Benzimidazole Drugs Research Articles

Resolution of a disputed albendazole result in the UK Official Control System – time for more guidance?

ABSTRACTAlbendazole, one of the benzimidazole anthelmintics, is used in ruminants and has maximum residue limits in muscle, fat and other tissue owing to reported teratogenicity. Albendazole is extensively metabolised in domestic animals and humans with rapid conversion to a sulphoxide and subsequently sulphone and amino sulphone metabolites. Sulphoxide metabolites are responsible for the systemic biological activity of benzimidazole drugs. Herein we report a case of disputed results for albendazole in a consignment sampled at import in which the Official Analyst certified against the consignment for excess albendazole. A laboratory acting for the importer reported data below the MRL, including a finding of the parent drug which is not included in the residue definition. The Government Chemist has a statutory duty as a route of technical appeal in the UK Official Food Control system and the case was referred for referee analysis. We report our findings based on a LC-MS/MS method, which confirmed the official findings, did not reveal the presence of the parent drug but identified hot spots of albendazole marker residues in the consignment. We discuss the need for recommendations on official sampling at import and interpretation of results.

Short-Term Effects of Albendazole on the Oxidative Stress Markers and Hematological Parameters in Tissues of African Catfish Clarias gariepinus.

Albendazole (ABZ) is a typical broad-spectrum benzimidazole drug used for the treatment of parasitic worm infestations in humans and animals. The present study investigated the oxidative stress biomarkers and hematological parameters in juvenile African Catfish (also known as Sharptooth Catfish) Clarias gariepinus exposed to ABZ for 96 h. Fish were exposed to 0 (control) 20, 40, and 60 mg/L ABZ. The liver and gill tissues were sampled at regular intervals of 24 h, and the results showed significant concentration- and time-dependent increases in the values of lipid peroxidation but reductions in glutathione peroxidase, catalase, superoxide dismutase, and glutathione reductase in both tissues. Erythrocytes were sampled to evaluate hematological parameters. The results showed significant concentration- and time-dependent increases in white blood cells but no significant differences in mean cellular hemoglobin. Hemoglobin values, red blood cell counts, packed cell volume, mean cell volume, and mean cellular hemoglobin concentration decreased significantly over the experimental period. The activities of lymphocytes and neutrophils increased significantly, whereas there were no significant differences in basophils, eosinophils, and monocytes among the treatment groups. Albendazole should be used with caution, as sublethal concentrations induced oxidative stress in the liver and gill tissues along with hematological changes that were more evident in liver cells. Received November 20, 2015; accepted May 4, 2015.

Odanacatib, a Cathepsin K Cysteine Protease Inhibitor, Kills Hookworm In Vivo.

Hookworm infection is chief among soil-transmitted helminthiases (STHs) for the chronic morbidly inflicted. Deworming via mass drug administration (MDA) programs most often employs single doses of benzimidazole drugs to which resistance is a constant threat. To discover new drugs, we employ a hamster model of hookworm infection with Ancylostoma ceylanicum and use albendazole (ABZ; 10 mg/kg orally) as the gold standard therapy. We previously showed that a single oral 100 mg/kg dose of the cathepsin cysteine protease (CP) inhibitor, K11777, offers near cure of infection that is associated with a 95% reduction in the parasite’s resident CP activity. We confirm these findings here and demonstrate that odanacatib (ODN), Merck’s cathepsin K inhibitor and post-clinical Phase III drug candidate for treatment of osteoporosis, decreases worm burden by 73% at the same dose with a 51% reduction in the parasite’s CP activity. Unlike K11777, ODN is a modest inhibitor of both mammalian cathepsin B and the predominant cathepsin B-like activity measureable in hookworm extracts. ODN’s somewhat unexpected efficacy, therefore, may be due to its excellent pharmacokinetic (PK) profile which allows for sustained plasma exposure and, possibly, sufficient perturbation of hookworm cathepsin B activity to be detrimental to survival. Accordingly, identifying a CP inhibitor(s) that combines the inhibition potency of K11777 and the PK attributes of ODN could lead to a drug that is effective at a lower dose. Achieving this would potentially provide an alternative or back-up to the current anti-hookworm drug, albendazole.

Microsatellite marker analysis of Haemonchus contortus populations from Pakistan suggests that frequent benzimidazole drug treatment does not result in a reduction of overall genetic diversity.

