-[(1H)-benzo[d]imidazol-2-yl]pyridin-2(1H)-one), have been prepared. Another study was carried out on luminescence properties and their potential applications for the detection of transition metal ions. From the one-pot synthesis approach, all the derivatives of the benzimidazole compounds were obtained. The compounds were characterized using HRMS, 1HNMR, 13CNMR, and X-ray crystallography. Herein, a mechanism has been deciphered by predicting the release of HCl(g). All compounds showed a strong deep blue emission when dissolved in dimethylacetamide (DMA), with emission wavelengths at 423, 428, 435, 423, and 421 nm, and half-times of 3.64, 2.77, 2, 19, 3.42 and 3.52 ns, respectively. In addition, their emission quantum yields were determined to be 72, 50, 42, 73 and 80%. Five new benzimidazole derivatives, BMPO, Me-BMPO, Di-MeBIPO, F-BIPO, and Cl-BIPO, have been successfully synthesized by the one-pot synthesis method, and their structures are characterized and confirmed. The compounds exhibited exceptional luminescence by emitting a strong blue light in DMA with high fluorescence quantum yields between 42~80%.

New modified Benzimidazole derivatives carried on different sugars and nanocrystalline cellulose: Anticancer and antioxidant activity estimation.

New modified Benzimidazole derivatives carried on different sugars and nanocrystalline cellulose: Anticancer and antioxidant activity estimation.

A highly efficient and magnetically separable Fe3O4/WO3 catalyst for the synthesis of some benzimidazoles, benzoxazoles, and benzothiazoles, serving as potential drugs to treat nephropathy diseases

Benzimidazole derivatives have shown potential in treating certain kidney diseases, renin inhibitors, and modulate inflammatory responses to address underlying mechanisms in nephropathy. Herein, Fe3O4/WO3 heterojunction catalyst, derived from the reducing aqueous extract of Plantain peel, is recommended as an innovative catalyst for the one-pot synthesis of various benzimidazoles, benzoxazoles, and benzothiazoles in mild conditions. Through characterization methods like XRD, EDS, TEM, FE-SEM, VSM, DRS, XPS, and FT-IR, its structure and properties are understood. This cutting-edge protocol showcases high yield across a broad range of substrates, all while being eco-friendly and efficient. Moreover, the catalyst exhibited remarkable stability over five cycles, illustrating its reusability without compromising catalytic efficiency. The hot filtration test further underlines its stability in the reaction medium. We believe that Fe3O4/WO3 catalyst offers several advantages in the synthesis of benzimidazoles, benzoxazoles, and benzothiazoles, including enhanced catalytic activity that promotes efficient formation of the desired heterocyclic compounds compared to many reported protocols. Furthermore, its magnetic properties guarantee high reusability and a straightforward work up by using an external magnet. This feature facilitates its reuse in multiple synthesis cycles, ultimately reducing waste and lowering costs. In addition, the Fe3O4/WO3 catalyst operates under mild conditions, minimizing the need for harsh reagents and contributing to a more environmental-friendly synthesis. With cost-effectiveness and easy recovery of the catalyst, this approach sets a new approach for the sustainable and efficient synthesis of substituted benzimidazoles, benzoxazoles, and benzothiazoles.

Sustainable Design and Revolutionary Synthesis of Highly Recyclable Sulfonic Acid–Based Magnetic Nanoparticles as a Solid Acid for Synthesis of 2‐Substituted Benzimidazole and Bis Indole Methane Derivatives

ABSTRACTConcerning the objectives of green chemistry, silica‐coated magnetite nanoparticles provide a new way to implement an efficient and effective system for assisting catalyst recovery across multiple organic reactions. With Fe3O4 spheres serving as the core shell, the synthesis of sulfonic acid‐functionalized silica‐coated magnetic nanoparticles is presented in this paper. FTIR, PXRD, SEM, TEM, EDX, TGA, XPS, and VSM techniques were used to assess the prepared catalyst. The proposed nanocatalyst was employed to produce biological relevance 2‐substituted benzimidazole and bis indole methane derivatives. High yield, quick reaction time, soothing reaction conditions, extended functional group tolerance, and an accessible workup approach are the main advantages of synthesized nanoparticles. Furthermore, the present nanocatalyst may be recovered using an external magnet and retaining its effectiveness for up to six cycles. These are distinctive functions of the present approach.

