Benzimidazole Compounds Research Articles

Chloroquine and chloroquinoline derivatives as models for the design of modulators of amyloid Peptide precursor metabolism.

The amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD). Preventing deregulated APP processing by inhibiting amyloidogenic processing of carboxy-terminal fragments (APP-CTFs), and reducing the toxic effect of amyloid beta (Aβ) peptides remain an effective therapeutic strategy. We report the design of piperazine-containing compounds derived from chloroquine structure and evaluation of their effects on APP metabolism and ability to modulate the processing of APP-CTF and the production of Aβ peptide. Compounds which retained alkaline properties and high affinity for acidic cell compartments were the most effective. The present study demonstrates that (1) the amino side chain of chloroquine can be efficiently substituted by a bis(alkylamino)piperazine chain, (2) the quinoline nucleus can be replaced by a benzyl or a benzimidazole moiety, and (3) pharmacomodulation of the chemical structure allows the redirection of APP metabolism toward a decrease of Aβ peptide release, and increased stability of APP-CTFs and amyloid intracellular fragment. Moreover, the benzimidazole compound 29 increases APP-CTFs in vivo and shows promising activity by the oral route. Together, this family of compounds retains a lysosomotropic activity which inhibits lysosome-related Aβ production, and is likely to be beneficial for therapeutic applications in AD.

Theoretical prediction and experimental study of 1-Butyl-2-(4-methylphenyl)benzimidazole as a novel corrosion inhibitor for mild steel in hydrochloric acid

The inhibition performance of a newly synthesized benzimidazole derivative, 1-Butyl-2-(4-methylphenyl)benzimidazole (BMPB), on the surface of mild steel in 1.0 M HCl was predicted theoretically using molecular dynamics method and quantum chemical calculations in comparison with benzimidazole (BI) compound. The theoretical results confirmed by electrochemical measurements and scanning electron microscopy study show that BMPB may exhibit better inhibitive performance than BI for mild steel in hydrochloric acid solution. The adsorption process and thermodynamic parameters of BMPB were calculated and discussed. It was found that BMPB is classified as a mixed type inhibitor, suppressing both anodic metal dissolution and cathodic hydrogen evolution reactions. The high inhibitory efficiency of BMPB is due to the formation of a protective film on the mild steel surface. This study shows that theoretical calculations can be used as a reliable method to select organic inhibitors prior to experiments.

High Throughput Screening Identifies a Novel Compound Protecting Cardiomyocytes from Doxorubicin-Induced Damage.

Antracyclines are effective antitumor agents. One of the most commonly used antracyclines is doxorubicin, which can be successfully used to treat a diverse spectrum of tumors. Application of these drugs is limited by their cardiotoxic effect, which is determined by a lifetime cumulative dose. We set out to identify by high throughput screening cardioprotective compounds protecting cardiomyocytes from doxorubicin-induced injury. Ten thousand compounds of ChemBridge's DIVERSet compound library were screened to identify compounds that can protect H9C2 rat cardiomyocytes against doxorubicin-induced cell death. The most effective compound proved protective in doxorubicin-treated primary rat cardiomyocytes and was further characterized to demonstrate that it significantly decreased doxorubicin-induced apoptotic and necrotic cell death and inhibited doxorubicin-induced activation of JNK MAP kinase without having considerable radical scavenging effect or interfering with the antitumor effect of doxorubicin. In fact the compound identified as 3-[2-(4-ethylphenyl)-2-oxoethyl]-1,2-dimethyl-1H-3,1-benzimidazol-3-ium bromide was toxic to all tumor cell lines tested even without doxorubicine treatment. This benzimidazole compound may lead, through further optimalization, to the development of a drug candidate protecting the heart from doxorubicin-induced injury.

