Substituted Benzimidazole Derivatives Research Articles

2D QSAR Modelling, Docking, Synthesis and Evaluation of 2-substituted Benzimidazole Derivatives as Anti-breast Cancer Agents

Background: Cancer is a leading cause of death worldwide and is anticipated to reach 28,4 million fresh cases globally by 2040. Despite all the progress made in cancer prevention, diagnosis, and treatment, mortality by cancer is in second place. Objectives: The design of novel 2-substituted benzimidazole modelled by QSAR study. Molecular docking studies on the novel derivatives and synthesis characterization and evaluation of the anticancer activity of the novel derivatives against breast cancer cell line MCF 7. Methods: We designed 10 novel benzimidazole derivatives modeled by 2D QSAR. From the ten compounds by applying insilico tools of ADME properties and toxicity and through molecular docking on Tyrosine Kinase (PDB ID: 2SRC). Compound 2AD showed the highest dock score of -9.5 kcal/mol followed by 2 BD and 2GD (-9.3kcal/mol) Molecular dynamic simulation studies were conducted using CABSflex an online molecular dynamic simulation tool. Six compounds were selected for synthesis. The synthesized compounds were characterized and the invitro pharmacological activity was tested on MCF-7 cell line by MTT assay. Results: The compounds 2AD and 2GD showed good percentage inhibition on MCF-7 cell line withIC50 values of 2.757 µg/ml and 2.875 µg/ml respectively. Conclusion: The novel 2-substituted benzimidazole derivatives are good lead compounds for cancer therapy. Optimization of these compounds will be providing more target-specific anticancer agents.

Novel Urea Substituted Benzimidazole Derivatives as Anthelmintics: In Silico and In Vitro Approaches

Novel Urea Substituted Benzimidazole Derivatives as Anthelmintics: In Silico and In Vitro Approaches

Synthesis and anti-inflammatory activity of benzimidazole derivatives; an in vitro, in vivo and in silico approach

Many non-steroidal anti-inflammatory drugs (NSAIDs) concurrently inhibit both COX-1 and COX-2, with a preference for specifically targeting COX-2 due to its significant involvement in various pathologies. In addition to COX enzymes, several other targets, including Aldose reductase, Aldo-ketoreductase family 1-member C2, and Phospholipase A2, have been identified as contributors to inflammation and a myriad of other diseases.In this context, a series of 2-substituted benzimidazole derivatives was synthesized and assessed for their anti-inflammatory potential through both in vitro and in vivo assays. Molecular docking studies were conducted to elucidate the mechanism of action of these compounds against COX enzymes and other therapeutic targets associated with NSAIDs, such as Aldose reductase, AIKRC, and Phospholipase A2.Among the synthesized compounds, B2, B4, B7, and B8 demonstrated IC50 values lower than the standard ibuprofen, as determined by the Luminol-enhanced chemiluminescence assay. Validation of these findings was achieved through an in vivo carrageenan-induced mice paw edema model, confirming a comparable anti-inflammatory effect to diclofenac sodium observed in vitro. Notably, these compounds exhibited significant binding affinity with all therapeutic targets investigated in this study.These results suggest that the newly synthesized derivatives possess noteworthy anti-inflammatory potential, warranting further exploration for the development of novel multi-targeting inhibitors.

Synthesis, Molecular Docking, Molecular Dynamic Simulation Studies, and Antitubercular Activity Evaluation of Substituted Benzimidazole Derivatives.

Tuberculosis, also known as TB, is a widespread bacterial infection that remains a significant global health issue. This study focuses on conducting a thorough investigation into the synthesis, evaluation of anti-Tb activity, molecular docking, and molecular dynamic simulation of substituted benzimidazole derivatives. A series of twelve substituted benzimidazole derivatives (1-12) were successfully synthesized, employing a scaffold consisting of electron-withdrawing and electron-donating groups. The newly synthesized compounds were defined by their FTIR, 1H NMR, and mass spectra. The microplate Alamar blue assay (MABA) was used to evaluate the antimycobacterial activity of the synthesized compound against Mycobacterium tuberculosis (Mtb). Compounds 7 (MIC = 0.8 g/mL) and 8 (MIC = 0.8 g/mL) demonstrated exceptional potential to inhibit M. tuberculosis compared to the standard drug (isoniazid). In addition, the synthesized compounds were docked with the Mtb KasA protein (PDB ID: 6P9K), and the results of molecular docking and molecular dynamic simulation confirmed the experimental results, as compounds 7 and 8 exhibited the highest binding energy of -7.36 and -7.17 kcal/mol, respectively. The simulation results such as the RMSD value, RMSF value, radius of gyration, and hydrogen bond analysis illustrated the optimum potential of compounds 7 and 8 to inhibit the M. tuberculosis strain. Hydrogen bond analysis suggested that compound 7 has greater stability and affinity towards the KasA protein compared to compound 8. Moreover, both compounds (7 and 8) were safe for acute inhalation and cutaneous sensitization. These two compounds have the potential to be potent M. tuberculosis inhibitors.