N-Aryl Benzimidazole and Benzotriazole Derivatives and Their Hybrids as Cytotoxic Agents: Design, Synthesis and Structure-Activity Relationship Studies.

The era of chemotherapy began in the 1940s, which is the basis of traditional antitumor approaches and, being one of the most high-tech treatment methods, is still widely used to treat various types of cancer. A promising direction in modern medicinal chemistry is currently the creation of hybrid molecules containing several pharmacophore fragments of different structures. This strategy is successfully used to increase the therapeutic efficacy of cytotoxic agents and reduce side effects. In this work, we synthesized 10 1-aryl derivatives of benzimidazole and benzotriazole and 11 hybrids based on them. Among the compounds obtained, the most promising hybrid molecules were diphenylamines, containing an amino group and a benzotriazole cycle in the ortho position to the bridging NH group, which showed significant cytotoxic activity, excellent antioxidant properties and the ability to suppress the migration activity of tumor cells. Taken together, our results demonstrate that substituted diphenylamine-based bipharmacophoric compounds may serve as a promising platform for further optimization to obtain effective antitumor compounds.

Cu(II) complexes based on benzimidazole ligands: synthesis, characterization, DFT, molecular docking & bioactivity study.

Aim: The biggest cause of cancer deaths globally was lung cancer. New cancer fighting drugs are needed due to the rising number of cancer patients and cancer cells' treatment resistance.Results: Two Cu(II) complexes, synthesized from ligands based on 2-aminomethyl benzimidazole and salicylaldehyde derivatives, were designed and evaluated for their effectiveness against A549 lung cancer. The compounds were subjected to computational calculation using Density Functional Theory (DFT) to gather information on their reactivity. Furthermore, molecular docking are utilized to simulate the interaction between the compound and the MPP-9 protein. The synthesis of the ligands and their Cu(II) metal complexes are efficient and straightforward. The complexation between copper atom and the ligand are in 1:1 ratio. The MTT assay of the compounds against A549 lung carcinoma reveals that the both Cu(II) complexes good cytotoxicity activity, in comparison to their respective ligands. The low HOMO-LUMO band gap based on the DFT calculation predicts the high reactivity of the compounds. Furthermore, the low binding energy and the numbers of interactions of the Cu(II) complexes with MMP-9 protein binding site coincide with the antiproliferative activity tested in vitro.Conclusion: The cytotoxicity studies performed for Cu(L1Br) are promising, indicating a good candidate for a future drug.

Synthesis of Mannich N-bases based on benzimidazole derivatives using SiO2[sbnd]OAlCl2 catalyst and their potential as antioxidant, antibacterial, and anticancer agents

This research aimed to synthesis of N-base compounds based on benzimidazole derivatives and their potential as antibacterials, antioxidants, and anticancer. The synthesis was conducted in two stages, namely the intermediate (benzimidazole derivatives) and the final product (N-mannich base), using five variations of organic acids and SiO2OAlCl2 as catalyst. The results showed that the catalyst was successfully synthesized and characterized by The Fourier transform infrared (FTIR), X-ray diffraction (XRD), and Scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDS). The purity of the synthesized compounds was monitored by Thin layer chromatography (TLC), melting point test, Ultraviolet-visible (UV–Vis), and Liquid chromatography-Mass spectrometry (LC-MS). The five intermediate compounds and five mannich base products yield 77 %-89 % and 65 %-85 %, respectively. The final products were applied through antibacterial testing against Staphylococcus aureus (Gram-positive bacteria) and Escherichia coli (Gram-negative bacteria) by disc diffusion. Mannich base compounds have potential antibacterial agents, but only 4A and 4E gave the best inhibition zone diameter. Meanwhile, the antioxidant testing result using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method showed the best activity in the mannich base compound 4E. The anticancer test result showed that the five mannich base compounds had potential as anticancer agents.

