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The traditional preparation of nanocomposite proton exchange membranes (PEM) is hindered by poor organic-inorganic interface compatibility, insufficient proton-conducting sites, easy aggregation of nanoparticles, and difficulty in leveraging nanoscale advantages. In this study, a novel method involving electrochemical anodic oxidation exfoliation was employed to prepare melamine-coated graphene oxide (Me@GO), which was subsequently subjected to in-situ polymerization with poly(2,5-benzimidazole) (ABPBI) to prepare a Me@GO/ABPBI composite proton exchange membrane. Benefiting from the strong hydrogen bonding and large π stacking interactions, melamine (Me) tightly bound to graphene oxide (GO), effectively preventing the secondary aggregation of GO after exfoliation. Moreover, the abundant alkaline functional groups of melamine enhanced the enhancement of phosphoric acid (PA) retention in the Me@GO/ABPBI membranes, thereby increasing the number of proton-conducting sites. The experimental results indicated that the introduction of Me@GO enhanced membrane properties. For Me@GO at a concentration of 1 wt%, the tensile strength of the 1Me@GO/ABPBI composite membrane reached 207 MPa, nearly 2.52 times that of the pure membrane. The proton conductivity of the 1Me@GO/ABPBI composite membrane reached 0.01 S cm-1 across a wide temperature range (40-180 °C), peaking at 0.087 S cm-1 at 180 °C. Additionally, a single-cell incorporating the 1Me@GO/ABPBI composite membrane achieved a peak power density of 0.304 W cm-2 at 160 °C, nearly 1.46 times that of the pure membrane. Benefiting from the well-dispersed and PA-enriched proton channels provided by Me@GO, the Me@GO/ABPBI composite membrane exhibits excellent prospects for wide-temperature range (40-180 °C) applications.

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Herein, a series of new Ag(I)-NHC complexes containing 1,3-dioxane group were synthesized by the direct reaction of Ag2O and benzimidazolium salts in light-free conditions. All Ag(I)-NHC complexes were spectrally characterized using 1H, 13C NMR, FT-IR, LC-MS, and elemental analysis. Additionally, the structures of compounds 1a and 1e were elucidated by the single X-ray diffraction techniques. Further, the synthesized Ag(I)-NHC complexes were evaluated for cytotoxicity study on the L-929 cells and the anticancer activity against the HCT 116 and MCF-7 cancer cell lines. Notably, 1a showed significant anticancer activity against HCT 116 with an IC50 of 6.37 ± 0.92 µg/mL compared to cisplatin (IC50 = 36.75 ± 1.76 µg/mL). 1c (IC50 = 3.21 ± 1.96 µg/mL) and 1e (IC50 = 3.72 ± 1.12 µg/mL) exhibited significant anticancer activity against MCF-7 cells and was similar to cisplatin (IC50 = 32.17 ± 2.85 µg/mL). Meanwhile, 1a and 1e displayed the highest selectivity index. Most importantly, the cell viability test showed that 1e induced neglectable cytotoxicity (IC50 = 36.38 ± 2.27 µg/mL) toward L-929 and was similar to cisplatin (IC50 = 36.11 ± 2.09 µg/mL). The anticancer activities of Ag(I)-NHC complexes vary depending on the substituent group of the silver complex and the cell line type. Moreover, the inhibitory mechanism of 1e was not dependent on caspase-associated apoptosis initiated by the lysosomal-mitochondrial pathway. Taken together, we conclude that this work provides a simple and rapid protocol for the synthesis of Ag(I)-NHC complexes and the featured Ag(I)-NHC complexes have an anticancer drug potential for biomedical applications.

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Methyl benzimidazole-2-carbamate anthelmintics are a class of oral drugs to treat parasitic worm infections via microtubule disruption for non-systemic indications and currently in use. In order to use for anticancer treatment, the new benzimidazoles needs to improve solubility and pharmacokinetic parameters while maintaining its cellular potency as for systemic drug. Structure-activity-relationship on the benzimidazole is thoroughly examined and a novel benzimidazole-2 propionamide BNZ-111 is identified having good oral exposure and bioavailability in rat. Molecular docking study suggests BNZ-111 have a specific binding mode to the ß subunit of curved tubulin. BNZ-111 is potent to cancer cells and possesses good drug-like properties as oral drug. Especially, BNZ-111 is not a P-gp substrate and it demonstrates its efficacy over Paclitaxel-resistance tumor in vivo.