BackgroundThe impact of drug selection pressure on the overall genetic diversity of parasitic nematode populations in the field is poorly understood. In this study, we address this issue for the small ruminant parasite Haemonchus contortus in the Punjab, Pakistan. This region provides an opportunity to compare H. contortus populations that have been subjected to a prolonged period of frequent benzimidazole drug treatments on government farms with parasite populations that have been exposed to little or no drug treatment in neighbouring pastoral herds.MethodsAdult H. contortus worms were collected from the abomasa of small ruminants from three government farms frequently using benzimidazole drugs, and closed to animal movement, for over 30 years and also from from eighteen pastoral herds subject to minimal drug selection. The frequency of three known benzimidazole resistance associated mutations was determined in each parasite population. For the seven parasite populations in which resistance mutations were found, the diversity, geographical distribution and phylogenetic relationships of isotype-1 β-tubulin benzimidazole resistance haplotypes were determined. In addition, the genetic diversity of the parasite populations on the three government farms were compared with those from four pastoral herds.ResultsThe F200Y (TAC) resistance mutation was present at a very high frequency in H. contortus populations from government herds, but not from pastoral herds, consistent with their respective drug selection histories. Population genetic analysis, using a panel of microsatellite markers, revealed that there was little genetic differentiation among the parasite populations with no significant difference in the overall genetic diversity between government and pastoral herds. In addition, sequence analysis of the isotype-1 β-tubulin locus revealed multiple F200Y (TAC) haplotypes demonstrating soft selective sweeps even in government herds with little or no contemporary parasite migration.ConclusionsThe results suggest that, although the frequent drug treatment used on government farms has selected for a high frequency of benzimidazole resistance mutations, there has been little or no reduction in the overall genetic diversity of the selected parasite populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1624-0) contains supplementary material, which is available to authorized users.

The Right Tool for the Job: Detection of Soil-Transmitted Helminths in Areas Co-endemic for Other Helminths.

BackgroundDue to the recent increased use of the McMaster (MM) fecal egg counting method for assessing benzimidazole drug efficacy for treating soil-transmitted helminth (STH) infections, the aim of the current study was to determine the operational value of including the MM method alongside the Kato-Katz (KK) fecal thick smear to increase the diagnostic sensitivity when STHs are co-endemic with trematode helminths (e.g., Schistosoma mansoni).MethodsA cross-sectional study was conducted in school-aged children aged 4-18 years in the northeastern region of the State of Minas Gerais (Brazil), where Necator americanus, Ascaris lumbricoides, Trichuris trichiura, and S. mansoni are co-endemic. One fecal sample from each participant was collected and transported to the field laboratory for analysis. Coprological diagnosis was performed on each fecal sample by three different methods: Formalin-Ether Sedimentation (FES), KK and the MM technique. The diagnostic sensitivity and negative predictive value (NPV) of each technique was calculated using the combination of all three techniques as the composite standard. In order to determine the agreement between the three techniques Fleiss´ kappa was used. Both the Cure Rate (CR) and the Fecal Egg Count Reduction (FECR) were calculated using the two quantification techniques (i.e., the MM and KK).ResultsFecal samples from 1260 children were analyzed. The KK had higher diagnostic sensitivity than the MM for the detection of both A. lumbricoides (KK 97.3%, MM 69.5%) and hookworm (KK 95.1%, MM 80.8%). The CR of a single dose of mebendazole varied significantly between the KK and MM for both A. lumbricoides (p = 0.016) and hookworm (p = 0.000), with lower rates obtained with the KK. On the other hand, the FECR was very similar between both techniques for both A. lumbricoides and hookworm.ConclusionThe MM did not add any diagnostic value over the KK in areas where both STHs and trematodes were co-endemic. The lower sensitivity of the MM would have an important impact on the administration of selective school-based treatment in this area since if only the MM were used, 36 (13.9%) children diagnosed with A. lumbricoides would have gone untreated.

Benzimidazole derivatives as anticancer drugs: A theoretical investigation

In this study the anticancer properties of a series of benzimidazole drugs 1–9 and their interactions with DNA base pairs were investigated. The obtained theoretical results for anticancer activity of synthesized drugs 1–5 were compared to corresponding published experimental results. Based on theoretical and published experimental anticancer scales, drugs 2 and 4 have higher anticancer activity among drugs 1–5. Obtained results reveal that interactions of studied drugs with DNA base pairs are energetically favorable and solvent and electric field (EF) increase the binding energies in comparison to gas phase. The binding energies of drugs 2, 5 and 4 with DNA base pairs are more negative than corresponding values for drug 1. We propose the novel drugs 6–9 to synthesize with higher anticancer activity. Results show that binding energies of novel drugs 6–9 were more negative than drugs 1–5. Finally, results show that chemical potential, electrophilicity and global hardness can be considered as admissible theoretical anticancer indexes for studied benzimidazole drugs 1–9.

