Benzimidazole Derivatives Research Articles

Diaryl-substituted benzimidazole derivatives as antiproliferative agents: Design, synthesis, in vitro activity, and SAR analysis

In this study, a series of 1,2-disubstituted benzimidazoles, designed to mimic nucleotides and interact favorably with amino acids in protein active sites, were synthesized and characterized. These compounds were characterized using IR, NMR spectral data, and elemental analyses, leveraging the recognition of substituted benzimidazoles as pharmacophores in the literature due to their documented anticancer activities. The compounds involved chloro and substituted phenyl rings, known for their anticancer activities, as key pharmacophores. Cytotoxicity assessments using the MTT assay were performed against MCF7, MDA-MB-231, and normal mouse fibroblasts (L929) for all synthesized compounds (11–19). Among them, compound 13 exhibited the most significant activity, inducing cell cycle arrest at the G0/G1 phase in MCF7 cells, suggesting its potential as an antitumor agent through apoptosis. To understand the underlying mechanisms of apoptotic cell death induced by compound 13, we investigated the involvement of apoptotic proteins such as Bax, Bcl-2, and p53. Our findings highlight Compound 13 as a promising scaffold for further optimization in the development of effective anticancer drugs.

Discovery of novel benzimidazole derivatives as potent HDACs inhibitors against leukemia with (Thio)Hydantoin as zinc-binding moiety: Design, synthesis, enzyme inhibition, and cellular mechanistic study

Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, a novel series of easy-to-synthesize benzimidazole-linked (thio)hydantoin derivatives was designed and synthesized as HDAC6 inhibitors. All target compounds potently inhibited HDAC6 at nanomolar levels with compounds 2c, 2d, 4b and 4c (IC50s = 51.84–74.36 nM) being more potent than SAHA reference drug (IC50 = 91.73 nM). Additionally, the most potent derivatives were further assessed for their in vitro cytotoxic activity against two human leukemia cells. Hydantoin derivative 4c was equipotent/superior to SAHA against MOLT-4/CCRF-CEM leukemia cells, respectively and demonstrated safety profile better than that of SAHA against non-cancerous human cells. 4c was also screened against different HDAC isoforms. 4c was superior to SAHA against HDAC1. Cell-based assessment of 4c revealed a significant cell cycle arrest and apoptosis induction. Moreover, western blotting analysis showed increased levels of acetylated histone H3, histone H4 and α-tubulin in CCRF-CEM cells. Furthermore, docking study exposed the ability of title compounds to chelate Zn2+ located within HDAC6 active site. As well, in-silico evaluation of physicochemical properties showed that target compounds are promising candidates in terms of pharmacokinetic aspects.

A Critical Review on Therapeutic Potential of Benzimidazole Derivatives: A Privileged Scaffold.

Benzimidazole nucleus is a predominant heterocycle displaying a wide spectrum of pharmacological activities. The privileged nature of the benzimidazole scaffold has been revealed by its presence in most small molecule drugs and in its ability to bind multiple receptors with high affinity. A literature review of the scaffold reveals several instances where structural modifications of the benzimidazole core have resulted in high-affinity lead compounds against a variety of biological targets. Hence, this structural moiety offers opportunities to discover novel, better, safe and highly potent biological agents. The goal of the present review is to compile the medicinal properties of benzimidazole derivatives with a focus on SAR (Structure-Activity Relationships).

Solvent-free strategy for facile synthesis and cytotoxicity evaluation of benzimidazole derivatives

This study reports a facile synthesis and the cytotoxic evaluation of N–H benzimidazoles. This synthetic method made use of the condensation reaction between o-phenylenediamine and benzylamine and was highlighted by its solvent-free reaction conditions and short reaction time with the use of Na2S2O5 as an inexpensive and environmentally friendly oxidizing agent. The cytotoxicity assays revealed that the benzimidazole derivatives 3l, 3h, and 3r displayed strong activity against the HeLa cancer cell line with the IC50 of 1.54 μM, 0.86 μM, and 1.03 μM, respectively, which were 5.6-fold, 10-fold, and 8-fold stronger than the positive control 5-fluorouracil (5-FU, IC50 = 8.61 μM). Furthermore, both compounds 3h and 3r exhibited similar cytotoxicities against MCF-7, which were equivalent to that of 5-FU and about 2.5-fold stronger than 5-FU towards the A549 cell line.

Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer

A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound 3b, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC50 = 16 nM and 1.03 µM, respectively). Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM). Moreover, 3b inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers in vivo, 3b was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC 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.

