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Synthesis of Tamiflu and its Phosphonate Congeners Possessing Potent Anti-Influenza Activity
Abstract
Using d-xylose as an appropriate chiral precursor, we have synthesized active neuraminidase inhibitor oseltamivir, antiflu drug Tamiflu, and novel phosphonate congeners that exhibit even stronger antiflu activities by inhibiting the neuraminidases of the wild-type and H274Y mutant of H1N1 and H5N1 viruses. Molecular modeling of the neuraminidase−phosphonate complex indicates a pertinent binding mode of the phosphonate with three arginine residues in the active site. Discovery of such potent neuraminidase inhibitors will offer an opportunity to the development of new anti-influenza drugs.
... To validate the efficacy of the synthesized compounds against influenza virus infection, we employed cell-based assay (chicken embryo fibroblasts, CEFs) that addressed the cytopathic effect (CPE) of influenza virus infection using the same virus strains with anti-NA assay [21,27,28]. We further chose 6g, 6l, 6y and 8c as representatives, and used oseltamivir carboxylate (OSC) as reference compound in parallel. ...
... The anti-influenza activity (EC 50 ) and cytotoxicity (CC 50 ) of the newly synthesized oseltamivir derivatives were evaluated with H5N1, H5N2 and H5N6 strains in Chicken Embryo Fibroblasts (CEFs) using Cell Counting Kit-8 (CCK-8, Dojindo Laboratories) method as described by Zhang et al. [21,27,28]. EC 50 are the concentrations of compound required for 50% protection of the influenza virus infection-mediated cytopathic effects (CPE). ...
... 100 MHz, D 2 O) d 175.20 (s), 168.78 (s), 136.66 (s), 134.05 (s), 132.76 (s), 130.40 (d, J ¼ 12.8 Hz), 128.61 (s), 127.77 (s), 126.35 (s), 124.05 (s), 84.17 (s), 74.97 (s), 53.15 (s), 52.61 (s), 49.08 (s), 34.55 (s),28.33 (s),25.38 (s),25.00 (s),22.32 ...
A novel series of 1,2,3-triazole oseltamivir derivatives, which could simultaneously occupy the classical NA catalytic site and the newly reported 430-cavity, were designed, synthesized, and evaluated for their anti-influenza activities. The results demonstrated that four compounds (6g, 6l, 6y and 8c) showed robust anti-influenza potencies against H5N1, H5N2 and H5N6 strains in both enzymatic assay and cellular assay. Especially, 6l was proved to possess the most potent and broad-spectrum anti-influenza activity, with IC50 values of 0.12 μM, 0.049 μM and 0.16 μM and EC50 values of 2.45 μM, 0.43 μM and 2.8 μM against H5N1, H5N2 and H5N6 strains, respectively, which were slightly weaker than oseltamivir carboxylate. In addition, in the embryonated egg model, 6l achieved the similar protective effect against H9N2 strain with oseltamivir carboxylate in the tested concentrations. Preliminary structure-activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed.
... Tamiflu or oseltamivir is an antiviral drug used for treating influenza [62]. Although promising results have not been obtained, several clinical trials are in progress to search for a perfect combination medication for Tamiflu for treatment against COVID-19 [63]. ...
Coronavirus disease 2019 (Covid-19) is caused by the Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) was firstly identified in the city of Wuhan of China in December 2019, which was spread and become a global issue due to its high transmission rate. To date, the outbreak of COVID-19 has resulted in infection to 150,356,672 people and the death of 3,167,010 patients. It paralyzed the economy of all the countries worldwide. Unfortunately, no specific FDA-approved antiviral treatment or vaccine is available to curb the outbreak. Considering the possible mutations of SARS-CoV-2, the current medical emergency required a longer time for drug design and vaccine development. Drug repurposing is a promising option for potent therapeutic against the pandemic. The present review encompasses various drugs or appropriate combinations of already FDA-approved antimalarial, antiviral, anticancer, anti-inflammatory, and antibiotic therapeutic candidates for use in the clinical trials as a ray of hope against COVID-19. It is expected to deliver better clinical and laboratory outcomes of drugs as a prevention strategy for the eradication of the disease.
... In the related study, tamiphosphor (TP, 22) was synthesized as the phosphonate congener of oseltamivir carboxylate by several methods (Fig. 10). The first synthesis [83] begins with introduction of a (diphosphoryl)methyl substituent to the C-5 position of D-xylose, and the subsequent intramolecular Horner−Wadsworth−Emmons (HWE) reaction constructs the cyclohexene-phosphonate core structure. Intramolecular HWE reaction was also applied to build up the scaffold of the polysubstituted cyclohexene ring in another TP synthesis starting with Nacetyl-D-glucosamine (D-GlcNAc) [84]. ...
Influenza is a long-standing health problem. For treatment of seasonal flu and possible pandemic infections, there is a need to develop new anti-influenza drugs that have good bioavailability against a broad spectrum of influenza viruses, including the resistant strains. Relenza™ (zanamivir), Tamiflu™ (the phosphate salt of oseltamivir), Inavir™ (laninamivir octanoate) and Rapivab™ (peramivir) are four anti-influenza drugs targeting the viral neuraminidases (NAs). However, some problems of these drugs should be resolved, such as oral availability, drug resistance and the induced cytokine storm. Two possible strategies have been applied to tackle these problems by devising congeners and conjugates. In this review, congeners are the related compounds having comparable chemical structures and biological functions, whereas conjugate refers to a compound having two bioactive entities joined by a covalent bond. The rational design of NA inhibitors is based on the mechanism of the enzymatic hydrolysis of the sialic acid (Neu5Ac)-terminated glycoprotein. To improve binding affinity and lipophilicity of the existing NA inhibitors, several methods are utilized, including conversion of carboxylic acid to ester prodrug, conversion of guanidine to acylguanidine, substitution of carboxylic acid with bioisostere, and modification of glycerol side chain. Alternatively, conjugating NA inhibitors with other therapeutic entity provides a synergistic anti-influenza activity; for example, to kill the existing viruses and suppress the cytokines caused by cross-species infection.
... The synthetic approaches to oseltamivir were investigated, and several approaches were found to be innovative or interesting [21][22][23][24], however, we followed our previous semi-synthetic procedure for oseltamivir (2) [18]. The synthetic route of the target compounds is depicted in Scheme 1. Oseltamivir was reacted with the corresponding sulfonyl chlorides to obtain 3a-3k [18,25,26]. ...