Progress in the Research of Copper Promoted C—H Functionalizations for the Synthesis of Fused Heterocycles Bearing Bridgehead Nitrogen

The copper-catalyzed C—H activation, selective functionalization and the development of cyclization strategy for the synthesis of novel fused-heterocyclic (heterocycles with ring-junction nitrogen or bridgehead nitrogen) compounds are discussed. This class of novel bridgehead nitrogen heterocycles includes indolizine, pyrazolopyridine, benzimidazole and other polyheterocyclic compounds. The series including modern amination, oxidative coupling and Csp2—H, Csp—H, Csp3—H and N—H activation catalyzed by Cu(I) or Cu(II) salts makes this green synthesis a superior and practical method providing entry into complex heterocycles. Some reaction mechanisms have also been summarized. Keywords copper-catalyzed; bridgehead nitrogen fused-heterocycles; oxidative coupling; C—H activation; N—H activation, cyclization; annulation

Odporność grzyba Botryotinia fuckeliana (De Bary) Whetzel (Botrytis cinerea Pers.) – patogena malin, truskawek i innych roślin uprawnych na fungicydy benzimidazolowe [Resistance of Botryotinia fuckeliana (De Bary) Whetzel (Botrytis cinerea Pers.) to benzimidazole fungicides

In the period 1975-1977 forms of the fungus <i>Botrytis cinerea</i> were found in Poland resistant to benzimidazole fungicides. The incidence of the resistant forms increases with the more intensive use of these fungicides. The resistance of <i>Botrytis cinerea</i> to benzimidazole compounds is a cross-resistance involving the whole group of these agents, nowithstanding wihich of them was applied. The resistance acquired by the fungus does not change its reaction to other prophylactic fungicides.

In vitro effect of 5-fluorouracil and paclitaxel on Echinococcus granulosus larvae and cells

Human cystic echinococcosis is a zoonosis caused by the metacestode stage of the tapeworm Echinococcus granulosus. Although benzimidazole compounds such as albendazole and mebendazole have been the cornerstone of chemotherapy for the disease, there is often no complete recovery after treatment. Hence, in searching for novel treatment options, we examined the in vitro efficacies of 5-fluorouracil (5-FU) and paclitaxel (PTX) against E. granulosus germinal cells, protoscoleces and cysts. 5-FU or PTX inhibited the growth of E. granulosus cells in a time dependent manner. Although both treatments had a protoscolicidal effect, 5-FU had a considerably stronger effect than PTX. 5-FU produced a dose- and time-dependent effect, provoking the complete loss of viability after 24 days of incubation. Moreover, cysts did not develop following the inoculation of treated protoscoleces into mice. The loss of viability was slower in PTX treated protoscoleces, reaching to approximately 60% after 30 days. The results of the in vitro treatment with 5-FU and PTX were similar in secondary murine cysts. The employment of SEM and TEM allowed us to examine, at an ultrastructural level, the effects induced by 5-FU and PTX on E. granulosus germinal cells, protoscoleces and murine cysts. In conclusion, the data obtained clearly demonstrated that 5-FU and PTX at clinically achievable concentrations inhibit the survival of larval cells, protoscoleces and metacestodes. In vivo studies to test the antiparasitic activities of 5-FU and PTX are currently being undertaken on the murine model of cystic echinococcosis.

ChemInform Abstract: Benzimidazole‐Biologically Attractive Scaffold for Protein Kinase Inhibitors

AbstractReview: [119 refs.

A combination treatment strategy using pyrantel pamoate and oxibendazole demonstrates additive effects for controlling equine cyathostomins

SummaryAnthelmintics of the avermectin/milbemycin class continue to demonstrate the highest efficacy against cyathostomin nematodes; however, over‐reliance on these drugs is increasing the likelihood that recent emerging resistance to these drugs will worsen. Use of benzimidazole and pyrantel compounds given concurrently may provide sufficiently high efficacy to serve as a viable treatment alternative to the avermectin/milbemycin drugs, thus reducing the selective pressures for resistance development. The study was conducted to determine if oxibendazole (OBZ) and pyrantel pamoate (PYR) would have greater efficacy when used in combination vs. what either drug could achieve individually, and to determine if the combination protocol would consistently achieve faecal egg count reduction (FECR) rates >90%, the general threshold for acceptable efficacy. Horses of various ages and breeds on 11 horse farms were assigned randomly to treatment with OBZ (n = 34), PYR (n = 35), or a combination of both (n = 61). A faecal egg count was performed for each horse prior to treatment and 9–14 days post treatment. Mean FECR percentages were calculated for each treatment group on individual farms, and for each treatment group across all farms. Combination treatment achieved >90% mean FECR on all 11 farms, and >95% on 9 of the 11 farms. Overall arithmetic mean FECR rates were 90.03%, 81.10% and 96.35% for horses treated respectively with OBZ, PYR, and the 2 drugs in combination. Combination treatment with OBZ and PYR demonstrated an additive effect whereby horses given both anthelmintics concurrently had mean FECR percentages that were significantly greater than in horses given either drug alone. Combination treatment with OBZ and PYR can be an efficacious and viable treatment choice for controlling cyathostomins, thereby reducing the over‐reliance on avermectin/milbemycin drugs.