A Linear and Nonlinear QSAR Analysis of Benzimidazole Derivative XY123 in Prostate Cancer Treatment

Background: Metastatic Castration-Resistant Prostate Cancer (mCRPC) represents a critical challenge in current prostate cancer treatment. Benzimidazole Derivative XY123 has emerged as a novel inhibitor for its treatment. Objective: This study aims to establish a robust Quantitative Structure-Activity Relationship (QSAR) model for predicting the activity of Benzimidazole Derivative XY123 derivatives, aiding the development of novel anti-prostate cancer drugs. Methods: Utilizing CODESSA software, descriptors were computed based on various moieties of Benzimidazole Derivative XY123 derivatives. Multiple linear regression models were constructed, and both linear and nonlinear QSAR models were developed using heuristics and gene expression programming. Results: The linear model with two descriptors demonstrated the best predictive capacity for inhibitor activity, while the nonlinear model generated through Gene Expression Programming (GEP) exhibited correlation coefficients of 0.83 and 0.82 for the training and test sets, respectively. The average errors were 0.03 and 0.05, indicating the stability and the improved predictive ability of the nonlinear model. Conclusion: The QSAR linear model has an advantage over the nonlinear model in optimizing Benzimidazole Derivative XY123, providing a direction for the development of effective drugs for mCRPC treatment.

Synthesis and antibacterial activities of novel hybrid molecules based on benzothiazole, benzimidazole, benzoxazole, and pyrimidine derivatives, each connected to N-arylacetamide and benzoate groups

Novel benzimidazoles, benzothiazoles, and benzoxazoles linked to N-arylacetamide were synthesized in good yields by reacting a series of 2-oxo-2-(arylamino)ethyl 4-formylbenzoates with o-phenylenediamine, 2-aminothiophenol, or 2-aminophenol in ethanol at reflux in the presence of NaHSO3. Attempts to use the new aldehydes as adaptable precursors for the synthesis of fused dihydropyran or fused dihydropyridine via Michael or Hantzsch's reactions were unsuccessful; instead, the processes produced the corresponding arylidene derivatives. The structures of the novel compounds were verified with a variety of spectra. All synthesized compounds were evaluated for antibacterial activity against four different bacterial strains. Compound 6a had good activity against Escherichia coli in an agar diffusion assay, with an inhibitory zone width of 30 mm compared to ofloxacin (20 mm). Compounds 18a and 18b were most effective against Bacillus subtilis, with MICs of 156.3 and 312.5 µg/mL, respectively. Molecular docking investigations demonstrated that compounds 6a, 18a, and 18b had high binding affinities for bacterial tyrosyl-tRNA synthetase and DNA gyrase.

Design, synthesis and computational study of benzimidazole derivatives as potential anti-SARS-CoV-2 agents

As the human world has constantly been plagued by the COVID-19 pandemic since its emergence, researchers have been putting mountain-high efforts into designing new weapons to combat the virus. To join this battle against coronavirus, the present communication explores the synthesis of four benzimidazoles (1–4) from aromatic diamines utilizing two separate synthetic strategies. Afterwards, the synthesized four benzimidazole analogues along with sixteen previously synthesized benzimidazole analogues from our laboratory were subjected to in silico prediction of drug-likeness properties and ADMET (absorption, distribution, metabolism, excretion and toxicity) parameters. Additionally, all the compounds were computationally evaluated through molecular docking analysis against four vital target proteins of SARS-CoV-2 namely the main protease, the papain-like protease, the RNA-dependent RNA polymerase and the spike receptor binding domain to gain insight into the interaction pattern of the ligands with the binding site residues of the protein targets and thus to analyze the SARS-CoV-2 inhibitory proficiency of the synthesized derivatives. Among the studied ligands, compounds 1, 2, 13, 14, 15, 16 and 18 displayed excellent docking scores against two or more protein targets as compared to the established antiviral drugs Nirmatrelvir and Remdesivir. Based on the docking scores, the best four complexes (compound 18-Mpro, compound 2-PLpro, compound 1-RdRp and compound 2-spike-RBD) were subjected to molecular dynamic (MD) simulation to examine the stability of the complexes during the simulation period. This integrated molecular docking and MD simulation study suggested two compounds (1 and 18) that could be evolved as promising candidates for the design and discovery of new anti-SARS-CoV-2 agents.