A series of NH2-sulfonyl oseltamivir analogues were designed, synthesized, and their inhibitory activities against neuraminidase from H5N1 subtype evaluated. The results indicated that the IC50 value of compound 4a, an oseltamivir analogue via methyl sulfonylation of C5-NH2, was 3.50 μM. Molecular docking simulations suggested that 4a retained most of the interactions formed by oseltamivir carboxylate moieties and formed an additional hydrogen bond with the methylsulfonyl group. Meanwhile, 4a showed high stability towards human liver microsomes. More importantly, 4a without basic moieties is not a zwitterion as reported on the general structure of neuraminidase inhibitors. This research will provide valuable reference for the research of new types of neuraminidase inhibitors.
... Continued efforts to modify the structures of NA inhibitors led to a number of potent inhibitors that are active against oseltamivir-resistant mutants. For example, one of the oseltamivir phosphonate derivatives, compound 13b (Table 2), was active against two strains of H274Y mutant, with IC 50 values of 7.39 nM and 19.5 nM, respectively, compared with 295 nM and 971 nM, respectively, for oseltamivir [64]. This is due to a stronger interaction exerted by phosphonate, compared to carboxylate, with the guanidinium ion. ...
Introduction: The emergence of drug-resistant influenza virus strains highlights the need for new antiviral therapeutics to combat future pandemic outbreaks as well as continuing seasonal cycles of influenza.
Areas covered: This review summarizes the mechanisms of current FDA-approved anti-influenza drugs and patterns of resistance to those drugs. It also discusses potential novel targets for broad-spectrum antiviral drugs and recent progress in novel drug design to overcome drug resistance in influenza.
Expert opinion: Using the available structural information about drug-binding pockets, research is currently underway to identify molecular interactions that can be exploited to generate new antiviral drugs. Despite continued efforts, antivirals targeting viral surface proteins like HA, NA, and M2, are all susceptible to developing resistance. Structural information on the internal viral polymerase complex (PB1, PB2, and PA) provides a new avenue for influenza drug discovery. Host factors, either at the initial step of viral infection or at the later step of nuclear trafficking of viral RNP complex, are being actively pursued to generate novel drugs with new modes of action, without resulting in drug resistance.
... After incubation for 40−60 min, the reaction was terminated by adding 150 μL of termination solution (6.01 g glycine and 3.20 g NaOH in 400 mL Milli-Q water Determination of EC 50 and CC 50 of NA Inhibitors in CEFs. The antiflu activity and cytotoxicity of the newly synthesized compounds were evaluated as described by Shie et al. 53 with minor modifications. Results were expressed as EC 50 values, which are the concentrations affording 50% protection against H5N1, H5N2, H5N6, and H5N8 virus infection-mediated cytopathic effects (CPE). ...
... The synthesis of 3-N-acryloyl-5-O-anilinopyrimidine ribose derivatives 1a and 1b commenced with 3-amino ribose derivative 3 that can be readily prepared from D-xylose 2 in 41% yield over six steps (Scheme 1; Shie et al., 2007). Protection of the primary hydroxyl group in 3 with TBDPSCl followed by condensation with acryloyl chloride using Et 3 N as base gave ribose derivative 4 in 92% yield (two steps). ...
The synthesis of a series of ribose-modified anilinopyrimidine derivatives was efficiently achieved by utilizing DBU or tBuOLi-promoted coupling of ribosyl alcohols with 2,4,5-trichloropyrimidine as key step. Preliminary biological evaluation of this type of compounds as new EGFR tyrosine kinase inhibitors for combating EGFR L858R/T790M mutant associated with drug resistance in the treatment of non-small cell lung cancer revealed that 3-N-acryloyl-5-O-anilinopyrimidine ribose derivative 1a possessed potent and specific inhibitory activity against EGFR L858R/T790M over WT EGFR. Based upon molecular docking studies of the binding mode between compound 1a and EGFR, the distance between the Michael receptor and the pyrimidine scaffold is considered as an important factor for the inhibitory potency and future design of selective EGFR tyrosine kinase inhibitors against EGFR L858R/T790M mutants.
... To further understand relationships between the anchors and NA inhibitors, we collected and analyzed known inhibitors including GS4071, zanamivir, zanamivir analogues from structure-activity relationship studies, and ATA since these compounds contain various moieties in the anchors of NA (Fig. S3) [43][44][45][46][47][48] . The moiety compositions between these compounds and the SiMMap anchors provide clues for lead optimization. ...
Influenza is an annual seasonal epidemic that has continually drawn public attentions, due to the potential death toll and drug resistance. Neuraminidase, which is essential for the spread of influenza virus, has been regarded as a valid target for the treatment of influenza infection. Although neuraminidase drugs have been developed, they are susceptible to drug-resistant mutations in the sialic-binding site. In this study, we established computational models (site-moiety maps) of H1N1 and H5N1 to determine properties of the 150-cavity, which is adjacent to the drug-binding site. The models reveal that hydrogen-bonding interactions with residues R118, D151, and R156 and van der Waals interactions with residues Q136, D151, and T439 are important for identifying 150-cavitiy inhibitors. Based on the models, we discovered three new inhibitors with IC50 values <10 μM that occupies both the 150-cavity and sialic sites. The experimental results identified inhibitors with similar activities against both wild-type and dual H274Y/I222R mutant neuraminidases and showed little cytotoxic effects. Furthermore, we identified three new inhibitors situated at the sialic-binding site with inhibitory effects for normal neuraminidase, but lowered effects for mutant strains. The results suggest that the new inhibitors can be used as a starting point to combat drug-resistant strains.
... The tamiphosphor and its analogs which are termed as the phosphonate congener of OTV demonstrated major inhibitory potency than OTV against the native NA strains of the H1N1 and H5N1 influenza viruses [31] . The OTV-2 compound with -CH2NH3+ substitution on the C3 position of OTV was suggested to be a drug candidate since it showed highly predicted binding affinity through an additional interaction with E119 as well as good bioavailability [32] . ...
Influenza viruses are major human pathogens accountable for respiratory diseases affecting millions of people worldwide and characterized by high morbidity and significant mortality. Influenza infections can be controlled by vaccination and antiviral drugs. However, vaccines need yearly updating and give limited protection. In addition, the currently available drugs suffer from the rapid and extensive emergence of drug resistance. All this highlights the urgent need for developing new antiviral strategies with novel mechanisms of action and with reduced drug resistance potential. Recent advances in the understanding of Influenza virus replication have discovered a number of cellular drug targets that counteract viral drug resistance. With expanded bioinformatics' knowledge on computational modeling and molecular dynamic simulations, novel small molecule inhibitors of herbal/ayurvedic origin are being explored due to their non-toxicity and affordability. Using in-silico techniques the structural details and information of influenza protein have been studied to identify the potential drugs for inhibition. Further, we have discussed the various computational studies carried out on major protein/targets of Influenza which could provide new clues for a newer class of antiviral (Ayurvedic) drugs. In the years to come ahead, the influenza treatment will go through major changes, with advancing our knowledge of pathogenesis as new methods becoming clinically validated.