Proton Conducting Compound of Benzimidazole with Sebacic Acid: Structure, Molecular Dynamics, and Proton Conductivity

Benzimidazole salt of sebacic acid, a new proton conductor from the family of benzimidazole compounds of dicarboxylic acids, was crystallized to search for the factors which determine the hydrogen bond motif and the structure of the crystals. The molecular structure of benzimidazole-sebacic acid salt was solved by using X-ray diffractions and confirmed by 1H and 13C MAS NMR experiments combined with DFT calculations. The salt of sebacic acid, with 10 carbon atoms in the chain, was found to exhibit an undulated layer-type structure with banana-shaped acid molecules linked by O–H···O bonds into rectangular-type wavy chains and flat base molecules attached to the carboxylic groups by N–H···O bonds. The undulated layers are not linked with hydrogen bonds. Comparison of the architecture of benzimidazole salts with weak dicarboxylic acids of shorter carbon chains, studied by us earlier, points at the role of the acid chain length in the formation of structural and hydrogen bond motifs. The dynamics of protons in the ordered crystalline phase and disordered surface layers was characterized by NMR spin–lattice relaxation measurements, whereas complex impedance studies yielded information on the activation energy of proton diffusion in the both phases.

Gold complexes with benzimidazole derivatives: synthesis, characterization and biological studies

Synthesis, characterization, DFT studies and biological assays of new gold(I) and gold(III) complexes of benzimidazole are reported. Molecular and structural characterizations of the compounds were based on elemental (C, H and N) and thermal (TG-DTA) analyses, and FT-IR and UV-Visible spectroscopic measurements. The structures of complexes were proposed based DFT calculations. The benzimidazole compounds (Lig1 and Lig2) and the gold complexes were tested against three Leishmania species related to cutaneous manifestations of leishmaniasis. The free benzimidazole compounds showed no leishmanicidal activity. On the other hand, the gold(I and III) complexes have shown to possess significant activity against Leishmania in both stages of parasite, and the gold(III) complex with Lig2 exhibited expressive leishmanicidal activity with IC50 values below 5.7μM. Also, the gold complexes showed high leishmania selectivity. The gold(I) complex with Lig1, for example, is almost 50 times more toxic for the parasite than for macrophages. Besides the leishmanicidal activity, all complexes exhibited toxic effect against SK-Mel 103 and Balb/c 3T3, cancer cells.

Benzimidazole-biologically attractive scaffold for protein kinase inhibitors

Great advances in elucidating molecular structures allow the precise determination of the interactions between a protein and a therapeutic agent. Enzyme inhibitors are used as a therapeutic agent with organic molecules, that interact with their targets through the weak linkages of hydrogen bonding and van der Waals interactions. These reduce the undesirable side effects and allow more non-specific interactions with non-target molecules. Benzimidazole acts as an enzyme inhibitor that may interact with different proteins and enzymes and has inspired chemists to carry out various structural variations of it. This review discusses the development of distinct benzimidazoles with an array of enzyme inhibitors viz., aurora kinase inhibitors, cyclin-dependent kinase inhibitors, mitogen activated protein kinase inhibitors, polo like kinase inhibitors, Tie kinase inhibitors, lymphocyte specific kinase inhibitors etc., also highlighting the molecular interaction with enzyme inhibitors. Various derivatives of benzimidazole, with different inhibitory activities, have been described on the basis of substitution around the central moiety, with an aim to help medicinal chemists to develop structure–activity relationships. The reviews in the literature till now are focused only on the biological activities of benzimidazole viz., antiviral, anticancer and antifungal, but the present review focuses on the latest work, describing the inhibitor aspects and the potential of the benzimidazole ring. This discussion will further help in the development of novel benzimidazole compounds.