Omeprazole and lansoprazole enantiomers induce CYP3A4 in human hepatocytes and cell lines via glucocorticoid receptor and pregnane X receptor axis.

Benzimidazole drugs lansoprazole and omeprazole are used for treatment of various gastrointestinal pathologies. Both compounds cause drug-drug interactions because they activate aryl hydrocarbon receptor and induce CYP1A genes. In the current paper, we examined the effects of lansoprazole and omeprazole enantiomers on the expression of key drug-metabolizing enzyme CYP3A4 in human hepatocytes and human cancer cell lines. Lansoprazole enantiomers, but not omeprazole, were equipotent inducers of CYP3A4 mRNA in HepG2 cells. All forms (S-, R-, rac-) of lansoprazole and omeprazole induced CYP3A4 mRNA and protein in human hepatocytes. The quantitative profiles of CYP3A4 induction by individual forms of lansoprazole and omeprazole exerted enantiospecific patterns. Lansoprazole dose-dependently activated pregnane X receptor PXR in gene reporter assays, and slightly modulated rifampicin-inducible PXR activity, with similar potency for each enantiomer. Omeprazole dose-dependently activated PXR and inhibited rifampicin-inducible PXR activity. The effects of S-omeprazole were much stronger as compared to those of R-omeprazole. All forms of lansoprazole, but not omeprazole, slightly activated glucocorticoid receptor and augmented dexamethasone-induced GR transcriptional activity. Omeprazole and lansoprazole influenced basal and ligand inducible expression of tyrosine aminotransferase, a GR-target gene, in HepG2 cells and human hepatocytes. Overall, we demonstrate here that omeprazole and lansoprazole enantiomers induce CYP3A4 in HepG2 cells and human hepatocytes. The induction comprises differential interactions of omeprazole and lansoprazole with transcriptional regulators PXR and GR, and some of the effects were enantiospecific. The data presented here might be of toxicological and clinical importance, since the effects occurred in therapeutically relevant concentrations.

The effect of risk factors of sheep flock management practices on the development of anthelmintic resistance in the Czech Republic

The in vivo faecal egg count reduction test was used for the evaluation of the benzimidazole and macrocylic lactone drug efficacies against gastrointestinal nematodes in 10 flocks of sheep. The same samples were tested concurrently in vitro for benzimidazole resistance using the egg hatch test, and for resistance to ivermectins using the microagar larval development test. The conformity of obtained results between in vivo and in vitro tests was recorded. When the selected methods were applied, anthelmintic resistance to benzimidazoles was detected at four (40%) farms while resistance to ivermectins was evident at one (10%) farm. At one farm (10%) ivermectin resistance was suspected. Moxidectin was effective at all surveyed farms. Teladorsagia was recognized as the only benzimidazole resistant genus in post-treatment coprocultures, whereas Haemonchus larvae were resistant to ivermectins. This represents the first recorded occurrence of ivermectin resistance in gastrointestinal nematodes of sheep in the Czech Republic. A linear mixed-effects model demonstrated that the majority of evaluated management practices have a significant effect on resistance to benzimidazoles. While application of preventive practices like quarantine and smart drenching maintains low levels of anthelmintic resistance, others like the dose-and-move strategy, administration of the same family of drugs over extended periods of time, and number of treatments per year are responsible for the increase of resistance to anthelmintics at evaluated farms. Only targeted selective treatments approaches had no effect on resistance status. This study indicates the importance of farm management practices in anthelmintic resistance development.

Health education and the control of intestinal worm infections in China: a new vision.

BackgroundThe transmission of soil-transmitted helminths (STHs) is associated with poverty, poor hygiene behaviour, lack of clean water and inadequate waste disposal and sanitation. Periodic administration of benzimidazole drugs is the mainstay for global STH control but it does not prevent re-infection, and is unlikely to interrupt transmission as a stand-alone intervention.FindingsWe reported recently on the development and successful testing in Hunan province, PR China, of a health education package to prevent STH infections in Han Chinese primary school students. We have recently commenced a new trial of the package in the ethnically diverse Xishuangbanna autonomous prefecture in Yunnan province and the approach is also being tested in West Africa, with further expansion into the Philippines in 2015.ConclusionsThe work in China illustrates well the direct impact that health education can have in improving knowledge and awareness, and in changing hygiene behaviour. Further, it can provide insight into the public health outcomes of a multi-component integrated control program, where health education prevents re-infection and periodic drug treatment reduces prevalence and morbidity.