Synthesis, Characterization and Biological Evaluation of Novel Benzimidazole Derivatives against Candida albicans

Synthesis, Characterization and Biological Evaluation of Novel Benzimidazole Derivatives against Candida albicans

Review on the Discovery of New Benzimidazole Derivatives as Anticancer Agents: Synthesis and Structure-activity Relationship (2010-2022)

Background: Benzimidazole (Benz-fused bicyclic ring system) is the most versatile class of heterocyclic compounds due to its numerous applications in industrial and synthetic organic chemistry because of its many biological actions. Benzimidazole analogs have been used to discover various medical problems, such as cancer, bacterial infections, fungi infections, etc. Researchers are studying nitrogencontaining hybrid heterocyclic compounds because they provide a broad range of therapeutic potential and have minimal side effects. Objective: The current literature review emphasizes recent developments in the design of new benzimidazole derivatives as possible anticancer agents with their relationship between structure and activity, which will give insight into the future design of more active benzimidazole molecules. Results: The present review consists of synthetic protocols for the synthesis of benzimidazole derivatives along with their pharmacological potentials and structure-activity relationship in correlation with synthetic molecules to provide a depth view of the work done on benzimidazole. Conclusion: It would be significant for further research in developing better drug molecules representing a potent derivative of medicinal agents.

Rapid identification of Radix Astragali origin by using fluorescence probe combined with chemometrics

Fluorescent probes for metal ion recognition can be divided into selective probes, weakly selective probes, and non-selective probes roughly. Weakly selective probes are not often used for quantitative analysis of metal ions due to their overlapping spectra resulting from simultaneous interactions with multiple metal ions. Conversely, the different metal ions contained in herbal medicine extracts from different geographical origins will produce corresponding fluorescence fingerprint profiles after interaction with weakly selective fluorescence probes. The performance can be used in the study of origin tracing of food or Chinese herbal medicine. Weakly selective fluorescent probes of benzimidazole derivatives have been synthesized and attempted to be used in the origin tracing of Radix Astragali in this work. Radix Astragali from different origins will produce different fluorescence fingerprint spectra due to the difference of metal ions and content in combination with the probe. Excitation-emission matrix (EEM) fluorescence spectroscopy in conjunction with N-way partial least squares discriminant analysis (N-PLS-DA), and unfolded partial least squares discriminant analysis (U-PLS-DA) were used to identify the origin of 150 Radix Astragali samples from five geographical origins. The prediction results showed that the correct recognition rates of the U-PLS-DA model and N-PLS-DA model are 95.92% and 93.88%, respectively. In comparison, the results of U-PLS-DA are slightly better than those of N-PLS-DA. These findings indicate that EEM fluorescence spectroscopy based on weakly selective fluorescent probes combined with multi-way chemometrics provides a good idea for the origin tracing of traditional Chinese medicine.

Receptor-based pharmacophore modeling, molecular docking, synthesis and biological evaluation of novel VEGFR-2, FGFR-1, and BRAF multi-kinase inhibitors

A receptor-based pharmacophore model describing the binding features required for the multi-kinase inhibition of the target kinases (VEGFR-2, FGFR-1, and BRAF) were constructed and validated. It showed a good overall quality in discriminating between the active and the inactive in a compiled test set compounds with F1 score of 0.502 and Mathew’s correlation coefficient of 0.513. It described the ligand binding to the hinge region Cys or Ala, the glutamate residue of the Glu-Lys αC helix conserved pair, the DFG motif Asp at the activation loop, and the allosteric back pocket next to the ATP binding site. Moreover, excluded volumes were used to define the steric extent of the binding sites. The application of the developed pharmacophore model in virtual screening of an in-house scaffold dataset resulted in the identification of a benzimidazole-based scaffold as a promising hit within the dataset. Compounds 8a-u were designed through structural optimization of the hit benzimidazole-based scaffold through (un)substituted aryl substitution on 2 and 5 positions of the benzimidazole ring. Molecular docking simulations and ADME properties predictions confirmed the promising characteristics of the designed compounds in terms of binding affinity and pharmacokinetic properties, respectively. The designed compounds 8a-u were synthesized, and they demonstrated moderate to potent VEGFR-2 inhibitory activity at 10 µM. Compound 8u exhibited a potent inhibitory activity against the target kinases (VEGFR-2, FGFR-1, and BRAF) with IC50 values of 0.93, 3.74, 0.25 µM, respectively. The benzimidazole derivatives 8a-u were all selected by the NCI (USA) to conduct their anti-proliferation screening. Compounds 8a and 8d resulted in a potent mean growth inhibition % (GI%) of 97.73% and 92.51%, respectively. Whereas compounds 8h, 8j, 8k, 8o, 8q, 8r, and 8u showed a mean GI% > 100% (lethal effect). The most potent compounds on the NCI panel of 60 different cancer cell lines were progressed further to NCI five-dose testing. The benzimidazole derivatives 8a, 8d, 8h, 8j, 8k, 8o, 8q, 8r and 8u exhibited potent anticancer activity on the tested cell lines reaching sub-micromolar range. Moreover, 8u was found to induce cell cycle arrest of MCF-7 cell line at the G2/M phase and accumulating cells at the sub-G1 phase as a result of cell apoptosis.