Catalysts generated in situ by the combination of pyridine–hydrazone N,N-ligands and Pd(TFA)2 have been applied to the addition of arylboronic acids to formylphosphonate-derived hydrazones, yielding α-aryl α-hydrazino phosphonates in excellent enantioselectivities (96 → 99% ee). Subsequent removal of the benzyloxycarbonyl (Cbz) N-protecting group afforded key building blocks en route to appealing artificial peptides, herbicides and antitumoral derivatives. Experimental and computational data support a stereochemical model based on aryl-palladium intermediates in which the phosphono hydrazone coordinates in its Z-configuration, maximizing the interactions between the substrate and the pyridine–hydrazone ligand.
Carbohydrates are the most abundant natural products and a major component on the cell surface of living beings. They are useful building blocks of various natural products and organic synthesis due to their presence of multiple chiral centers and hydroxy groups. The recent outbreak of COVID-19 and other life-threatening viral infections necessitates the development of potent antiviral drugs. In this review, we focused on the synthesis of antiviral drugs to treat influenza, HIV, herpes, hepatitis, and other diseases, from different monosaccharides such as D-glucose, D-mannose, D-xylose, N-acetyl-D-glucosamine, D-gluconolactone, etc., such as anti-influenza drugs remdesivir, Tamiflu, zanamivir, and so on.
Herein, a practical and efficient method for synthesizing monofluoroalkenyl phosphine oxides via photoinduced decarboxylative/dehydrogenative coupling of α-fluoroacrylic acids with phosphine oxides and phosphonates has been developed. Various α-fluoroacrylic acids and P(O)H compounds containing relevant functional groups, including tetrafluorobenzene and pentafluorobenzene, were converted into corresponding products with excellent E-stereoselectivity in satisfactory yields. This method can be extended to achieve the synthesis of monofluoroalkenyl silanes under similar conditions.
The antiviral activity of nanoparticles is facilitated by their unique properties that make them attractive tools for viral treatment. The nanoscale size of particles can facilitate cellular uptake and allow reaching anatomically privileged sites. The large surface area-to-volume ratios can ensure decoration with large payloads of functional molecules that can increase the interaction with pathogens, leading to optimized drug dosing and delivery and increasing stability. The surface charge can facilitate binding to infectious agents and subsequently inhibit the initial steps of infection. In addition, nanoparticles can contain biomimetic characteristics that enhance their intrinsic antiviral properties as in the case of silver and gold nanoparticles and dendrimers.
As already indicated in Chapter 2, Nanomaterials to aid wound healing and infection control, various types of metallic- and nonmetallic nanomaterials can be used to aid the wound healing process and to keep bacterial infections in check. While serving as powerful tools on their own, various types of nanomaterials can unravel their true potential by being embedded inside a variety of scaffolds and coatings, differing both in chemistry and morphologies. Being embedded inside the material or by covering its surface, NMs alter its physicochemical properties and serve as a means for localized controlled release of various bioactive compounds. By employing such strategies, one can obtain highly functional materials, having great potential to enter clinical applications. This chapter is aimed to summarize the current advances in the field of nanocomposite wound dressings, scaffolds, and coatings. These are used as efficient tools to improve the wound healing efficiency as well as inhibit and/or eradicate microbial infections.
The management and treatment of infectious bacterial diseases in wound healing have both become significant research areas in the biomedical field. While current treatments show limitations related to toxicity and exposure time, nanotechnology has become a potential alternative to overcome such challenges. The application of different nanomaterials, with a wide range of elemental compositions, morphologies, and features, has become an essential tool in managing wound healing infections. This book chapter shows an updated view of the newest trends in the control and treatment of bacterial proliferation in the wound bed by utilizing various metal- and nonmetal-based nanostructures.
A general scientific principle taught in the areas of biology and biochemistry is that structure determines function. This principle and its consequences have permeated other areas and disciplines, especially in the research and applications of nanomaterials. Particularly in nanoparticle applications to biomedical research, this leitmotiv drives the investigation and advances in nanomedicine, where to achieve effective findings, along bold biomedical applications, it is necessary to design the functionalization of nanoparticles as one of the main objectives. Nanoparticles’ functionalization determines properties such as wettability, stability, biochemical affinity, loading capacity, cell adhesion, intracellular delivery, toxicity, and therapeutic performance. In this chapter review, we present the main functionalization routes such as ligand exchange, phase transfer, bioconjugation, and orthogonal chemistry methods. First, a current overview regarding the global spread of nanotechnology, particularly applied to health sciences, is summarized. Then, to illustrate the effect of the nanomaterials’ surface functionalization and bioconjugation, we discuss punctual cases comprising inorganic nanoparticles, their initial development stages, and potential applications. Finally, the remaining challenge includes the safe-by-design of these nanoparticles that should increase clinic translation. And this goal may be achieved by developing more in situ, eco-friendly, low cost, scalable, efficient, and straightforward production routes.
The reduced graphene oxide and copper oxide loaded on zinc oxide (rGO/CuO/ZnO) was successfully synthesized, fully characterized, and applied as a highly efficient reusable nano photocatalyst for the synthesis of aryl phosphonate derivatives starting from trialkyl phosphites and arylhydrazines in the presence of visible light radiation at room temperature in the air atmosphere under eco‐friendly and very mild reaction conditions without using base, oxidant, additive or ligand. Moreover, this strategy is the first report of the use of rGO/CuO/ZnO ternary nanocomposite as heterogeneous photocatalyst in organic synthesis.
Influenza virus is the main cause of an infectious disease called influenza affecting the respiratory system including the throat, nose and lungs. Neuraminidase inhibitors are reagents used to block the enzyme called neuraminidase to prevent the influenza infection from spreading. Neuraminidase inhibitors are widely used in the treatment of influenza infection, but still there is a need to develop more potent agents for the more effective treatment of influenza. Complications of the influenza disease lead to death, and one of these complications is drug resistance; hence, there is an urgent need to develop more effective agents. This review focuses on the recent advances in chemical synthesis pathways used for the development of new neuraminidase agents along with the medicinal aspects of chemically modified molecules, including the structure–activity relationship, which provides further rational designs of more active small molecules.
We report a simple photocatalytic protocol for the direct synthesis of γ-amino phosphonates via the α-C–H alkylation of unprotected, aliphatic primary amines with diethyl vinylphosphonate. These motifs are valuable bioisosteres of γ-amino acids and O-phosphorylated amino alcohols. Visible-light photoredox catalysis in combination with hydrogen atom transfer (HAT) catalysis is used to access the necessary α-amino radical intermediates for C–C bond formation. The procedure is also demonstrated on gram-scale in continuous flow for the synthesis of a racemic, protected derivative of the mGlu agonist 2-amino-4-phosphonobutyric acid (AP4).