Benzimidazole-resistant gastrointestinal nematodes in indigenous Chiapas and Pelibuey sheep breeds from Chiapas, Mexico

Because of the natural adaptation of Mexican sheep, the aim of the present study was to identify the presence or absence of gastrointestinal parasitic nematodes (GIN) resistant to benzimidazole (BZ) in both Chiapas and Pelibuey sheep breeds on local farms. Both male and female GIN-infected grazing sheep of the two breeds were selected. Sheep faecal samples were collected to obtain infective larvae (L3). This evolving stage of the parasite was used for taxonomic identification of the genus, based on its morphological characteristics. BZ anthelmintic resistance was evaluated using a nematode-compound in vitro interaction bioassay and the allele-specific polymerase chain reaction technique to detect mutations of residues 198 and 200 on isotype 1 of the β-tubulin gene. Three BZ-based compounds (febendazole (FBZ), tiabendazole (TBZ) and albendazole (ABZ)) at concentrations of 1, 0.5, 0.25, 0.125, 0.062 and 0.03mg/ml were used to estimate the anthelmintic efficacy and lethal dose (LD50, LD90 and LD99) of the drugs. Two parasitic nematodes, Haemonchus and Teladorsagia, were identified in both isolates. Also, the proportions of anthelmintic resistance identified in GIN of the two sheep breeds were 68% in isolates from the Chiapas breed and 71.8% in the Pelibuey breed. The specific lethal activity obtained with FBZ was higher than 90%. However, TBZ and ABZ showed a lethal activity lower than 50%. High variability in the discriminating dose values was found among the BZ drugs. For example, FBZ LD ranged from 0.01 to 1.20mg/ml; on the other hand, TBZ and ABZ required a dose ranging from 0.178 to 759mg/ml. In addition, amino acid changes of Phe (TTC) to Tyr (TAC) at codon 200 of the β-tubulin gene, showing resistance to BZ, and no changes at codon 198 Glu (GAA) to Ala (GCA) were observed for both isolates. These results confirmed the presence of a genetic mutation associated with BZ in both Chiapas and Pelibuey nematode isolates.

Antiproliferative effect of benzimidazole anthelmintics albendazole, ricobendazole, and flubendazole in intestinal cancer cell lines

This study aimed to test the antiproliferative effect of three benzimidazole anthelmintics in intestinal cancer cells and to investigate whether these drugs, which inhibit tubulin polymerization, can potentiate the efficacy of the microtubule-stabilizing drug paclitaxel (PTX). Four intestinal cancer cell lines, SW480, SW620, HCT8, and Caco2, with different origins and growth characteristics were used. The antiproliferative effect of albendazole (ABZ), ricobendazole (RBZ), flubendazole (FLU), and their combinations with PTX was tested using three different end-point viability assays, cell cycle distribution analysis, and the x-CELLigence System for real-time cell analysis. ABZ and FLU inhibited cell proliferation significantly in a concentration-dependent and time-dependent manner through cell arrest in the G2/M phase. RBZ was not effective at any concentration tested. The cell lines differed in sensitivity to FLU and ABZ, with HCT8 being the most sensitive, showing IC₅₀ values for ABZ and FLU that reached 0.3 and 0.9 μmol/l, respectively. Combinations of PTX+ABZ and PTX+FLU decreased cell viability more effectively when compared with treatment with individual drugs alone. The anthelmintic benzimidazole drugs ABZ and FLU show a significant cytostatic effect and potentiate the efficacy of PTX in intestinal cancer cells.

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.