Metabolism-directed structure optimization of benzimidazole-based Francisella tularensis enoyl-reductase (FabI) inhibitors

1. FabI is a potential antibiotic target against Francisella tularensis, which has been classified as a Category A biowarfare agent of high risk to public health. Our previous work demonstrated that N-benzyl benzimidazole compounds possess promising FabI inhibitory activity, but their druggability properties, including metabolic stability, are unknown.2. The objective of this study was to characterize structure–metabolism relationships of a series of N-benzyl benzimidazole compounds to guide chemical optimization for better metabolic stability. To this end, metabolic stability data were obtained for 22 initial lead compounds using mouse hepatic microsomes.3. Metabolic hotspots on the benzimidazole core structure as well as the benzyl ring were identified and verified by metabolite identification studies of four model compounds. Interestingly, the proposed structure–metabolism relationships did not apply to nine newly synthesized cyclopentane or oxacyclopentane derivatives of N-benzyl benzimidazole.4. Subsequently, in silico quantitative structure–property relationship models were developed. Four molecular descriptors representing molecular polarity/polarisability, symmetry and size were identified to best explain variability in metabolic stability of different compounds. Multi-linear and non-linear regression models based on the selected molecular descriptors were developed and validated.5. The structure–metabolism relationships for N-benzyl benzimidazole compounds should help optimization of N-benzyl benzimidazole compounds for better pharmacokinetic behavior.

Research in Benzimidazole Compounds as Antibacterial Agents

Benzimidazole compounds are known to possess varied biological activities and so far various types of benzimidazole drugs have extensively been used in clinic. Benzimidazole compounds as a antibacterial agents has been a quite rapidly developing and is gradually becoming a relatively independent scientific area. In this paper we presented the recent advances of benzimidazole compounds as antibacterial agents. The perspective of the foreseeable future and potential application of benzimidazole as antibacterial agents are also presented.

Ultra-high performance liquid chromatography–atmospheric pressure chemical ionization–tandem mass spectrometry for the analysis of benzimidazole compounds in milk samples

In this work the atmospheric pressure ionization behavior and the tandem mass spectrometry fragmentation of 19 benzimidazoles was studied. Several atmospheric pressure ionization (API) sources (ESI, APCI and APPI) were evaluated showing that APCI was the best option, mainly for KETO-TCB that provided a 20 times improvement versus ESI. From the studies of tandem mass spectrometry, fragmentation pathways were proposed thus characterizing the most abundant and interesting product ions and selecting the most abundant and selective ones for the confirmatory quantitative method performed in SRM mode in a triple quadrupole mass analyzer. For quantitative analysis, the 19 benzimidazoles were separated in less than 7min using a C18 column packed with superficially porous particles providing high efficiency within the range of UHPLC. A QuEChERS-like sample treatment was applied to milk samples before the UHPLC–APCI–MS/MS determination providing method limits of quantitation that ranged from 0.6 to 3μgkg−1 and showing good repeatability (RSD: 2–18%) and accuracy (relative errors: 1–23%) suitable for using this method for routine analysis.

Designing and Biological Evaluation of New Benzimidazole Compounds

Benzimidazole derivatives play important role in medical field with many important properties. The potency of these clinically useful drugs in the treatment of bacterial infections and other activities encouraged the development of some more potent and significant compounds. This research article is summarized to know about the chemistry of different derivatives of substituted benzimidazoles along with their pharmacological activities. In the present research the new benzimidazole derivatives were synthesized. The reaction was carried out by condensing o-phenylene diamine with carboxylic acid by using Phillip's condensation. The free N-H group in benzimidazole was allowed for acetylation. The acetylated product was made to react with different aromatic aldehydes in the presence of alkali to give different chalcones (III A-III F) by aldol condensation. The compounds were synthesized in good yield and their structures were confirmed by M.P, TLC and spectral data. All the synthesized compounds were screened for their antibacterial activity.

Synthesis and Biological Evaluation of Some 1,2‐Disubstituted Benzimidazole Derivatives as New Potential Anticancer Agents

The synthesis of some new 1-(2-aryl-2-oxoethyl)-2-[(morpholine-4-yl)thioxomethyl]benzimidazole derivatives and investigation of their anticancer activities were the aims of this work. 2-(Chloromethyl)benzimidazole compound was reacted with sulfur and morpholine via Willgerodt-Kindler reaction to give 2-[(morpholine-4-yl)thioxomethyl]benzimidazole. Then, the obtained compound was reacted with appropriate α-bromoacetophenone derivatives in the presence of potassium carbonate to give the final products. Structure elucidation of the final compounds was achieved by FT-IR, (1)H NMR spectroscopy and MS spectrometry. The anticancer activities of the final compounds were evaluated by MTT assay, BrdU method, and flow cytometric analysis on C6, MCF-7, and A549 tumor cells. Most of the synthesized compounds exhibited considerable selectivity against the MCF-7 and C6 cell lines.