An influenza pandemic can have devastating effect on world populations and is a global concern. With the emergence of Fujian flu, caused by a mutation of the H5N1 strain of avian flu (A type) in 2004–2005, it quickly became apparent that, in the face of this new and virulent virus, resistant to known treatments and with a high potential for further mutation, new defensive medicinal weaponry was needed. Among the large number of compounds produced, Zanamivir and Oseltamivir emerged as forerunners. This chapter illustrates how research carried out in the pharmaceutical industry towards the production of the active pharmaceutical ingredient and worldwide sales of the finished drug product of Oseltamivir evolved. It discusses the retrosynthetic analysis, first reported synthesis and the industrial chemical syntheses of Oseltamivir. Both shikimic and quinic acids are structurally close to the drug substance making a semi‐synthesis from either an excellent choice for implementation on a large scale.
A series of phosphine oxides and H-phosphinates were vinylated in the presence of the iodine(iii) reagents vinylbenziodoxolones (VBX), providing the corresponding alk-1-enyl phosphine oxides and alk-1-enyl phosphinates in good yields with complete chemo- and regioselectivity. The vinylation proceeds in open flask under mild and transition metal-free conditions.
Influenza is a serious respiratory disease responsible for significant morbidity and mortality due to both annual epidemics and pandemics; its treatment involves the use of neuraminidase inhibitors. (−)-Oseltamivir phosphate (Tamiflu) approved in 1999, is one of the most potent oral anti-influenza neuraminidase inhibitors. Consequently, more than 70 Tamiflu synthetic procedures have been developed to date. Herein, we highlight the evolution of Tamiflu synthesis since its discovery over 20 years ago in the quest for a truly efficient, safe, cost-effective and environmentally benign synthetic procedure. We have selected a few representative routes to give a clear account of the past, present and the future with the advent of enabling technologies.
Influenza A and B viruses cause seasonal worldwide influenza epidemics each winter, and are a major public health concern and cause of morbidity and mortality. A substantial reduction in influenza-related deaths can be attributed to both vaccination and administration of oseltamivir (OS), which is approved for oral administration and inhibits viral neuraminidase (NA), a transmembrane protein. OS carboxylate (OSC), the active form of OS, is formed by the action of endogenous esterase, which targets NA and is shown to significantly reduce influenza-related deaths. However, the development of resistance in various viral variants, including H3N2 and H5N1, has raised concern about the effectiveness of OS. This comprehensive review covers a range of OS analogs shown to be effective against influenza virus, comparing different types of substituent group that contribute to the activity and bioavailability of these compounds.
Addition of P-H species to carbonyl groups, namely the Pudovik reaction, normally delivers hydroxyl phosphorus compounds, along with phosphate byproducts in some cases. A few controllable systems starting from phosphites were set up to mainly provide the phosphates. Herein, we present a highly selective protocol starting from phosphonate precursors leading to phosphinate derivatives. Enantioenriched phosphinates were successfully achieved from chiral phosphine oxide precursors. Experimental and theoretical investigations were conducted to understand the mechanistic details.
Tamiflu (oseltamivir phosphate), clinically working antiviral chiral drug, is most effective against the infectious disease caused by both influenza A and B. It is also the last resort drug for the treatment of N1H1 virus infection at a high cost with minimal global availability. The current industrial method uses natural (‐)‐shikimic acid obtained from Chinese star anise and coffee beans, hence the limited natural resource and scarcity restricted the Tamiflu production. While most of the synthetic methods reported were composed of natural chiral pools and relatively low‐cost reagents, however, the industrial process is fundamentally limited to the use of hazardous azide or tedious purification methods. In case of an influenza outbreak, producing the Tamiflu according to its demand may be difficult. This document detailed the synthetic progress of chemistry over the last two decades emphasizing the starting materials, hazards of reagents, time needed, number of steps, and overall yields etc. for the interest in academia as well as industrial research.
The most of potent neuraminidase inhibitors as zwitterions with poor lipophilicity suffered from the poor oral bioavailability. Herein, we describe a rational journey to discover a non-zwitterionic neuraminidase inhibitor 24a containing urea. It showed potent inhibitions against neuraminidases from group 1(H5N1 and H1N1) and group 2 (H3N2) subtypes and exhibited more strong inhibitory activities against neuraminidases from H274Y mutants than oseltamivir carboxylate. Whether administrated by orally or intravenous injection, the pharmacokinetic profile of compound 24a in SD rats were improved compared to oseltamivir carboxylate.
Phosphorus‐substituted heterocycles represent an important class of organophosphorus compounds, which not only widely exist in biologically active pharmaceuticals, agrochemicals, but also have widespread applications in material science and organic synthesis as ligands for transition metal complexes. The synthesis of such compounds integrates the development of new synthetic methods and exploration of efficient catalytic systems, reflects the latest achievements in organic, transition metal, photo and even electrochemical catalysis, and facilitates the synthesis of sufficient quantities of related compounds as potential medicinal agents and biological probes in this area. Over the past few decades, two major synthetic strategies have been established toward phosphorus‐substituted heterocycles. This review summarizes the recent progress in this field and discusses the reaction mechanisms in detail. The advantages and limitations of each subdivisional tactic are presented, and the synthetic opportunities still open are outlined.
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Herein we report that iodine-catalyzed guanylation of primary amines can be accomplished with N,N′-di-Boc-thiourea and TBHP to afford the corresponding guanidines in 40–99% yields. Oxidation of the HI byproduct by...
Bis(dimethylamino)phosphorodiamidate (BDMDAP) enables an efficient and one-pot cyclophosphorylation of vicinal cis-diol moiety of polyol-organics of biological importance without the need for protecting group chemistry and is amenable to large-scale reactions. The utility of this reagent is demonstrated through the synthesis of high-value targets such as cyclic phosphates of myo-inositol, nucleosides, metabolites, and drug molecules.
The I2 mediated desulfurization of N,N′-di-Boc-thiourea was developed. Various primary amines, including sterically and electronically deactivated primary amines, were transformed into the corresponding bis-Boc protected guanidines under mild conditions.
An efficient and convenient C(sp ³ )[sbnd]H phosphorylation has been achieved via the DDQ-promoted cross-dehydrogenative coupling between cycloheptatriene and P(O)H compounds at room temperature. This transformation provides a direct synthetic route to the construction of C(sp ³ )[sbnd]P bonds with good functional group compatibility, leading to the formation of cyclohepta-2,4,6-trien-1-ylphosphonates in up to 99% yield.