Efficiency of a genetic test to detect benzimidazole resistant Haemonchus contortus nematodes in sheep farms in Quebec, Canada

Haemonchus contortus is a hemophilic nematode which infects sheep and causes anemia and death to lambs. Benzimidazole drugs are used to remove these parasites, but the phenomenon of resistance has arisen worldwide. A sensitive test to detect resistance before treatment would be a useful tool to enable farmers to anticipate the efficiency of the drug before drenching the flock. In this study, we compared a test for benzimidazole resistance based on detection of genetic markers in H. contortus before treatment with the common method of fecal egg count reduction test (FECRT). We recruited 11 farms from different regions of Quebec for this study. Fecal samples from animals were collected per rectum before and after treatment in control and treated groups (10 animals per group). The 10 sheep were treated with fenbendazole at the recommended dose rate. Among the 11 farms participating in the study, we found H. contortus in 8 of them and it was the most predominant nematode species detected by egg count. Using the genetic test, we found benzimidazole resistance in each of these 8 farms. In 5 of these 8 farms there were sufficient sheep with an egg count for H. contortus above 150 eggs per gram to allow the FECRT test to be conducted. Benzimidazole resistance was observed in each of these 5 farms by the FECRT. When we compared the results from the genetic test for samples off pasture and from individual sheep, with the results from the FECRT, we concluded that the genetic test can be applied to samples collected off pasture to estimate benzimidazole resistance levels before treatment for H. contortus infections.

Efficacy of different albendazole and mebendazole regimens against heavy-intensity Trichuris trichiura infections in school children, Jimma Town, Ethiopia

Recent studies have shown that the efficacy of benzimidazole drugs is influenced by the intensity of trichuriasis. Therefore, the objective of this study was to determine the efficacy of albendazole (ALB) and mebendazole (MBZ) administered randomly for 1 (ALB×1 and MBZ×1) or 2 days (ALB×2 and MBZ×2) to 385 school children with heavy-intensity trichuriasis (mean faecal egg counts (FEC) >1000 eggs per gram of stool (epg)) in Jimma Town, Ethiopia. The efficacies (95% confidence intervals) by means of reduction in faecal egg counts (FECs) were 29·3% (−9·9–56·2), 60·0% (48·5–70·9), 73·5% (64·2–81·3), and 87·1% (81·4–91·2) for ALB×1, MBZ×1, ALB×2, and MBZ×2, respectively. These observations highlight that assessment of the anthelmintic efficacy of existing or new compounds against Trichuris trichiura should be assessed under varying levels of infection intensity.

Adsorptive stripping differential pulse voltammetric determination of mebendazole at a graphene nanosheets and carbon nanospheres/chitosan modified glassy carbon electrode

For the first time graphene nanosheets and carbon nanospheres/chitosan (GNS–CNS/CS) based nanocomposite film modified electrode was used for the electro-oxidation of mebendazole (MD). MD is a benzimidazole drug that is used to treat human infections caused by parasitic worms. MD causes slow immobilization and death of the worms by selectively and irreversibly blocking uptake of glucose. The electrochemical behavior of MD at GNS–CNS/CS modified glassy carbon electrode has been investigated using cyclic and differential pulse voltammetry in aqueous media at different pHs. The prepared electrode showed an excellent electrochemical activity toward the electro-oxidation of MD leading to a significant improvement in sensitivity as compared to the bare glassy carbon electrode. The adsorptive stripping differential pulse voltammetry was used as an efficient method for the electroanalytical determination of MD. Under the optimal conditions, the modified electrode showed a wide linear response to the concentration of MD in the range of 0.02–1μM with a low detection limit (10.5nM).

Application of Continuous Flow Micromixing Reactor Technology for Synthesis of Benzimidazole Drugs

Synthesis of pharmaceutically active compounds by employing continuous flow micromixing reactor technology is an interesting research area. In this article we describe the synthesis of benzimidazol...

Molecular and Biological Diagnostic Tests for Monitoring Benzimidazole Resistance in Human Soil-Transmitted Helminths

In endemic countries with soil-transmitted helminths mass drug administration with albendazole or mebendazole are being implemented as a control strategy. However, it is well known in veterinary helminths that the use of the same benzimidazole drugs can place selection on the β-tubulin gene, leading to resistance. Given the concern that resistance could arise in human soil-transmitted helminths, there is an urgent need to develop accurate diagnostic tools for monitoring resistance. In this study, we developed molecular assays to detect putative resistance genetic changes in Ascaris lumbricoides, Trichuris trichiura, and hookworms, and we optimized an egg hatch assay for the canine hookworm Ancylostoma caninum and applied it to Necator americanus. Both assays were tested on field samples. The molecular assays demonstrated their reproducibility and capacity to detect the presence of worms carrying putative resistance-associated genetic changes. However, further investigations are needed to validate our molecular and biological tests on additional field isolates.

