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the mechanism of benzimidazole formation from o-phenylenediamine
Treatment with DNA synthesis inhibitors resulted in a longer delay before the appearance of infectious virus. In cultures treated with 1263W94, the amount of infectious HCMV measured at 42 h after compound removal was ~9% of that seen in the untreated control. The longest delay in appearance of infectious virus occurred in cells treated with GCV, with infectious virus produced at only ~2% of the level measured in the untreated control at 52 h following compound removal. Throughout the experimental time course, cultures treated with BDCRB or GW275175X produced higher titers than cultures treated with 1263W94 or GCV. This more rapid appearance of infectious virus following BDCRB and GW275175X removal suggests that DNA maturation is a mechanism of action. In the presence of either of these compounds, the precursor polygenomic DNA could still be synthesized and would thus be available for processing and packaging into capsids after compound removal.
Over the years of active research, benzimidazole and its derivatives have evolved as important privileged structures in medicinal chemistry encompassing a diverse range of biological activities including antiparasitic (specifically anthelmintics, e.g., albendazole, mebendazole), antiulcer (proton pump inhibitors (PPIs), e.g., omeprazole), antihypertensive (angiotensin II receptor blockers, e.g., candesartan, telmisartan), antihistaminic (H 1 -receptor antagonists, e.g., bilastine), anti-cancer (nitrogen mustard alkylating agents, e.g., bendamustine), antiemetic/antipsychotics (e.g., droperidol) [3–5] .In the recent years, pain and inflammation are recognized as an overwhelming burden to the healthcare status of our population and the underlying basis of a significant number of diseases  .
The Chemistry of the Benzimidazoles. - Chemical …
Synthetic chemistry efforts were then directed towards improving the in vivo stability of BDCRB (). Approaches utilized included the synthesis of carbocyclic analogs of benzimidazole nucleosides (), fluoro-sugar analogs (), C-nucleoside analogs (, ), -ribofuranosyl sugar analogs (), and -ribopyranosyl sugar analogs. These efforts provided two classes of compounds that were pursued as clinical candidates for the treatment of HCMV diseases: (i) compounds such as the -sugar analogue 5,6-dichloro-2-(isopropylamino)-1-β--ribofuranosyl-1H-benzimidazole (1263W94, maribavir), an agent that inhibits HCMV DNA synthesis () and nuclear egress (, ), and (ii) compounds including -sugar analogs, represented here by GW275175X (2-bromo-5,6-dichloro-1-β--ribopyranosyl-1H-benzimidazole), which also inhibits HCMV activity in vitro. Previous reports on 1263W94 have described in vitro antiviral activity and mechanism of action (), preclinical toxicology (), and results of initial phase I and II clinical trials with subjects with HCMV infection ().
In this report, we present an initial description of the activity of GW275175X against HCMV, other herpesviruses, and selected nonherpesviruses and show that the mechanism of action is like that of the original parent compound, BDCRB, rather than 1263W94 or any other anti-HCMV drug approved for marketing.
The Chemistry of the Benzimidazoles
In summary, GW275175X has demonstrated good activity against laboratory HCMV strains, clinical isolates, and HCMV strains resistant to clinically relevant anti-HCMV agents. In addition, GW275175X exerts its antiviral effect by inhibition of viral DNA maturation, unlike currently available anti-HCMV agents. Since the formation and packaging of DNA concatemers lacks a known analogous function in mammalian cells, inhibition of viral DNA maturation and packaging might be expected to provide a selective and less toxic antiviral effect than DNA synthesis inhibitors. Moreover, GW275175X has shown promising results in extensive pharmacokinetic and toxicity analyses, including a phase I trial in healthy volunteers (unpublished data). With in vitro antiviral activity equal to or greater than that of GCV and with a unique mechanism of action, GW275175X is a strong candidate for development as a new anti-HCMV agent for clinical use.
Additional evidence that GW275175X is a DNA maturation inhibitor comes from CHEF analysis of the generation of unit length HCMV genomes. This approach allows direct measurement of large DNA molecules up to and including such large molecules as yeast genomes (). The HCMV AD169 genome, approximately 230 kb in size, was previously analyzed using CHEF in a study of the mechanism of action of BDCRB (). Our experiments demonstrated that GW275175X, like the parent compound BDCRB, inhibited HCMV genome maturation in a dose-dependent fashion.
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Benzimidazole synthesis - Organic Chemistry Portal
Imidazole and its derivatives are widely used as intermediates in synthesis of organic target compounds including pharmaceuticals, agrochemicals, dyes, photographic chemicals, corrosion inhibitors, epoxy curing agents, adhesives and plastic modifiers.
Imidazole and benzimidazole synthesis - Organic chemistry
In the oxidative addition/reductive elimination pathway, oxidative addition first produces a copper(III) intermediate in which the nucleophile and arene are both ligated to the metal. Subsequent reductive elimination generates the product and regenerates the catalyst. This mechanism is supported by the reactivity trend of aryl halides (ArI > ArBr > ArCl >> ArF) and by observations of hydrodehalogenation, which is proposed to occur via β-hydride elimination of the amide ligand followed by reductive elimination to form a C–H bond.
The benzimidazole is dissolved in 750 cc
Some uncertainty remains regarding the mechanism of copper-catalyzed aminations, as evidence exists for both single-electron transfer (SET) and oxidative addition/reductive elimination (OA/RE) pathways. In some cases, both mechanisms may be operating simultaneously. Despite this uncertainty, copper-catalyzed aminations have been applied in a number of syntheses of natural products. Aromatic or heteroaromatic halides are the most common electrophiles employed, although alkenyl halides are also reactive in many cases. Amines may be unactivated or contain an electron-withdrawing group to facilitate deprotonation with a base of moderate strength.
12.8 (for benzimidazole) and 5.6 (for the conjugate acid) Hazards; ..
2-mercapto-1(β-4-pyridethyl)benzimidazole (MPB) inhibited the development of antiviral activity induced by interferon in chick cells. The MPB effect was reversed by washing the cells. The action of MPB was on a step immediately following interferon binding but before the cellular RNA and protein synthesis that appear to be required for interferon action. The step blocked by MPB possibly involves cellular phospholipid synthesis.
Synthesis of Benzimidazole | Catalysis | Aldehyde
New human cytomegalovirus (HCMV) therapies with novel mechanisms of action are needed to treat drug-resistant HCMV that arises during therapy with currently approved agents. 2-Bromo-5,6-dichloro-1-β--ribofuranosyl-1H-benzimidazole (BDCRB) is an effective anti-HCMV agent with a novel mechanism of action, but problems with in vivo stability preclude clinical development. A -ribopyranosyl derivative of BDCRB, GW275175X, displays similar antiviral activity without the in vivo stability problems. We present an initial description of the activity of GW275175X against HCMV, other herpesviruses, and selected nonherpesviruses. In addition, we show that it acts as a DNA maturation inhibitor like the parent compound, BDCRB, rather than via the mechanisms of action of 1263W94 or any anti-HCMV drugs approved for marketing. GW275175X is a promising candidate for clinical development as an anti-HCMV agent.
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