NiII immobilized on aminated Fe3O4@TiO2 yolk-shell NPs functionalized by (3-glycidyloxypropyl)trimethoxysilane (Fe3O4@TiO2 YS-GLYMO-UNNiII) was prepared as a stable, highly efficient, and reusable magnetic nanostructured catalyst for the C-P cross coupling reaction. A variety of spectroscopic and microscopic techniques such as fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD) analysis, transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDS), EDS-map, thermogravimetric analysis (TGA), vibrating sample magnetometry (VSM), inductively coupled plasma atomic emission spectroscopy (ICP-OES) and CHNS analysis were used to characterize the synthesized nanostructured catalyst. The characterizations determined that the nanostructured catalyst is superparamagnetic in nature, structured as core-shell and its average particle size is 30-32 nm. The catalytic activity of this new magnetic nanostructured catalyst (Fe3O4@TiO2 YS-GLYMO-UNNiII) was examined in the C-P cross coupling reaction of aryl halides/ arylboronic acids/ styrene/ phenylacetylene with diethylphosphite/ triethylphosphite in the presence of WERSA so that arylphosphonates/ vinylphosphonate/ alkynylphosphonate could be prepared in a short period of time. In all the cases, the nanostructured catalyst could be easily recovered magnetically for at least seven runs and a simple work-up procedure was used to isolate the obtained products. The present methodology proved to be quite suitable for scale-up and commercialization.
Influenza neuraminidase is responsible for the escape of new viral particles from the infected cell surface. Several neuraminidase inhibitors are used clinically to treat patients or stockpiled for emergencies. However, the increasing development of viral resistance against approved inhibitors has underscored the need for the development of new antivirals effective against resistant influenza strains. A facile, sensitive, and inexpensive screening method would help achieve this goal. Recently, we described a multiwell plate-based DNA-linked inhibitor antibody assay (DIANA). This highly sensitive method can quantify femtomolar concentrations of enzymes. DIANA also has been applied to high-throughput enzyme inhibitor screening, allowing the evaluation of inhibition constants from a single inhibitor concentration. Here, we report the design, synthesis, and structural characterization of a tamiphosphor derivative linked to a reporter DNA oligonucleotide for the development of a DIANA-type assay to screen potential influenza neuraminidase inhibitors. The neuraminidase is first captured by an immobilized antibody, and the test compound competes for binding to the enzyme with the oligo-linked detection probe, which is then quantified by qPCR. We validated this novel assay by comparing it with the standard fluorometric assay and demonstrated its usefulness for sensitive neuraminidase detection as well as high-throughput screening of potential new neuraminidase inhibitors.
Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five sub-series of oseltamivir derivatives were designed and synthesized to improve their activity towards drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6 and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity and potent antiviral activity in vivo, and high metabolic stability. Overall, above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.
A convenient and efficient C(sp3)–H phosphorylation has been achieved via the metal-free DDQ-mediated cross-dehydrogenative coupling between diarylphosphine oxides and xanthene derivatives at room temperature. This transformation provides a direct synthetic...
We herein report a gram-scale, enantioselective synthesis of Tamiflu, in which the key trans-diamino moiety has been efficiently installed via an iron-catalyzed stereoselective olefin diazidation. This significantly improved, iron-catalyzed method is uniquely effective for highly functionalized yet electronically deactivated substrates that have been previously problematic. Preliminary catalyst structure–reactivity–stereoselectivity relationship studies revealed that both the iron catalyst and the complex substrate cooperatively modulate the stereoselectivity for diazidation. Safety assessment using both differential scanning calorimetry (DSC) and drop weight test (DWT) has also demonstrated the feasibility of carrying out this iron-catalyzed olefin diazidation for large-scale Tamiflu synthesis.
A novel and efficient method has been developed for the construction of Ar-P bond formation by using Cu2O/TiO2 nanoparticles as inexpensive and available photocatalyst, under visible light irradiation. This protocol...
The electrochemically-assisted synthesis of (hetero)arylphosphonates from (hetero)aryl halides and dimethyl phosphite is described. Very mild and simple conditions are employed as the cross-coupling is carried out under galvanostatic mode, in an undivided cell at room temperature, using NiBr2bpy as easily available pre-catalyst and acetonitrile as the solvent. In addition, both aryl bromides and iodides can be used as well, providing the corresponding (hetero)arylphosphonates in generally good yields. A mechanism involving the in situ generation of a Ni ate complex is proposed.
An efficient and practical approach towards bifunctional phosphorus phenols has been developed through a reaction of diphenylphosphine oxide and the o-quinone methides in situ generated from 2-tosylalkyl phenols under basic conditions. This protocol features simple experimental procedures under mild conditions and is easily scaled up. With this method, a variety of diarylmethyl phosphine oxides can be produced with up to 92% yield.
A protocol for the cross coupling of aryl halides with secondary phosphine oxides over Ni/CeO2 or Ni/Al2O3 catalysts has been developed for the first time. The advantages offered using this protocol are operational simplicity and the use of an inexpensive heterogeneous nickel catalyst in the absence of any additional ligand. A broad range of aryl bromides and iodides are efficiently coupled with secondary phosphine oxides using low loadings of a catalyst (1 mol%) via this procedure, with good to high yield (up to 86%). Moreover, the influence of nickel particle size and catalyst support on P-arylation of secondary phosphine oxides has also been established.
We examined ten strains of cultured whole-cell yeasts for the asymmetric reduction of commercially available ethyl 2-oxocyclohexanecarboxylate, and found that the (1S,2S)-stereoisomer of ethyl 2-hydroxycyclohexanecarboxylate was the major stereoisomer produced by Williopsis californica JCM 3600. The ethyl group of the ester was then substituted with a benzyl group with low volatility and increased hydrophobicity to facilitate the isolation of the expected product. Incubation with W. californica furnished benzyl (1S,2S)-2-hydroxycyclohexanecarboxylate (>99.9% ee) in 51.0% yield together with its (1R,2S)-isomer (>99.9% ee) in 35.4% yield. Upon treatment of the same substrate bearing the benzyl ester with a screening kit of purified overexpressed carbonyl reductases (Daicel Chiralscreen® OH), two enzymes (E031, E078) furnished the (1R,2S)-isomer as the major product. With another enzyme (E007), the (1S,2R)-isomer was obtained, but its ee was very low (25.6%). The highly enantiomerically enriched (1S,2S)-isomer obtained by W. californica was transformed to the (1S,2R)-isomer (>99.9% ee), whose availability until now has been low, in 43.3% yield over two steps involving tosylation and subsequent inversive attack with tetrabutylammonium nitrite.