Sythesis, characterisation, anticancer and antimicrobial activity of Ag-N-heterocyclic carbene complexes containing benzimidazole derivatives

To prepare a novel series of silver(I) complexes, the interaction of benzimidazolium salts having their two nitrogen atoms substituted by bulky groups with Ag2O in DCM has been carried out. Their structures were characterized by elemental analyses, 1H NMR, 13C NMR, elemental analysis, and IR spectroscopy techniques. Further, the antimicrobial and antifungal activities properties of both the salts and their silver(I)–NHC complexes were tested against positive and negative bacteria using the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) respectively. The results show that silver complexes are effective against E. coli, P. aeruginosa and S. aureus bacterial species with moderate to high activity, and their minimum inhibitory concentrations ranging from 25 to 400 µg/Ml. It was also observed that 3b compound, which has the best antifungal properties among the synthesized compounds, showed high antimicrobial activity when all bacterial species were taken into account. In addition, the salts and complexes were then evaluated for their ability to inhibit the proliferation of four different cancer cell lines (A549, MCF-7, HCT116, SH-SY5Y and BEAS-2B cells lines). AlamarBlue assay demonstrated that the salts and complexes exhibited potent cytotoxicity towards all cancer lines. 2c compound showed the highest cytotoxic activity against BEAS-2B, A549 and MCF-7 cell lines. Except for 2c, compounds 3d, 3e and 3f showed cytotoxic activity at the lowest concentrations against MCF7 cell line.The study highlights the importance of N-heterocyclic carbene ligands in the development of silver-based drugs with anticancer properties.

Synthesis, Anticancer Activity, and In Silico Modeling of Alkylsulfonyl Benzimidazole Derivatives: Unveiling Potent Bcl-2 Inhibitors for Breast Cancer.

A series of alkylsulfonyl 1H-benzo[d]imidazole derivatives were synthesized and evaluated for anticancer activity against human breast cancer cells, MCF-7 in vitro. The cytotoxic potential was determined using the xCELLigence real-time cell analysis, and expression levels of genes related to microtubule organization, tumor suppression, apoptosis, cell cycle, and proliferation were examined by quantitative real-time polymerase chain reaction. Molecular docking against Bcl-2 was carried out using AutoDock Vina, while ADME studies were performed to predict the physicochemical and drug-likeness properties of the synthesized compounds. The results revealed that compounds 23 and 27 were the most potent cytotoxic derivatives against MCF-7 cells. Gene expression analysis showed that BCL-2 was the most prominent gene studied. Treatment of MCF-7 cells with compounds 23 and 27 resulted in significant downregulation of the BCL-2 gene, with fold changes of 128 and 256, respectively. Docking analysis predicted a strong interaction between the compounds and the target protein. Interestingly, all of the compounds exhibit a higher binding affinity toward Bcl-2 than the standard drug (compound 27 vina score = -9.6 kcal/mol, vincristine = -6.7 kcal/mol). Molecular dynamics simulations of compounds 23 and 27 showed a permanent stabilization in the binding site of Bcl-2 for 200 ns. Based on Lipinski and Veber's filters, all synthesized compounds displayed drug-like characteristics. These findings suggest that compounds 23 and 27 were the most promising cytotoxic compounds and downregulated the expression of the BCL-2 gene. These derivatives could be further explored as potential candidates for the treatment of breast cancer.

Impact of COVID-19 on the thyroid gland in Iraqi females

Impact of COVID-19 on the thyroid gland in Iraqi females

Synthesis and Biological Evaluation of Novel Amino and Amido Substituted Pentacyclic Benzimidazole Derivatives as Antiproliferative Agents.

Newly designed pentacyclic benzimidazole derivatives featuring amino or amido side chains were synthesized to assess their in vitro antiproliferative activity. Additionally, we investigated their direct interaction with nucleic acids, aiming to uncover potential mechanisms of biological action. These compounds were prepared using conventional organic synthesis methodologies alongside photochemical and microwave-assisted reactions. Upon synthesis, the newly derived compounds underwent in vitro testing for their antiproliferative effects on various human cancer cell lines. Notably, derivatives 6 and 9 exhibited significant antiproliferative activity within the submicromolar concentration range. The biological activity was strongly influenced by the N atom's position on the quinoline moiety and the position and nature of the side chain on the pentacyclic skeleton. Findings from fluorescence, circular dichroism spectroscopy, and thermal melting assays pointed toward a mixed binding mode-comprising intercalation and the binding of aggregated compounds along the polynucleotide backbone-of these pentacyclic benzimidazoles with DNA and RNA.