Molecular docking, pharmacokinetic profiling and toxicity studies of 2-substituted benzimidazole derivatives against breast cancer

The most prevalent malignancy among women is breast cancer, which had almost 1.3 million new cases in 2020. It is the second most common cancer in the world, followed by lung cancer. The survival rate would be 99% if the cancerous tumour was limited to the breast. If the cancer migrated to neighbouring lymph nodes, the survival percentage would be 85% and it would drop to 27% if it spread to distant regions. In fact, the most prevalent breast cancer subtype is that caused by excessive estrogen levels. The enhancement of pertinent treatment techniques depends on the estrogen receptors (ER) in both healthy and pathological conditions. There are two primary types of ER, ERα and ERβ, which are each encoded by a different gene. ER status is the most important indicator of breast cancer prediction. To develop novel therapeutics for breast cancer, 30 newly designed benzimidazole compounds targeting the ER were docked. Among them, a compound with a glide score of −9.293 was discovered to be the leading compound. ADME investigations provided additional validation of the docking results. The pyrazole fused benzimidazole nucleus is therefore suggested as a potential pharmacophore for the development of innovative anticancer treatment for breast cancer.

Improved and ligand-free copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from o-bromoarylamine and nitriles.

We present an improved copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from o-bromoarylamine and nitriles, under mild and ligand-free conditions. The optimal conditions yielded exceptional products of up to 98%, demonstrating the broad applicability of this synthetic strategy in generating a wide range of valuable imidazole derivatives. This methodology enables the efficient synthesis of various substituted benzimidazole derivatives and offers an environmentally friendly alternative to conventional methods. By eliminating the use of harsh reagents and high temperatures associated with traditional synthesis approaches, this method proves to be more efficient and robust. Notably, we successfully applied this synthetic approach to the synthesis of bendazol and thiabendazole, yielding 82% and 78%, respectively, on a 100 gram scale.

Study on the host-guest interactions between tetramethyl cucurbit[6]uril and 2-heterocyclic-substituted benzimidazoles.

Cucurbit[n]urils (Q[n]s) are a class of supramolecular host compounds with hydrophilic carbonyl ports and hydrophobic cavities, which can selectively form host-guest inclusion complexes with guest molecules to change the properties of guest molecules. In this paper, tetramethyl cucurbit[6]uril (TMeQ[6]) was used as the host and three 2-heterocyclic substituted benzimidazole derivatives as the guests, and their modes of interaction were investigated using X-ray crystallography, 1H NMR spectrometry, and other analytical techniques. The results showed that TMeQ[6] formed a 1 : 1 host-guest inclusion complex with three guest molecules, and the binding process between them was mainly enthalpy-driven. The X-ray diffraction analysis indicated that the main driving forces for the formation of these three inclusion complexes included hydrogen bonding interactions and ion dipole interactions. There are two modes of interaction between G3 and TMeQ[6] in the liquid phase, indicating that the benzimidazole ring and heterocyclic substituents on the guest molecule compete with the cavity of TMeQ[6]. Besides, the addition of TMeQ[6] significantly enhanced the fluorescence of these guests and slightly improved their solubility.

Synthesis, characterization and in vitro cytotoxic activity of platinum(II) oxalato complexes involving 2-substitutedimidazole or 2-substitutedbenzimidazole derivatives as carrier ligands

Synthesis, characterization and in vitro cytotoxic activity of platinum(II) oxalato complexes involving 2-substitutedimidazole or 2-substitutedbenzimidazole derivatives as carrier ligands

Water extract of onion: chemoselective synthesis of 2-substituted benzimidazole derivatives

Water extract of onion: chemoselective synthesis of 2-substituted benzimidazole derivatives

2-(2-Hydroxyphenyl) substituted benzimidazole derivatives: Suitable sensitizers for Tb3+ characteristic luminescence

Two series of 2-(2-hydroxyphenyl) substituted benzimidazole derivatives, (1-phenyl-2-(2-hydroxy-3-methoxyphenyl)benzimidazole, HL1; 1-methyl-2-(2-hydroxy-3-methoxyphenyl)benzimidazole, HL2) and their bimetallic complexes Zn–Ln(III)–L (Ln = Tb, Nd, Eu and Y) were prepared. The structures of ligands and complexes were characterized by 1H-NMR, FT-IR and single crystal X-ray diffraction. The UV–Visible absorption spectra, emission spectra and luminescent lifetime were measured. These results suggested that the ligands could efficiently sensitize the characteristic luminescence of Tb(III) and the photoluminescence quantum yield(PLQY) for Tb(III) complexes 3 and 7 were 74.8% and 55.3% respectively. While Nd(III) complexes 1 and 5 shown weak emission, and the Eu(III) complexes could not give the typical emission of lanthanide ions maybe due to the photo-induced electron transfer. In addition, the internal quantum yields of Nd(III) complexes were calculated utilizing luminescent lifetime.