Neuraminidase inhibitors can deter nascent viruses from infecting intact cells by preventing their release from host cells. Herein, a neuraminidase inhibitor 11b absent of basic moieties was discovered in the process of searching for inhibitors targeting 150 cavity. It exhibited potent inhibitions against wild-type neuraminidases from group 1 (H5N1 and H1N1) and group 2 (H7N9) subtypes with IC50 values similar to those of oseltamivir carboxylate. Moreover, 11b showed moderate inhibitions against mutant neuraminidases from H5N1-H274Y and H1N1-H274Y with IC50 values of 2075 nM and 1382 nM, which were inferior to those of oseltamivir carboxylate (6095 nM and 4071 nM). The results were not consistent with the recognized SARs that a basic moiety was an indispensable part of a potent inhibitor.
We describe here the synthesis of a sulfone analog of an oseltamivir precursor. The synthesis comprises cyclization of two advanced building blocks via one-pot Michael addition and Horner–Wadsworth–Emmons reaction. The first building block was synthesized by an organocatalytic Michael addition of pentyloxyacetaldehyde to a nitroalkene. The second, alkenylsulfone, building block was prepared by oxidation followed by a Mannich type reaction. The cyclization was accomplished under microwave irradiation.
Influenza pandemics are an ongoing threat for the human population, as the avian influenza viruses H5N1 and H7N9 continue to circulate in the bird population and the chance of avian to human transmission increases. Neuraminidase, a glycoprotein located on the surface of the influenza virus, plays a crucial role in the viral replication process and, hence, has proven to be a useful target enzyme for the treatment of influenza infections. The discovery that certain subtypes of influenza neuraminidase have an additional cavity, the 150 cavity, near the substrate binding site has triggered considerable interest in the design of influenza inhibitors that exploit this feature. Currently available antiviral drugs, neuraminidase inhibitors oseltamivir and zanamivir, were designed using crystal structures predating this discovery by some years. This mini review is aimed at summarizing our group's efforts, together with related work from other groups, on neuraminidase inhibitors that are designed to exploit both the catalytic site and the 150 cavity. The design of a parent scaffold that yields a potent inhibitor that is active in cell culture assays and retains activity against several neuraminidases from mutant strains is also described. Finally, the role of serendipity in the discovery of a new class of potent neuraminidase inhibitors with a novel spirolactam scaffold is also highlighted.
Neuraminidase, which plays a critical role in the influenza virus life cycle, is a target for new therapeutic agents. The study of structure-activity relationships revealed that the C-5 position amino group of oseltamivir was pointed to 150-cavity of the neuraminidase in group-1. This cavity is important for selectivity of inhibitors against N1 versus N2 NA. A serial of influenza neuraminidase inhibitors with the oseltavimir scaffold containing lipophilic side chains at the C-5 position have been synthesized and evaluated for their influenza neuraminidase inhibitory activity and selectivity. The results indicated that compound 13o (H5N1 IC50 = 0.1 ±0.04μM,H3N2 IC50 = 0.26±0.18 μM) showed better inhibitory activity and selectivity against the group-1 neuraminidase. This study may provide a clue to design of better group-1 neuraminidase inhibitors. This article is protected by copyright. All rights reserved.
The first successful oxidative coupling reaction of aryl pinacol boronic esters with H-phosphonates to deliver aryl phosphorous compounds is reported herein. These reactions between aryl boronic reagents and H-phosphonates were carried out synergistically using a Pd catalyst, additive and oxidant. Without using bases and ligands, phosphorylation was accomplished in an environmentally-friendly manner under mild conditions in ethanol.
Recent cross species transmission of avian influenza has highlighted the threat of pandemic influenza. Oseltamivir (Tamiflu) has been shown to be effective in the treatment and prevention of epidemic influenza infection in adults, adolescents and children (> or = 1 year). Although oseltamivir has not been approved for prophylactic use in children, it has been shown to be effective. Oseltamivir is also active against avian influenza virus strains. Evidence suggests that lower doses or shorter durations of treatment/chemoprophylaxis other than those approved may not be effective and may contribute to emergence of viral resistance. Safety data from dose ranging studies show that 5 day courses of 150 mg twice daily for treatment and 6 week courses of 75 mg twice daily for prophylaxis were as well tolerated as the approved dose regimens. The use of oseltamivir in a pandemic is influenced by the goals of the pandemic plan developed by the responsible Government and Health Authority. To optimize use of antiviral medications, processes will be needed to collect, collate and report outcome data from treated patients and/or from use for chemoprophylaxis of pandemic influenza during the first-wave outbreaks. If oseltamivir is included in a national or regional pandemic plan, stockpiling of the material, either in the form of capsules or the bulk active pharmaceutical ingredient will be necessary. In the absence of a stockpile, there is no guarantee that an adequate supply of oseltamivir will be available.
Gao , Hai-Nv Lu , Hong-Zhou Cao , Bin Du , Bin Shang , Hong Gan , Jian-He Lu , Shui-Hua Yang , Yi-Da Fang , Qiang Shen , Yin-Zhong Xi , Xiu-Ming Gu , Qin Zhou , Xian-Mei Qu , Hong-Ping Yan , Zheng Li , Fang-Ming Zhao , Wei Gao , Zhan-Cheng Wang , Guang-Fa Ruan , Ling-Xiang Wang , Wei-Hong Ye , Jun Cao , Hui-Fang Li , Xing-Wang Zhang , Wen-Hong Fang , Xu-Chen He , Jian Liang , Wei-Feng Xie , Juan Zeng , Mei Wu , Xian-Zheng Li , Jun Xia , Qi Jin , Zhao-Chen Chen , Qi Tang , Chao Zhang , Zhi-Yong Hou , Bao-Min Feng , Zhi-Xian Sheng , Ji-Fang Zhong , Nan-Shan Li , Lan-Juan . (2013) Clinical Findings in 111 Cases of Influenza A (H7N9) Virus Infection. New England Journal of Medicine 368:24, 2277-2285
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Philip W.Smith, Arthur O.Anderson, George W.Christopher, Theodore J.Cieslak, G. J.Devreede, Glen A.Fosdick, Carl B.Greiner, John M.Hauser, Steven H.Hinrichs, Kermit D.Huebner, Peter C.Iwen, Dawn R.Jourdan, Mark G.Kortepeter, V. PaulLandon, Patricia A.Lenaghan, Robert E.Leopold, Leroy A.Marklund, James W.Martin, Sharon J.Medcalf, Robert J.Mussack, Randall H.Neal, Bruce S.Ribner, Jonathan Y.Richmond, ChuckRogge, Leo A.Daly, Gary A.Roselle, Mark E.Rupp, Anthony R.Sambol, Joann E.Schaefer, JohnSibley, Andrew J.Streifel, Susanna G. VonEssen, Kelly L.Warfield. (2006) Designing a Biocontainment Unit to Care for Patients with Serious Communicable Diseases: A Consensus Statement. Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science 4, 351-365
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Kandun , I. Nyoman Wibisono , Hariadi Sedyaningsih , Endang R. Yusharmen Hadisoedarsuno , Widarso Purba , Wilfried Santoso , Hari Septiawati , Chita Tresnaningsih , Erna Heriyanto , Bambang Yuwono , Djoko Harun , Syahrial Soeroso , Santoso Giriputra , Sardikin Blair , Patrick J. Jeremijenko , Andrew Kosasih , Herman Putnam , Shannon D. Samaan , Gina Silitonga , Marlinggom Chan , K.H. Poon , Leo L.M. Lim , Wilina Klimov , Alexander Lindstrom , Stephen Guan , Yi Donis , Ruben Katz , Jacqueline Cox , Nancy Peiris , Malik Uyeki , Timothy M. . (2006) Three Indonesian Clusters of H5N1 Virus Infection in 2005. New England Journal of Medicine 355:21, 2186-2194
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The persistence of H5N1 avian influenza viruses in many Asian countries and their ability to cause fatal infections in humans have raised serious concerns about a global flu pandemic. Here we report the isolation of an H5N1 virus from a Vietnamese girl that is resistant to the drug oseltamivir, which is an inhibitor of the viral enzyme neuraminidase and is currently used for protection against and treatment of influenza. Further investigation is necessary to determine the prevalence of oseltamivir-resistant H5N1 viruses among patients treated with this drug.