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To increase the success rate of drug discovery, one practical strategy is to begin molecular hybridisation. The presence of two or more pharmacophores in a single unit leads to a pharmacological potency greater than the sum of each individual moiety's potency. Heterocyclic compounds are very widely distributed in nature and are essential for life activities. Benzimidazole and oxadiazole are privileged structures in medicinal chemistry and are widely used in drug discovery and development due to their vast biological properties. The drug-like properties (like pharmacokinetics and pharmacodynamics) of the individual scaffolds can be improved by benzimidazole-oxadiazole chimeric molecules via a molecular hybridisation approach. Benzimidazole and oxadiazole cores can either be fused or incorporated using either functional groups/bonds. Over the last few decades, drug discovery scientists have predicted that these moieties could be interconnected to yield a novel or modified hybrid compound. Benzimidazole and oxadiazole hybrids were identified as the most potent anticancer, antimicrobial, anti-inflammatory, antioxidant, anticonvulsant, antidepressant, antihypertensive and antitubercular agents. In this context, the present review describes the biological properties of benzimidazole-oxadiazole (1,3,4 and 1,2,4) hybrids, their possible structure-activity relationship and the mechanism of action studies presented. This review article is intended to stimulate fresh ideas in the search for rational designs of more active and less toxic benzimidazole-oxadiazole hybrid prospective therapeutic candidates, as well as more effective diagnostic agents and pathologic probes.

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In this work, a series of dibenzimidazole derivatives 1-4, act as highly reversible colorimetric and fluorescent pH chemosensor, were designed and synthesized. Excellent reversible pH response of these sensors could be found by a specific pH change through obvious fluorescent color changes. The response is not affected by common cations (including Al3+, Cu2+, Ca2+, Cd2+, Co2+, Cr3+, Mg2+, Na+, K+, Ni2+, Pb2+ and Zn2+) and anions (including F-, Cl-, Br-, I-, ClO4-, H2PO4-, HSO4-, HCO3- and CH3COO-). Notably, these sensors can be reused more than 10 times without losing functionality. Unlike previous reports, the distinct properties of 1-4 are attributed to the varied link groups. Based on comprehensive experimental data and mechanistic analyses, it is concluded that sensors 1-4 are promising candidates for use as highly reversible "on-off-on" fluorescence switches under precise pH control.

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To address the urgent need for new antifungal agents, a collection of novel pyrazole carboxamide derivatives incorporating a benzimidazole group were innovatively designed, synthesized, and evaluated for their efficacy against fungal pathogens. The bioassay results revealed that the EC50 values for the compounds A7 (3-(difluoromethyl)-1-methyl-N-(1-propyl-1H-benzo[d]imidazol-2-yl)-1H-pyrazole-4-carboxamide) and B11 (N-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide) against B. cinerea were notably low to 0.79 µg/mL and 0.56 µg/mL, respectively, demonstrating the potency comparable to that of the control fungicide boscalid, which has an EC50 value of 0.60 µg/mL. Noteworthy is the fact that in vivo tests demonstrated that A7 and B11 showed superior protective effects on tomatoes and strawberries against B. cinerea infection when juxtaposed with the commercial fungicide carbendazim. The examination through scanning electron microscopy revealed that B11 notably alters the morphology of the fungal mycelium, inducing shrinkage and roughening of the hyphal surfaces. To elucidate the mechanism of action, the study on molecular docking and molecular dynamics simulations was conducted, which suggested that B11 effectively interacts with crucial amino acid residues within the active site of succinate dehydrogenase (SDH). This investigation contributes a novel perspective for the structural design and diversification of potential SDH inhibitors, offering a promising avenue for the development of antifungal therapeutics.

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The recent re-emergence and the increasing popularity of nitazenes, a group of new synthetic opioids (NSO) that belong to the benzimidazole chemical class, has raised public health concerns. As a class of potential opioid analgesic agents whose development was discontinued in the 1960s due to their high potential for abuse, very little is known about their metabolism and physiologic disposition. In the current study, three nitazenes-butonitazene, isotonitazene and protonitaze were incubated in human liver microsomes (HLM), human S9 (HS9) fractions and recombinant cytochrome P450 enzymes. All three nitazenes were rapidly metabolized in both HLM and HS9 with over 95% depletion within 60 min. In HLM, butonitazene, isotonitazene and protonitazene had in vitro intrinsic clearance (CLint) (µL/min/mg protein) values of 309, 221 and 216 respectively compared to 150 of verapamil, the positive control. In HS9, CLint values were 217, 139, and 150 for butonitazene, isotonitazene and protonitazene respectively compared to only 35 for testosterone, the control probe substrate. Putative metabolite identified from this study include products of hydroxylation, desethylation, dealkylation, desethylation followed by dealkylation, and desethylation followed by hydroxylation. The metabolic phenotyping showed CYP2D6, CYP2B6 and CYP2C8 and the major hepatic enzymes responsible for the metabolism of nitazenes. Within 30 min of incubation, CYP2D6 depleted butonitazene (99%), isotonitazene (72%) and butonitazene (100%) significantly. The rapid metabolism of nitazenes may be an important factor in accurate and timely detections and quantitation of the unchanged drugs in human matrices following intoxication or in forensic analysis. The involvement of multiple polymorphic CYPs in their metabolism may play important roles in the susceptibility to intoxication and/or addiction, depending on the activity of the metabolites.