Discovery of 4-(4-(3-(1-(2-(piperidin-1-yl)ethyl)-1H-benzo[d]imidazole-2-yl)isoxazol-5-yl)phenyl)morpholine as a novel c-Myc inhibitor against lung cancer in vitro and in vivo

The critical role of c-Myc as a driving factor in the development and progression of lung cancer establishes it as a pivotal target for anti-lung cancer therapeutic research. In our previous study, we reported on the discovery of D347–2761, a novel small-molecule inhibitor that specifically targets the unstable domain of c-Myc and disrupts the c-Myc/Max heterodimer. To enhance targeted therapies further, we conducted an extensive structural analysis and designed a series of innovative benzimidazole derivatives. The cytotoxic activities of these compounds were assessed using the CCK-8 assay, revealing that compound A1 displayed IC50 values of 6.32 μM and 11.39 μM against the A549 and NCI–H1299 lung cancer cell lines, respectively, while compound A5 exhibited IC50 values of 4.08 μM and 7.86 μM against the same cell lines. Our findings revealed that compounds A1 and A5 exhibited potent anticancer activity by disrupting the interaction between c-Myc and Max proteins, leading to the downregulation of c-Myc protein levels and induction of apoptosis through apoptotic pathways. Notably, compound A5 demonstrated superior inhibitory capacity compared to other compounds tested. Furthermore, in a syngeneic tumor model, compound A5 exhibited excellent efficacy with a tumor growth inhibition rate reaching up to 76.4 %, accompanied by a significant reduction in c-Myc protein expression levels. Therefore, compound A5 holds promise as a potential agent for targeting c-Myc in anti-lung cancer therapy.

Serious adverse events reported with benzimidazole derivatives: A disproportionality analysis from the World Health Organization's pharmacovigilance database.

Benzimidazole derivatives are widely used anthelmintic drugs, particularly in mass campaigns for intestinal parasitosis treatment. Despite their generally good safety profile, serious adverse reactions have been reported. This study aims to identify potential pharmacovigilance signals for benzimidazole derivatives using disproportionality analysis in the WHO database. A case/non-case study was conducted using data from the WHO VigiBase database (2000-2023). Cases were individual case safety reports (ICSRs) where at least one suspected serious adverse event of interest was reported, while non-cases were ICSRs reporting any adverse events other than the serious adverse events of interest. Reporting Odds Ratios (RORs) and 95% confidence intervals were calculated to assess disproportionate reporting. Analyses were adjusted for potential confounding factors and a sensitivity analysis with imputed missing data was performed. Among 19,068 serious reports analyzed, significant disproportionality signals were found for benzimidazole derivatives compared to other anthelmintic drugs, notably for bone marrow failure and hypoplastic anemia (adjusted ROR 9.44 [5.01-18.9]), serious leukopenia (3.89 [2.64-5.76]), serious hepatic disorders (3.10 [2.59-3.71]), hepatitis (2.88, 95% CI 2.29-3.63) and serious urticaria (2.02, 95% CI 1.36-2.99). We have also highlighted a new signal not mentioned in the summaries of product characteristics for seizures with benzimidazole derivatives. Secondary analysis revealed these signals were primarily reported with albendazole. This study identified potential pharmacovigilance signals for serious hematological and hepatic adverse events for benzimidazole derivatives, particularly albendazole. New signal for benzimidazole derivatives has been described for seizures. These findings underscore the need for vigilant monitoring during benzimidazole derivatives use and warrant further pharmacoepidemiologic studies to confirm these signals and investigate underlying mechanisms.