The worldwide spread of H5N1 avian influenza has raised concerns that this virus might acquire the ability to pass readily among humans and cause a pandemic. Two anti-influenza drugs currently being used to treat infected patients are oseltamivir (Tamiflu) and zanamivir (Relenza), both of which target the neuraminidase enzyme of the virus. Reports of the emergence of drug resistance make the development of new anti-influenza molecules a priority. Neuraminidases from influenza type A viruses form two genetically distinct groups: group-1 contains the N1 neuraminidase of the H5N1 avian virus and group-2 contains the N2 and N9 enzymes used for the structure-based design of current drugs. Here we show by X-ray crystallography that these two groups are structurally distinct. Group-1 neuraminidases contain a cavity adjacent to their active sites that closes on ligand binding. Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs.
A new, azide-free transformation of the key precursor epoxide 6 to the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (1, Tamiflu) is described. This sequence represents a new and efficient transformation of an epoxide into a 1,2-diamino compound devoid of potentially toxic and hazardous azide reagents and intermediates and avoids reduction and hydrogenation conditions. Using catalytic MgBr2·OEt2 as a new, inexpensive Lewis acid, the introduction of the first amino function was accomplished by opening of the oxirane ring with allylamine followed by Pd/C-catalyzed deallylation to the amino alcohol 16. The introduction of the second amino group was then accomplished via an efficient reaction cascade involving a domino sequence preferably utilizing a transient imino protection. Selective acetylation of the resulting diamine 17 was achieved under acidic conditions providing the crystalline 4-acetamido-5-N-allylamino-derivative 18, which upon deallylation over Pd/C and phosphate salt formation afforded drug substance 1. The overall yield of this route from 6 of 35−38% exceeds the yield of the azide-based process (27−29%) and does not require any chromatographic purification.
Our third generation synthesis of Tamiflu was achieved in 12 steps from commercially available starting materials, using the Diels–Alder reaction and Curtius rearrangement as key steps.
l-xylo Configured cyclohexenephosphonates 1 and 2 have been synthesized as scaffolds for sialidase inhibitor libraries. These compounds were obtained by chain elongation and cyclization of suitably protected l-xylose. An unexpected phosphorylation was observed, however, the resulting phosphate could be removed in a final enzymatic step. Optimization of the reaction conditions avoided the undesired phosphorylation and opened the way to a purely chemical synthesis.
A second-generation manufacturing process from a shikimic acid-derived epoxide to oseltamivir phosphate features a magnesium chloride−amine complex-catalyzed ring opening of the epoxide by tert-butylamine, a selective O-sulfonylation of the resulting tert-butylamino alcohol, a surprisingly efficient cleavage of a tert-butyl group from an aliphatic tert-butylamide, and the isolation of oseltamivir phosphate from a palladium-catalyzed allyl transfer reaction mixture. The overall yield from the epoxide to oseltamivir phosphate has been increased from 27 to 29% or 35−38% for two previous processes, respectively, to 61%.
A theoretical analysis has been made of the relationship between the inhibition constant (KI) of a substance and the (I50) value which expresses the concentration of inhibitor required to produce 50 per cent inhibition of an enzymic reaction at a specific substrate concentration. A comparison has been made of the relationships between KI and I50 for monosubstrate reactions when noncompetitive or uncompetitive inhibition kinetics apply, as well as for bisubstrate reactions under conditions of competitive, noncompetitive and uncompetitive inhibition kinetics. Precautions have been indicated against the indiscriminate use of I50 values in agreement with the admonitions previously described in the literature. The analysis described shows KI does not equal I50 when competitive inhibition kinetics apply; however, KI is equal to I50 under conditions of either noncompetitive or uncompetitive kinetics.
The objective of this paper is to review the literature on the use of prodrugs to overcome the drug delivery obstacles associated with phosphate, phosphonate and phosphinate functional group-containing drugs. This is an important area of research because, although we have been successful at identifying numerous phosphate and phosphonate functional group-containing drugs as antiviral and anticancer agents, as well as for other uses, our ability to orally deliver these drugs and to target them to desired sites has led to limited success. Various acyloxymethyl- and aryl-ester prodrugs have shown promise. Alternative and imaginative approaches may be necessary before complete success is realized. It is our hope that this review will stimulate further innovative prodrug research into overcoming the barriers to the delivery of these important drugs.
Two potent inhibitors based on the crystal structure of influenza virus sialidase have been designed. These compounds are effective inhibitors not only of the enzyme, but also of the virus in cell culture and in animal models. The results provide an example of the power of rational, computer-assisted drug design, as well as indicating significant progress in the development of a new therapeutic or prophylactic treatment for influenza infection. Yes Yes
A phosphonate analog of N-acetyl neuraminic acid (PANA) has been designed as a potential neuraminidase (NA) inhibitor and synthesized as both the alpha (ePANA) and beta (aPANA) anomers. Inhibition of type A (N2) and type B NA activity by ePANA was approximately a 100-fold better than by sialic acid, but inhibition of type A (N9) NA was only ten-fold better than by sialic acid. The aPANA compound was not a strong inhibitor for any of the NA strains tested. The crystal structures at 2.4 A resolution of ePANA complexed to type A (N2) NA, type A (N9) NA and type B NA and aPANA complexed to type A (N2) NA showed that neither of the PANA compounds distorted the NA active site upon binding. No significant differences in the NA-ePANA complex structures were found to explain the anomalous inhibition of N9 neuraminidase by ePANA. We put forward the hypothesis that an increase in the ePANA inhibition compared to that caused by sialic acid is due to (1) a stronger electrostatic interaction between the inhibitor phosphonyl group and the active site arginine pocket and (2) a lower distortion energy requirement for binding of ePANA.