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In this study, two new molecules were synthesized from the reaction of 2-methyl-1H-benzo[d]imidazole with aryl halides in the presence of a strong base. The structures newly of synthesized 1,2-disubstituted benzimidazole compounds were characterized using spectroscopic techniques (FT-IR, 1HNMR, 13CNMR) and chromatographic technique (LC/MS). For discovering an effective anticancer drug, the developed heterocyclic compounds were screened against three different human cancer cell lines (A549, DLD-1, and L929). The results demonstrated that of IC50 values of compound 2a were higher as compared to cisplatin for the A549 and DLD-1 cell lines. The frontier molecular orbital (FMO), and molecular electrostatic potential map (MEP) analyses were studied by using DFT (density functional theory) calculations at B3LYP/6-31G** level of theory. The molecular docking studies of the synthesized compound with lung cancer protein, PDB ID: 1M17, and colon cancer antigen proteins, PDB ID: 2HQ6 were performed to compare with experimental and theoretical data. Compound 2a had shown the best binding affinity with -6.6 kcal/mol. It was observed that the theoretical and experimental studies carried out supported each other.

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Anthelmintic resistance is an increasing problem in many gastrointestinal parasites of grazing animals. Among these, the equine roundworm, Parascaris spp., has developed wide-spread resistance to macrocyclic lactones over the past decades. Additionally, there are recent observations of emerging treatment failure of both tetrahydropyrimidine and fenbendazole. Therefore, the aims of this study were to further investigate the occurrence of fenbendazole resistance on breeding farms and to explore potential management-related risk factors associated with resistance in Parascaris spp. in Sweden. Eleven farms with 92 foals positive for Parascaris spp. were included in a faecal egg count reduction test during the years 2021-2023. According to the clinical protocol of the guidelines of the World Association for the Advancement of Veterinary Parasitology, fenbendazole resistance was present on four farms with efficacies varying from 45 % to 96 %. Having previously reported reduced efficacy on one of these farms, we can now confirm that fenbendazole resistance in Parascaris spp. has established. Farms with more than 40 yearly born foals had a significantly higher probability of having resistant Parascaris spp. Populations compared with smaller farms, (generalized linear model (GLM), t = 70.39, p < 0.001). In addition, there was a correlation between the number of foals on the farm and the frequency of yearly treatments showing that farms with < 20 foals were notably inclined to administer treatments twice during the first year (GLM, t=2.76, p < 0.05) in contrast to larger farms with > 40 foals that were using more frequent treatment intervals. In conclusion, this study confirms the establishment of fenbendazole resistance in Parascaris spp. populations on Swedish stud farms with the number of foals on the farm identified as a risk factor for development of anthelmintic resistance.

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Chemotherapeutic drug delivery systems are commonly limited by their short half-lives, poor bioavailability, and unsuccessful targetability. Herein, pH-responsive hybrid NPs consist of benzimidazole-coated mesoporous silica nanoparticles (BZ-MSN) loaded with naturally occurring flavonoid quercetin (QUE-BZ-MSN). The NPs were further capped with beta-cyclodextrin (BCD) to obtain our desired BCD-QUE-BZMSN, with a zeta potential around 7.05 ± 2.37 mV and diameter about 115.2 ± 19.02 nm. The abundance of BZ onto the nanoparticles facilitates targeted quercetin chemotherapy against model lung and liver cancer cell lines. FTIR, EDX, and NMR analyses revealed evidence of possible surface functionalizations. Powder XRD analysis showed that our designed BCD-QUE-BZMSN formulation is amorphous in nature. The UV and SEM showed that our designed BCD-QUE-BZMSN has high drug entrapment efficiency and a nearly spherical morphology. In vitro, drug release assessments show controlled pH-dependent release profiles that could enhance the targeted chemotherapeutic response against mildly acidic regions in cancer cell lines. The obtained BCD-QUE-BZMSN nanovalve achieved significantly higher cytotoxic efficacy as compared to QUE alone, which was evaluated by in vitro cellular uptake against liver and lung cancer cell lines, and the cellular morphological ablation was further confirmed via inverted microscopy. The outcomes of the study imply that our designed BCD-QUE-BZMSN nanovalve is a potential carrier for cancer chemotherapeutics.