Green synthesis of benzimidazole derivatives using copper(II)-supported on alginate hydrogel beads

The study addresses the challenge of developing sustainable and efficient catalytic systems for the synthesis of benzimidazole derivatives, which are of significant importance in the field of medicinal chemistry due to their diverse biological activities. The objective is to develop a recyclable and environmentally friendly catalyst utilizing copper(II)-loaded alginate hydrogel beads, which can facilitate the synthesis of these compounds while minimizing environmental impact. The preparation process entails crosslinking sodium alginate with copper(II) ions to form hydrogel beads, which are then washed and characterized through techniques such as scanning electron microscopy (SEM), Energy dispersive X-ray spectroscopy (EDX), Fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction (XRD), Inductively coupled plasma (ICP), and Zeta potential to analyses the morphology, composition and porosity of the beads. The catalytic performance is evaluated through recycling tests, which demonstrate the catalyst's ability to maintain selectivity and activity over multiple reaction cycles. The Cu(II)-Alg hydrogel beads were used for synthesizing substituted benzimidazole derivatives in a water-ethanol solvent at room temperature. This method offers significant advantages, including extremely mild reaction conditions, short reaction times (<1 h), high yields (70–94 %), and ease of processing. The most significant results indicate that the Cu(II)-alginate catalyst exhibits a high loading capacity and retains its catalytic efficiency for at least 3 cycles, thereby highlighting its potential for sustainable applications in organic synthesis.

[EMIM]AlCl4-ionic liquid catalyzed mechanochemically assisted green approach towards the synthesis of quinoxaline, 6H-indolo[2,3-b]quinoxaline and benzimidazole derivatives

In the presented work, a convenient and effective methodology for the synthesis of quinoxaline, 6H-indolo[2,3-b]quinoxaline and benzimidazole derivatives has been developed. The reaction of 1,2-diamines with various substituted benzil, isatin and aldehydes produces quinoxaline, 6H-indolo[2,3-b]quinoxaline and benzimidazole derivatives respectively. The reaction between 1,2-diamines with various substituted benzils, isatins and aldehydes was carried out in presence of catalytic amount of [EMIM]AlCl4 (1-ethyl-3-methylimidazolium tetrachloroaluminate) ionic liquid in ethanol under the grinding condition in mortar and pestle. The ease of handling of catalyst, inclusion of eco-friendly solvent, attractive yield of the product, shorter reaction time and overall operational simplicity are some significant outcome of this procedure.

Discovery and Development of HDAC Inhibitors: Approaches for the Treatment of Cancer a Mini-review.

Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics due to their ability to induce differentiation, cell cycle arrest, and apoptosis in cancer cells. In the present review, we have described the systemic discovery and development of HDAC inhibitors. Researchers across the globe have identified various small molecules like benzo[d][1,3]dioxol derivatives, belinostat analogs, pyrazine derivatives, quinazolin-4-one-based derivatives, 2,4-imidazolinedione derivatives, acridine hydroxamic acid derivatives, coumarin derivatives, tetrahydroisoquinoline derivatives, thiazole-5-carboxamide, salicylamide derivatives, β-peptoid-capped HDAC inhibitors, quinazoline derivatives, benzimidazole and benzothiazole derivatives, and β- elemene scaffold containing HDAC inhibitors. Most of the scaffolds have shown attractive IC50 (μM) in various cell lines like HDAC1, HDAC2, HDAC6, PI3K, HeLa, MDA-MB-231, MCF-10A, MCF-7, U937, K562 and Bcr-Abl cell lines.

Design, Synthesis and Evaluation of Benzimidazole Derivatives as IL-6 Inhibitors and Their Role in Rheumatoid Arthritis.