From molecule to complex: Design of smart fluorescent anion-sensors

A novel 2-(2-pyridyl)benzimidazole (a) compound with hydrogen bond unit was synthesized as an anion receptor. It is noteworthy that only fluoride anions can led to its fluorescence change from ultraviolet (362nm) to visible region (408nm) compared with AcO−, Cl−, Br−, and I−. Spectroscopic studies demonstrated that the recognition process can be attributed to the hydrogen bonding interactions between F− and the imidazole-NH. More importantly, this ligand can coordinate to europium ion and a novel europium complex Eu(a)3(NO3)3·H2O possessing red emission was prepared. We noted that the luminescence of this complex can be completely quenched by F− as well as AcO−. However, we recognized that the competitive coordination interactions between anions and ligand resulted in the quenching effects.

A Selective Inhibitor of Heme Biosynthesis in Endosymbiotic Bacteria Elicits Antifilarial Activity In Vitro

Lymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic α-proteobacteria Wolbachia are essential for these parasites throughout their life cycle. Using a high-throughput chemical screen, we identified a benzimidazole compound, wALADin1, that selectively targets the δ-aminolevulinic acid dehydratase (ALAD) of Wolbachia (wALAD) and exhibits macrofilaricidal effects on Wolbachia-containing filarial worms invitro. wALADin1 is a mixed competitive/noncompetitive inhibitor that interferes with the Mg(2+)-induced activation of wALAD. This mechanism inherently excludes activity against the Zn(2+)-dependent human ortholog and might be translatable to Mg(2+)-responsive orthologs of other bacterial or protozoan pathogens. The specificity profile of wALADin1 derivatives reveals chemical features responsible for inhibitory potency and species selectivity. Our findings validate wALADins as a basis for developing potent leads that meet current requirements for antifilarial drugs.

FORMULATION AND EVALUATION OF MUCOADHESIVE BUCCAL TABLET OF DOMPERIDONE MALEATE

The objective of the present study was to develop and evaluate mucoadhesive dosage form of Domperidone maleate. It is an antiemetic synthetic benzimidazole compound that acts as a dopamine D2 receptor antagonist. Mucoadhesive Domperidone maleate tablet formulation was prepared by direct compression method. The formulation F3 containing (Carbopol 940 + sodium alginate) was found to be best among all the formulation batches because of its consistent release rate for 7 h and extent of drug release was 94.44%. Graphical treatment of the formulation F3 to Higuchi’s equation showed that the drug release was diffusion mediated. In-vitro permeability study for formulation F3 for 7 h had shown 76.69% drug release. FTIR studies showed no evidence on interaction between drug and polymers. Key words: Domperidone maleate, Mucoadhesive tablet, antiemetic

HQSAR Study and Molecular Design of Benzimidazole Derivatives as Corrosion Inhibitors

Hologram quantitative structure-activity relationship (HQSAR) analysis was conducted on a series of benzimidazole compounds to build the HQSAR model between corrosion inhibition properties and molecular structures in acid environment. The optimal HQSAR model was determined by investigating the influence of different fragment distinction and fragment size on the models, and the models stability and predictive ability were evaluated. The results show that the optimal HQSAR model was generated using atoms(A), bonds(B), connectivity(C), hydrogen(H), chirality(Ch), donor and acceptor(DA) as fragment distinction and fragment size of 1-3. The model had a non-cross validated coefficient (r 2 ) value of 0.996, a cross-validated (q 2 ) value of 0.960, and a cross-validated standard error (SE cv ) value of 3.709, which indicates good statistics stability and predictive power. On the basis of the maps derived from the optimal HQSAR model, 38 new benzimidazole derivatives were designed and screened using the optimal HQSAR model, giving potential candidates with high predictive inhibition efficiency. This work provides valuable information for further research and design of more promising corrosion inhibitors in the oil and gas field.