Rational drug design utilizing available X-ray crystal structures of sialic acid analogues bound to the active site of influenza virus neuraminidase has led to the discovery of a series of potent carbocyclic influenza neuraminidase inhibitors. From this series, GS 4104 (oseltamivir, TAMIFLU ) has emerged as a promising antiviral for the treatment and prophylaxis of human influenza infection. This article will summarize the design, discovery, and development of oseltamivir as an oral therapeutic to treat influenza infection.
Widespread outbreaks of avian influenza in domestic fowl throughout eastern Asia have reawakened concern that avian influenza
viruses may again cross species barriers to infect the human population and thereby initiate a new influenza pandemic. Simultaneous
infection of humans (or swine) by avian influenza viruses in the presence of human influenza viruses could theoretically generate
novel influenza viruses with pandemic potential as a result of reassortment of genome subunits between avian and mammalian
influenza viruses. These hybrid viruses would have the potential to express surface antigens from avian viruses to which the
human population has no preexisting immunity. This article reviews current knowledge of the routes of transmission of avian
influenza A viruses to humans, places the risk of appearance of a new pandemic influenza virus in perspective, and describes
the recently observed epidemiology and clinical syndromes of avian influenza in humans.
An overview of work pertaining to noncovalent binding interactions involving primarily the cationic guanidinium group and the anionic sulf[on]ate and phosph[on]ate groups is given. First, the basics behind the systems including structure, environment, mode of interaction, and general techniques for analysis are discussed. Following this, specific examples of research and their impact on the development of the field are outlined. Finally, factors and finds uncovered by studying from each point of view are used to elaborate on the collective interaction scheme.
Michael P.Clark, Mark W.Ledeboer, IoanaDavies, Randal A.Byrn, Steven M.Jones, EmanuelePerola, AliceTsai, MarcJacobs, KwameNti-Addae, Upul K.Bandarage, Michael J.Boyd, Randy S.Bethiel, John J.Court, HongboDeng, John P.Duffy, Warren A.Dorsch, Luc J.Farmer, HuaiGao, WenxinGu, KatrinaJackson, Dylan H.Jacobs, Joseph M.Kennedy, BrianLedford, JianglinLiang, FrançoisMaltais, MarkMurcko, TianshengWang, M. WoodsWannamaker, Hamilton B.Bennett, Joshua R.Leeman, ColleenMcNeil, William P.Taylor, ChristineMemmott, MinJiang, ReneRijnbrand, ChristopherBral, UrsulaGermann, AzinNezami, YuegangZhang, Francesco G.Salituro, Youssef L.Bennani, Paul S.Charifson. (2014) Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2. Journal of Medicinal Chemistry 57, 6668-6678
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A variable synthesis of a new class of sialylmimetics which provides access to pseudo-sialosides containing the successful cyclohexene motif in the sialic acid mimicking part has been developed. The D- and L-xylo cyclohexenephosphonate scaffolds allow attachment of selected aglycons or aglycon mimetics via mixed phosphonate diester strategies and some target compounds thus synthesized displayed promising inhibitory properties when tested with parasitic or bacterial sialidases.
The design, synthesis, and in vitro evaluation of the novel carbocycles as transition-state-based inhibitors of influenza neuraminidase (NA) are described. The double bond position in the carbocyclic analogues plays an important role in NA inhibition as demonstrated by the antiviral activity of 8 (IC50 = 6.3 microM) vs 9 (IC50 > 200 microM). Structure-activity studies of a series of carbocyclic analogues 6a-i identified the 3-pentyloxy moiety as an apparent optimal group at the C3 position with an IC50 value of 1 nM for NA inhibition. The X-ray crystallographic structure of 6h bound to NA revealed the presence of a large hydrophobic pocket in the region corresponding to the glycerol subsite of sialic acid. The high antiviral potency observed for 6h appears to be attributed to a highly favorable hydrophobic interaction in this pocket. The practical synthesis of 6 starting from (-)-quinic acid is also described.
An asymmetric ring-opening reaction of meso-aziridines with TMSN3 was developed using a catalyst prepared from Y(OiPr)3 and chiral ligand 2 in a 1:2 ratio. Excellent enantioselectivity was realized from a wide range of substrates with a practical catalyst loading. The products were efficiently converted to enantiomerically enriched 1,2-diamines, which are versatile chiral building blocks for pharmaceuticals and chiral ligands. This reaction was applied to a catalytic asymmetric synthesis of Tamiflu, a very important anti-influenza drug containing a chiral 1,2-diamino functionality.
A short synthetic pathway has been developed for the synthesis of oseltamivir (1) or the enantiomer (ent-1). The intermediates and conditions for this process are summarized in Scheme 1. The synthesis provides a number of advantages: (1) use of inexpensive and abundant starting materials; (2) complete enantio-, regio-, and diastereocontrol; (3) avoidance of explosive, azide-type intermediates; (4) good overall yield (ca. 30%, still not completely optimized); and (5) scalability.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
The recent outbreaks of avian influenza A (H5N1) virus, its expanding geographic distribution and its ability to transfer to humans and cause severe infection have raised serious concerns about the measures available to control an avian or human pandemic of influenza A. In anticipation of such a pandemic, several preventive and therapeutic strategies have been proposed, including the stockpiling of antiviral drugs, in particular the neuraminidase inhibitors oseltamivir (Tamiflu; Roche) and zanamivir (Relenza; GlaxoSmithKline). This article reviews agents that have been shown to have activity against influenza A viruses and discusses their therapeutic potential, and also describes emerging strategies for targeting these viruses.
Catalytic asymmetric synthesis of Tamiflu, an important antiinfluenza drug, was achieved. After the catalytic enantioselective desymmetrization of meso-aziridine 3 with TMSN3, using a Y catalyst (1 mol %) derived from ligand 2, an allylic oxygen function and C1 unit on the C=C double bond were introduced through cyanophosphorylation of enone and allylic substitution with an oxygen nucleophile. This second generation route of Tamiflu is more practical than our previously reported route. [reaction: see text].
Based on a strategy previously reported by us, we have synthesized D-xylo configured cyclohexenephosphonates designed to mimic the transition state of the sialidase reaction. The double bond orientation corresponds to the benchmark inhibitor Neu5Ac2en and we could selectively introduce hydroxyalkyl substituents in order to simulate the glycerol side-chain of neuraminic acid. The inhibitory activity of a set of compounds towards bacterial sialidases was tested and interesting differences in activity were found.
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