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a major role in the development of Rheumatoid Arthritis (RA). In the present study, benzimidazole and benzene sulfonyl scaffold were identified as pharmacophore by analysis of literature reports and novel small molecule IL-6 inhibitors were designed. These were screened via docking with IL-6 (PDB: 1ALU), then and through Lipinski's rule of 5. Based on docking score, 10 best compounds (4a-4e and 7a-7e) were selected for synthesis and evaluated for IL-6 inhibitory activity invitro. Compounds 4b and 7b showed the maximum inhibition of IL-6 (87.55% and 82.75%, respectively). These compounds were further explored for anti-arthritic activity invivo using the Incomplete Freund's Adjuvant Model and by morphological and histopathological studies of the inflamed paw. Compound 4b was significantly more active than compound 7b and both were found to be slightly less active than methotrexate. These findings indicate that a benzimidazole nucleus linked to a benzene sulphonyl moiety may prove to be a useful template for the development of new chemical moieties against RA.

Design, synthesis, and evaluation of some benzimidazole analogs as AMPK agonists

AMP-activated protein kinase is a crucial regulator of cellular metabolism with potential therapeutic implications in various diseases. In this study, the benzimidazole scaffold was chosen for investigation with EX-229 as the lead compound. Modifications were made to the terminal carboxyl group, and the methylindole moiety was replaced with phenylpyrrolidinone to synthesize and assess the AMP-activated protein kinase-activating properties of 13 benzimidazole derivatives. In vitro studies have shown that most of the synthesized compounds have significant excitatory effects on AMP-activated protein kinase. Particularly, A11 demonstrated the most potent activity with an EC50 value of 39 nM. Combining activity data and molecular docking analysis revealed the necessity of end-molecule hydrogen bond donors for LYS29, and the importance of an appropriate torsion angle at the pyrrolidinone position to facilitate the formation of a crucial hydrogen bond with LYS31. These discoveries offer preliminary insights into the interaction of small-molecule drugs with the AMP-activated protein kinase protein and establish a foundation for the future development of AMP-activated protein kinase activators guided by structure–activity relationships.

An Insight into the Structure-Activity Relationship of Benzimidazole and Pyrazole Derivatives as Anticancer Agents.

Cancer is a leading cause of death worldwide, driving the urgent need for new and effective treatments. Benzimidazole and pyrazole derivatives have gained attention for their potential as anticancer agents due to their diverse biological activities. The development of resistance in cancer cells, toxicity concerns, and inconsistent efficacy across different types of cancer are a few of the challenges. To overcome these challenges, optimisation of these nuclei using the structure-activity relationships is necessary. This review aimed to examine various benzimidazole, pyrazole, and their hybrid derivatives by focusing on their structure-activity relationships (SAR) as anticancer agents. Results of the most potent and least potent benzimidazole, pyrazole compounds, and their hybrid derivatives published by researchers were compiled. The findings of different researchers working on benzimidazole and pyrazole nuclei were reviewed and analysed for different targets and cell lines. Moreover, substitutions on different positions of pyrazole, benzimidazole, and their hybrid were summarised to derive an optimised pharmacophore. Based on our analysis of existing studies, we anticipate that this review will guide researchers in creating potent pyrazole, benzimidazole, and hybrid derivatives crucial for combating cancer effectively. Structure-Activity Relationship (SAR) studies can help in developing pyrazolebenzimidazole hybrids that are more powerful and selective in targeting specific aspects of cancer.

Novel 1,2-Disubstituted Benzimidazole Derivatives: Synthesis and in silico Antibacterial Activity

A series of 14 novel 1,2-disubstituted benzimidazole derivatives was synthesized by reacting substituted benzimidazoles with ethyl succinyl chloride and characterized by spectroscopic techniques (FTIR, 1H NMR and Mass). The molecular docking analyses with AutoDock Tools-1.5.7 were used to examine the interactions between the compounds and the active site residues of Topoisomerase-II enzyme (PDB ID: 1JIJ). Amongst the 14 derivatives, 11 derivatives had shown greater binding affinity with the receptor in comparison with standard drug pefloxacin.