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Benzimidazole compounds are known for their broad spectrum therapeutic potentials. A small library of benzimidazole derivatives were designed and synthesized via a one-pot telescopic grinding approach. The ability of these molecules as proposed anticancer agents were evaluated by their potential to bind to two important cancer pathway protein targets, human estrogen receptors and cyclin dependant kinases, 3ERT and 5FGK respectively. Further nucleic acid binding and reactive oxygen species (ROS) scavenging capacity being in the scope for anticancer potential evaluations, the ability of these molecules have been evaluated for the same. Further, to support the experimental and computational results, AI-assisted tools were employed to predict the anticancer activity (PASS) as well as to identify false positives (PAINS). Also, the druggability of the proposed compounds was evaluated by following their pharmacokinetic parameters - ADME.

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To understand the benzimidazole (BZ) resistance of Haemonchus contortus in Southern Xinjiang, three single nucleotide polymorphisms (SNPs) designated as F167Y, E198A, and F200Y, in the isotype-1 ß-tubulin gene which are associated with BZ resistance, were investigated for H. contortus populations from sheep in Hejing and Minfeng counties of Southern Xinjiang. In brief, a total of 190 H. contortus adults were collected from 52 out of 70 slaughtered sheep in city abattoirs across two regions in Southern Xinjiang. The species identity of each adult worm was confirmed by PCR amplification of ITS-2 using H. contortus-specific primers targeting the ITS-2. The samples were then investigated for BZ-related SNPs at locus 167, 198, and 200, by PCR-sequencing of the isotype-1 ß-tubulin gene. The results showed that only E198A and F200Y mutations were detected in the investigated H. contortus populations. The E198A mutation (homozygous and heterozygote resistant: found in 40% and 30% of sequenced samples from Minfeng and Hejing counties, respectively) was predominant compared with the F200Y mutation (homozygous and heterozygote resistant: found in 14% and 13.3% of sequenced samples from Minfeng and Hejing counties, respectively). The results indicate a high prevalence of BZ resistance in H. contortus populations from certain areas of Southern Xinjiang. Our findings provide valuable information for the prevention and control of H. contortus in areas with similar conditions.

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Given the malignancy of gastric cancer, developing highly effective and low-toxic targeted drugs is essential to prolong patient survival and improve patient outcomes. In this study, we conducted structural optimizations based on the benzimidazole scaffold. Notably, compound 8 f presented the most potent antiproliferative activity in MGC803 cells and induced cell cycle arrest at the G0/G1 phase. Further mechanistic studies demonstrated that compound 8 f caused the apoptosis of MGC803 cells by elevating intracellular reactive oxygen species (ROS) levels and activating the mitogen-activated protein kinase (MAPK) signaling pathway, accompanied by corresponding markers change. In vivo investigations additionally validated the inhibitory effect of compound 8 f on tumor growth in xenograft models bearing MGC803 cells without obvious toxicity. Our studies suggest that compound 8 f holds promise as a potential and safe lead compound for developing anti-gastric cancer agents.

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The direct-linked coumarin-benzimidazole hybrids, featuring aryl and n-butyl substituents at the N1-position of benzimidazole were synthesized through a Knoevenagel condensation reaction. This reaction involved the condensation of 1,2-diaminobenzene derivatives with coumarin-3-carboxylic acids in the presence of polyphosphoric acid (PPA) at 154 °C. The in vitro antibacterial potency of the hybrid molecules against different gram-positive and gram-negative bacterial strains led to the identification of the hybrids 6m and 6p with a MIC value of 6.25 µg/mL against a gram-negative bacterium, Klebsiella pneumonia ATCC 27736. Cell viability studies on THP-1 cells demonstrated that the compounds 6m and 6p were non-toxic at a concentration of 50 µM. Furthermore, in vivo efficacy studies using a murine neutropenic thigh infection model revealed that both compounds significantly reduced bacterial (Klebsiella pneumonia ATCC 27736) counts (more than 2 log) compared to the control group. Additionally, both compounds exhibited favorable physicochemical properties and drug-likeness characteristics. Consequently, these compounds hold promise as lead candidates for further development of effective antibacterial drugs.