Alternative methods for the control of gastrointestinal parasites in horses with a special focus on nematode predatory fungi: a review / Alternatywne metody kontroli pasożytów przewodu pokarmowego u koni ze szczególnym uwzględnieniem drapieżnych grzybów nicieniobójczych: artykuł przeglądowy

Abstract The paper describes a review of alternative methods of horse parasite control. Horses serve as hosts for a wide array of parasites, among which strongylid nematodes (Strongylidae) constitute considerable pathogens. Due to the short and monoxenous life cycle of these parasites and also the resistance to benzimidazole and other drugs, the control strategies are often ineffective. Thus, the treatment of strongylids constitutes a priority aiming at the improvement of animal welfare, with special attention paid to the stable and pasture organization. The treatment carried out in the stable should consider the frequent exchange of horse bedding at regular time intervals, periodic disinfection of stalls and maximum limitation of contact of feed and water with the stable substratum. An application of feed supplements, i.e. plants or plant extracts, which act as natural dewormers, also constitutes an important factor in the control of parasitic infections. Among the treatments applied to the pasture, the regular removal of waste, quarter pasturing, as well as an alternate pasturing with other animal species, are of special importance. The use of deworming properties of fungi, which constitute a natural component of green growth in pasture, seems to be the next method of nematode control, already confirmed by several studies.

Characterization and comparative analysis of the complete Haemonchus contortus β-tubulin gene family and implications for benzimidazole resistance in strongylid nematodes

Parasitic nematode β-tubulin genes are of particular interest because they are the targets of benzimidazole drugs. However, in spite of this, the full β-tubulin gene family has not been characterized for any parasitic nematode to date. Haemonchus contortus is the parasite species for which we understand benzimidazole resistance the best and its close phylogenetic relationship with Caenorhabditis elegans potentially allows inferences of gene function by comparative analysis. Consequently, we have characterized the full β-tubulin gene family in H. contortus. Further to the previously identified Hco-tbb-iso-1 and Hco-tbb-iso-2 genes, we have characterized two additional family members designated Hco-tbb-iso-3 and Hco-tbb-iso-4. We show that Hco-tbb-iso-1 is not a one-to-one orthologue with Cel-ben-1, the only β-tubulin gene in C. elegans that is a benzimidazole drug target. Instead, both Hco-tbb-iso-1 and Hco-tbb-iso-2 have a complex evolutionary relationship with three C. elegans β-tubulin genes: Cel-ben-1, Cel-tbb-1 and Cel-tbb-2. Furthermore, we show that both Hco-tbb-iso-1 and Hco-tbb-iso-2 are highly expressed in adult worms; in contrast, Hco-tbb-iso-3 and Hco-tbb-iso-4 are expressed only at very low levels and are orthologous to the Cel-mec-7 and Cel-tbb-4 genes, respectively, suggesting that they have specialized functional roles. Indeed, we have found that the expression pattern of Hco-tbb-iso-3 in H. contortus is identical to that of Cel-mec-7 in C. elegans, being expressed in just six “touch receptor” mechano-sensory neurons. These results suggest that further investigation is warranted into the potential involvement of strongylid isotype-2 β-tubulin genes in mechanisms of benzimidazole resistance.

Synthesis and self-assembly processes of monofunctionalized cucurbit[7]uril.

We present a building-block approach toward functionalized CB[7] derivatives by the condensation of methylene-bridged glycoluril hexamer 1 and glycoluril bis(cyclic ethers) 2 and 12. The CB[7] derivatives Me2CB[7] and CyCB[7] are highly soluble in water (264 mM and 181 mM, respectively). As a result of the high intrinsic solubility of Me2CB[7], it is able to solubilize the insoluble benzimidazole drug albendazole. The reaction of hexamer 1 with glycoluril derivative 12, which bears a primary alkyl chloride group, gives CB[7] derivative 18 in 16% isolated yield. Compound 18 reacts with NaN3 to yield azide-substituted CB[7] 19 in 81% yield, which subsequently undergoes click reaction with propargylammonium chloride (21) to yield CB[7] derivative 20 in 95% yield, which bears a covalently attached triazolyl ammonium group along its equator. The results of NMR spectroscopy ((1)H, variable-temperature, and DOSY) and electrospray mass spectrometry establish that 20 undergoes self-assembly to form a cyclic tetrameric assembly (204) in aqueous solution. CB[7] derivatives bearing reactive functional groups (e.g., N3, Cl) are now available for incorporation into more complex functional systems.