Pharmacophore, QSAR, molecular docking, molecular dynamics and ADMET study of trisubstituted benzimidazole derivatives as potent anti-tubercular agents

The objective of this study was to develop and verify a QSAR model for predicting the antitubercular effects of trisubstituted benzimidazole derivatives. For this study, 50 compounds with antitubercular activity targeting FtsZ protein were retrieved from published studies. The PharmaGist web server was used to create the pharmacophore model. The best pharmacophore model had seven special features and a score of 56.79. Molecular descriptors were computed using PaDEL-descriptor software and the ChemDes web server. A predictive QSAR model was created using the QSARINS software. The best QSAR Model 4, which had R2: 0.9114, R2adj: 0.8924, LOF: 0.1131, Q2-F1: 0.6499, Q2-F2: 0. 6499, Q2-F3:0.8356; and CCCext: 0.8522 identified a good fit. The descriptors AATS8e, AATSC7p, SpMin2_Bhm, nHBint6, SHssNH, and XLogP were essential for antitubercular activity. Molecular descriptors, such as SpMin2_Bhm, nHBint6, SHssNH, and XLogP positively contributed to the antitubercular activity. Molecular descriptors such as AATS8e and AATSC7p were negatively associated with antitubercular activity. From the above data, we have designed four series of trisubstituted benzimidazole derivatives, including 1A–E, 2A–E, 3A–E and 4A–E. All these newly designed compounds were used for molecular docking simulation and ADMET studies. Compound 1B exhibited the best ADMET features and highest binding affinity. Consequently, it was subjected to dynamic simulations for 100 ns. The binding stability of the FtsZ protein-compound 1B complex was confirmed by RMSD, RMSF, H-bond interaction, and percentage occupancy.

Predicting the risk and speed of drug resistance emerging in soil-transmitted helminths during preventive chemotherapy

Control of soil-transmitted helminths relies heavily on regular large-scale deworming of high-risk groups (e.g., children) with benzimidazole derivatives. Although drug resistance has not yet been documented in human soil-transmitted helminths, regular deworming of cattle and sheep has led to widespread benzimidazole resistance in veterinary helminths. Here we predict the population dynamics of human soil-transmitted helminth infections and drug resistance during 20 years of regular preventive chemotherapy, using an individual-based model. With the current preventive chemotherapy strategy of mainly targeting children in schools, drug resistance may evolve in soil-transmitted helminths within a decade. More intense preventive chemotherapy strategies increase the prospects of soil-transmitted helminths elimination, but also increase the speed at which drug efficacy declines, especially when implementing community-based preventive chemotherapy (population-wide deworming). If during the last decade, preventive chemotherapy against soil-transmitted helminths has led to resistance, we may not have detected it as drug efficacy has not been structurally monitored, or incorrectly so. These findings highlight the need to develop and implement strategies to monitor and mitigate the evolution of benzimidazole resistance.

Unlocking the Pharmacological Potential of Benzimidazole Derivatives: A Pathway to Drug Development.

Heterocyclic molecules have fascinated a massive interest in medicinal chemistry. They are heterocyclic compounds that have gained significance due to their diverse variety of pharmacological activities. Benzimidazole is a heterocyclic compound consisting of benzene and imidazole rings. The ease of synthesis and the structural versatility of benzimidazole make it a promising scaffold for drug development. Many biological actions of benzimidazole derivatives have been well documented, including antibacterial, antiviral, anticancer, anti-inflammatory, antitubercular, and anthelmintic properties. The mechanism of action of benzimidazole derivatives varies with their chemical structure and target enzyme. This review has explored numerous methods for producing benzimidazole derivatives as well as a broad range of pharmacological activities. SAR investigations are also discussed in this review as they provide crucial details regarding the essential structural qualities that benzimidazole derivatives must have in order to be biologically active, which could aid in the rational design of new drug candidates. Benzimidazole scaffold is an exclusive structure in drug design and discovery. Many new pharmaceutical drugs containing benzimidazole are anticipated to be available within the next ten years as a result of the extensive therapeutic applications of benzimidazole and its derivatives. This review inspired many researchers to develop more biologically active compounds bearing benzimidazole, expanding the scope of finding a remedy for other diseases. From this study, we concluded that 2-substituted benzimidazole was considered more extensively by researchers.