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In this study, we aimed to enhance the bioavailability of a benzimidazole derivative with potent anticancer potential through a nano-based approach. Benzimidazole-loaded polyethylene glycol-ß-cyclodextrin-functionalized curcumin nanocomplex (BMPE-Cur) was prepared and characterized for its physicochemical properties and drug release profiles under different pH conditions. In addition, the biological activities of the nanocomplex including antioxidant potentials and pro-apoptogenic properties, against HepG2, PC3, and the chemo-resistant MCF-7-ADR cell lines relative to the normal Wi-38 cell line were in vitro assessed and compared with those of the free benzimidazole compound. In addition to FTIR, XRD, and NMR spectral studies, a polymeric nanocomplex with an average particle size of 467.7 nm and high stability was successfully developed, as indicated by the negative zeta potential (-28.24 mV). The nanocomplex also showed prolonged pH-sensitive sustained drug release under conditions that replicated the tumor's extra/intracellular pH. The formulated nanocomplex also demonstrated potent radical scavenging capacity owing to the inclusion of curcumin, a known radical quencher. In addition, compared with the free compound, BMPE-Cur induced DNA fragmentation-driven cell cycle arrest in HepG2, PC3, and MCF-7-ADR cells at the G1/S, G1 & S phases; respectively, with remarkable selectivity. In conclusion, the newly formulated BMPE-Cur nanocomplex represents an attractive multitarget anticancer candidate.

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In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 µM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 µM, SI = 1390). Another compound (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 µM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.

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In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT1R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1H NMR, 13C NMR and mass spectral data. Through biosimulation, compounds 1-7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of calcium channel. Molecular docking studies helped to understand at the molecular level the dual vasorelaxant effects with the recognition sites of the AT1R and the L-type calcium channel. In an in vivo spontaneously hypertensive rat model (SHR), intraperitoneally administration of compound 1 at 20 mg/kg resulted in a 25 % reduction in systolic blood pressure, demonstrating both ex vivo vasorelaxant action and in vivo antihypertensive multitarget efficacy. ©2024 Elsevier.

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Benzimidazole scaffolds have potent anticancer activity due to their structure similarity to nucleoside. In addition, benzimidazoles could function as hydrogen donors or acceptors and bind to different drug targets that participate in cancer progression. The literature had many anticancer agents containing benzimidazole cores that gained much interest. Provoked by our endless interest in benzimidazoles as anticancer agents, we summarized the successful trials of the benzimidazole scaffolds in this concern. Moreover, we discuss the substantial opportunities in cancer treatment using benzimidazole-based drugs that may direct medicinal chemists for a compelling future design of more active chemotherapeutic agents with potential clinical applications. The uniqueness of this work lies in the highlighted benzimidazole scaffold hybridization with different molecules and benzimidazole-metal complexes, detailed mechanisms of action, and the IC50 of the developed compounds determined by different laboratories after 2015.

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Benzimidazoles, the representative pharmacophore of fungicides, have excellent antifungal potency, but their simple structure and single site of action have hindered their wider application in agriculture. In order to extend the structural diversity of tubulin-targeted benzimidazoles, novel benzimidazole derivatives were prepared by introducing the attractive pyrimidine pharmacophore. 2-((6-(4-(trifluoromethyl)phenoxy)pyrimidin-4-yl)thio)-1H-benzo[d]imidazole (A25) exhibited optimal antifungal activity against Sclerotinia sclerotiorum (S. s.), affording an excellent half-maximal effective concentration (EC50) of 0.158 µg/mL, which was higher than that of the reference agent carbendazim (EC50 = 0.594 µg/mL). Pot experiments revealed that compound A25 (200 µg/mL) had acceptable protective activity (84.7%) and curative activity (78.1%), which were comparable with that of carbendazim (protective activity: 90.8%; curative activity: 69.9%). Molecular docking displayed that multiple hydrogen bonds and π-π interactions could be formed between A25 and ß-tubulin, resulting in a stronger bonding effect than carbendazim. Fluorescence imaging revealed that the structure of intracellular microtubules can be changed significantly after A25 treatment. Overall, these remarkable antifungal profiles of constructed novel benzimidazole derivatives could facilitate the application of novel microtubule-targeting agents.

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The structure of polymeric catena-poly[2-amino-benzimidazolium [[dioxidovanadium(V)]-µ-oxido]], {(C7H8N3)2[V2O6]} n , has monoclinic symmetry. The title compound is of inter-est with respect to anti-cancer activity. In the crystal structure, infinite linear zigzag vanadate (V2O6)2- chains, constructed from corner-sharing VO4 tetra-hedra and that run parallel to the a axis, are present. Two different protonated 2-amino-benzimidazole mol-ecules are located between the (V2O6)2- chains and form classical N-H⋯O hydrogen bonds with the vanadate oxygen atoms, which contribute to the cohesion of the structure.