Preparation and in vitro Antimicrobial Evaluation of some Substituted Benzimidazole Derivatives

A variety of benzimidazole compounds were synthesized by reacting the nitrophenylenediamine with aromatic carboxylic acids, followed by the reduction of nitrobenzimidazole derivatives to obtain the targeted, 4-aminobenzimidazole derivatives (2a-e). The in vitro antimicrobial (both antibacterial and antifungal) activities were determined by the diameter of the zone of inhibition of synthesized compounds and compared with ciprofloxacin as a reference drug. The results showed that these compounds have good potential antimicrobial activities for fighting against pathogenic bacterial and fungal strains.. KEYWORDS :Antibacterial, Antifungal activity, Benzimidazoles, Ciprofloxacin.

Synthesis of 2-Substituted Benzimidazole Derivatives as a Platform for the Development of UV Filters and Radical Scavengers in Sunscreens

The modern trend in sunscreen products is towards the development of UV filters with multi-functional properties, to provide a broad shielding against ultraviolet radiation, antioxidant activity, and the prevention of skin cancer. Additionally, they should also be safe for humans as well as the environment. The benzimidazole heterocycle is a suitable platform for the development of such multifunctional molecules with potential application in cosmetic formulations, due to their ability to act as both UV protectors and reactive pharmacophores. This review presents for the first time the progress in the synthesis and optimization of benzimidazole compounds as UV sunscreen filters. The modifications to the substitution pattern of the lead compound and structure–activity relationships are discussed, as well as the synthetic approaches for the preparation of 2-substituted benzimidazoles. These aggregated data will be useful in future in the development of modern benzimidazole-based sunscreen.

Synthesis, Characterization and Biological Evaluation of Some Novel N-Mannich Bases of Benzimidazole Derivative

Over the past few decades, Mannich bases of heterocyclic molecules have been grabbing the attention of the synthetic chemists for their wide gamut of biological activities ranging from antibacterial, anticancer, antiparkinson to anticonvulsant, anti-inflammatory, analgesic and anti-HIV. Using the knowledge of important features a novel series was designed to obtain improved antibacterial and antifungal activity. Therefore in the present research, we decided to synthesize 2-substituted benzimidazole derivatives by conventional method. Further the study will extended to introduce sulphanilamide and piperazine group substitution on N-1 position of 2-substituted benzimidazole by Mannich reaction and to screen the newly synthesized compounds for their antibacterial and antifungal activity.

Synthesis, Molecular Docking Studies and Cytotoxic Screening of Novel 2-Substituted Benzimidazole Derivatives

Cancer is one of the most serious lifethreatening diseases for which there is presently no cure. According to current World Health Organization (WHO) reports cancer is responsible for one out of every six deaths worldwide. Benzimidazole is a heterocyclic, aromatic molecule that acts as a biological scaffold with anticancer, antitumor, and antiproliferative activities, among other biological effects. benzimidazole and oxazole are the important pharmacophore in the medicinal chemistry, due to their widespread pharmacological activities. So, to exploit their anticancer potential we have selected these two for our research work. So, in order to develop potential anticancer agents, it was considered of interest to synthesize some benzimidazole derivatives. Before synthesis of molecule, Molecular docking was done and afterwards the compound with lowest dock score selected for synthesis. Synthesized derivatives Characterized By Proton Nuclear Magnetic Resonance (1H NMR), Infra-Red (IR), And Mass Spectroscopy (MS) and screen for cytotoxic activity.

Synchronous Proton-Hydride Transfer by a Pyrazole-Functionalized Protic Mn(I) Complex in Catalytic Alcohol Dehydrogenative Coupling.

A series of Mn(I) complexes Mn(L1)(CO)3Br, Mn(L2)(CO)3Br, Mn(L1)(CO)3(OAc) and Mn(L3)(CO)3Br [L1 = 2-(5-tert-butyl-1H-pyrazol-3-yl)-1,8-naphthyridine, L2 = 2-(5-tert-butyl-1H-pyrazol-3-yl)pyridine, L3 = 2-(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)-1,8-naphthyridine] were synthesized and fully characterized. The acid-base equilibrium between the pyrazole and the pyrazolato forms of Mn(L1)(CO)3Br was studied by 1H NMR and UV-vis spectra. These complexes are screened as catalysts for acceptorless dehydrogenative coupling (ADC) of primary alcohols and aromatic diamines for the synthesis of benzimidazole and quinoline derivatives with the release of H2 and H2O as byproducts. The protic complex Mn(L1)(CO)3Br shows the highest catalytic activity for the synthesis of 2-substituted benzimidazole derivatives with broad substrate scope, whereas a related complex [Mn(L3)(CO)3Br], which is devoid of the proton responsive β-NH unit, shows significantly reduced catalytic efficiency validating the crucial role of the β-NH functionality for the alcohol dehydrogenation reactions. Control experiments, kinetic and deuterated studies, and density functional theory (DFT) calculations reveal a synchronous hydride-proton transfer by the metal-ligand construct in the alcohol dehydrogenation step.

In vitro Studies of Antibacterial and Antifungal Activity of Novel Substituted Benzimidazole Derivatives

A series of 2-substituted amino-1-(1H-benzo[d]imidazol-1-yl)ethanone was prepared by reacting with benzimidazole and chloroacetyl chloride by stirring method. The resultant compound was dissolved in ethanol and refluxed with aryl/aralkyl amine in the presence of anhydrous potassium carbonate. The tested compounds were evaluated against bacterial agents such as E. coli, P. aeruginosa, K. pneumonia, S. typhi, and S. aureus, amoxicillin has been used as a control drug, and also screened for antifungal activity against C. albicans and A. niger at 50 and 100 mg/mL level, griseofulvin used as control drug. The structure-activity relationship led to the conclusion compound PS3 showed equipotent potent, PS4 showed moderate, and PS2 showed less moderate activity. The aromatic/aliphatic chain containing compounds PS1 and PS5 showed the least activity against all bacteria. Compound PS3, PS4 and PS1 showed better activity against C. albicans at 100 µg/mL concentration. The tested compounds PS1, PS3, PS2 and PS4 showed good activity at 100 µg/mL concentration. The compound PS3 can serve as a lead molecule for further development as a new class of antimicrobial agent. GRAPHICAL ABSTRACT

A comprehensive review on 2-substituted benzimidazole derivatives and its biological importance

Condensation of o-phenylene-diamine with formic acid is used in the synthesis of commercially available benzimidazole. N-ribosyldimethyl benzimidazole is the most common benzimidazole compound found in nature, and it functions as an axial ligand for cobalt in vitamin B12. The benzimidazole and its derivatives are important therapeutic agents, such as antiulcer and anthelmintic drugs. Benzimidazole compounds also possess antimicrobial, antiviral, anticancer, anti-inflammatory, analgesic, and other pharmacological properties. The chemistry and pharmacological actions of substituted benzimidazoles are summarised in this article.

Synthesis and biological evaluation of some substituted benzimidazole derivatives as antihypertensive activities

Synthesis and biological evaluation of some substituted benzimidazole derivatives as antihypertensive activities

Facile Synthesis of Benzimidazoles via Oxidative Cyclization of Acyclic Monoterpene Aldehyde with Diamines: Studies on Antimicrobial and in Vivo Evaluation of Zebrafish.

Citral (1a), a bioactive component of Cymbopogon citratus (lemongrass) could be isolated and semi-synthetic analogs synthesized with improved therapeutic properties. Herein we first report describes citral (1a) as a primary material for the synthesis of benzimidazole derivatives between various o-phenylenediamines (2a-l) in the presence of Diisopropylethylamine (DIPEA) as a commercially available environmentally benign base, ethanol as a green solvent and the yield of all benzimidazole derivatives (3a-l) was between 68-76 %; The semi-synthetically prepared benzimidazole derivatives (3a-l) were assessed for their anti-bacterial and anti-fungal properties. The benzimidazole compounds (3a-b, and 3g-j) exhibit good anti-microbial activity. In addition, in silico study was carried out to determine the specific binding affinity of the diamine halogen substituted benzimidazole derivatives to the specific target proteins. In silico analysis revealed a high correlation between docking results and experimental results. Finally, benzimidazole demonstrated significant antibacterial and antifungal activity. Zebrafish embryos were subjected to In vivo toxicological test found that all of the benzimidazole compounds (3a-l) were non-toxic and had low embryotoxicity after 96 h, with an LC50 of 36.425 μg, which could facilitate the design of novel antimicrobial agents using a cost-effective method.

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.