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[Image: see text] In targeted protein degradation of kinases, key discoveries have been made specifically involving selective kinase degradation. Structural and biophysical studies on the ternary complex formation have provided a clear understanding of the basis for achieving degradation selectivity which is important in guiding the design of efficient and selective protein degraders.

With the large number of Pd(II)-catalyzed C-H activation reactions of native substrates developed in the past decade, the development of catalysts to enable the use of green oxidants under safe and practical conditions has become an increasingly important challenge. Notably, the compatibility of Pd(II) catalysts with sustainable aqueous H

Easing oxygen into arenes Although oxygen is all around us, it is often surprisingly difficult to use it for selective chemical oxidations, necessitating more expensive, wasteful alternatives. Li et al. report that careful ligand optimization produces palladium catalysts that can efficiently activate oxygen to hydroxylate a variety of aryl and heteroaromatic rings adjacent to a carboxylic acid substituent. The ligand binds to palladium through pyridine and pyridone components, and the authors posit that tautomerization between dative and anionic coordination modes plays a role in its effectiveness. Science , abg2362, this issue p. 1452

The development of C(sp

Fluorine is known to promote ortho-C-H metalation. Based upon this reactivity, we employed an activated norbornene that traps the ortho-palladation intermediate and is then relayed to the meta position, leading to meta-selective C-H arylation of fluoroarenes. Deuterium experiment suggests that this meta-arylation is initiated by ortho C-H activation and the catalytic cycle is terminated by C-2 protonation. A dual-ligand system is crucial for the observed high reactivity and site selectivity. Applying this approach to simple benzene or other arenes also affords arylation products with good yield and site selectivity.

The use of chiral transient directing groups (TDGs) is a promising approach for developing PdII -catalyzed enantioselective C(sp3 )-H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C-H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to PdII centers, which can result in a mixture of reactive complexes. We report a PdII -catalyzed enantioselective β-C(sp3 )-H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono-substituted cyclobutane through sequential C-H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron-deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.

γ-Lactams form important structural cores of a range of medicinally-relevant natural products and clinical drugs, principal examples being the new generation of immunomodulatory imide drugs (IMiDs) and the brivaracetam family. Compared to conventional multistep synthesis, an intramolecular γ-C─H amination of aliphatic amides would allow for the direct construction of valuable γ-lactam motifs from abundant amino acid precursors. Herein we report a novel pyridone ligand enabled Pd(II)-catalyzed γ-C(sp(3))─H lactamization of amino acid derived native amides, providing the convenient synthesis of γ-lactams, isoindolinones, and 2-imidazolidinones. 6-Substitution of the 2-pyridone ligand is crucial for the lactam formation. This protocol features the use of N-acyl amino acids, which serve as both the directing group and cyclization partner, practical and environmentally benign tert-butyl hydrogen peroxide (TBHP) as the sole bystanding oxidant, and a broad substrate scope. The utility of this protocol was demonstrated through the two-step syntheses of a lenalidomide analog and brivaracetam from readily available carboxylic acids and amino acids.

Controlling site selectivity of C–H activation without using a directing group remains a significant challenge. While Pd(II) catalysts modulated by a mutually repulsive pyridine-type ligand have been shown to favor the relatively electron-rich carbon centers of arenes, reversing the selectivity to favor palladation at the relatively electron-deficient positions has not been possible. Herein we report the first catalytic system that effectively performs meta C–H arylation of a variety of alkoxy aromatics including 2,3-dihydrobenzofuran and chromane with exclusive meta site selectivity, thus reversing the conventional site selectivity governed by native electronic effects. The identification of an effective ligand and modified norbornene (NBE-CO(2)Me), as well as taking advantage of the statistics, are essential for achieving the exclusive meta selectivity.

We herein report the first example of a 2-pyridone accelerated non-directed C–H cyanation with an arene as the limiting reagent. This protocol is compatible with a broad scope of arenes, including advanced intermediates, drug molecules, and natural products. A kinetic isotope experiment (k(H)/k(D) = 4.40) indicates that the C–H bond cleavage is the rate-limiting step. Also, the reaction is readily scalable, further showcasing the synthetic utility of this method.

The utilization of chiral transient directing groups (TDGs) has recently emerged as a promising approach for developing Pd(II)-catalyzed enantioselective C(sp(3))−H activation reactions. However, this strategy is particularly challenging because the stereogenic center present on the TDG is often far from the C–H bond. Additionally, the TDG covalently attached to the substrate and the free TDG are both capable of coordinating to Pd(II) centers, which can result in a mixture of reactive complexes that may lead to opposite asymmetric induction. To date, the single example of TDG-enabled enantioselective C(sp(3))−H activation is limited to the functionalization of benzylic C–H bonds. Herein we report the first example of a Pd(II)-catalyzed enantioselective β-C(sp(3))−H arylation reaction of aliphatic ketones using a chiral transient directing group. A chiral trisubstituted cyclobutane is efficiently synthesized from a mono-substituted cyclobutane via sequential C–H arylation reactions, demonstrating the ability of this method to access structurally complex products from simple starting materials. The use of an electron-deficient pyridone ligand is also crucial for the observed high enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity in the C(sp(3))−H arylation reaction. These key mechanistic findings will provide insight for future development of Pd(II)-catalyzed enantioselective C(sp(3))−H activation reactions with chiral TDGs.

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.

1. Due to its unique C-C and C-H bonding properties, conformational preferences and relative hydrophilicity, the cyclopropyl ring has been used as a synthetic building block in drug discovery to modulate potency and drug-like properties. During an effort to discover inhibitors of the hepatitis C virus non-structural protein 5B with improved potency and genotype-coverage profiles, the use of a pyrimidinylcyclopropylbenzamide moiety linked to a C6-substituted benzofuran or azabenzofuran core scaffold was explored in an effort to balance antiviral potency and metabolic stability. 2. In vitro metabolism studies of two compounds from this C6-substituted series revealed an NADPH-dependent bioactivation pathway leading to the formation of multiple glutathione (GSH) conjugates. Analysis of these conjugates by LC-MS and NMR demonstrated that the cyclopropyl group was the site of bioactivation. Based on the putative structures and molecular weights of the cyclopropyl-GSH conjugates, a multi-step mechanism was proposed to explain the formation of these metabolites by P450. This mechanism involves hydrogen atom abstraction to form a cyclopropyl radical, followed by a ring opening rearrangement and reaction with GSH. 3. These findings provided important information to the medicinal chemistry team which responded by replacing the cyclopropyl ring with a gem-dimethyl group. Subsequent compounds bearing this feature were shown to avert the bioactivation pathways in question.

The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.

Iterative structure–activity analyses in a class of highly functionalized furo[2,3-b]pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (14), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 (14) is described.

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.

Pd-catalyzed C–H functionalizations promoted by transient directing groups remain largely limited to C–H arylation only. Herein, we report a diverse set of ortho-C(sp2)–H functionalizations of benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary directing group, Pd(II)-catalyzed C–H arylation, chlorination, bromination, and Ir(III)-catalyzed amidation, could be achieved on benzaldehyde substrates. The transient directing groups formed in situ via imine linkage can override other coordinating functional groups capable of directing C–H activation or catalyst poisoning, significantly expanding the scope for metal-catalyzed C–H functionalization of benzaldehydes. The utility of this approach is demonstrated through multiple applications, including late-stage diversification of a drug analogue.

A simple and efficient nitrile-directed meta-C-H olefination, acetoxylation, and iodination of biaryl compounds is reported. Compared to the previous approach of installing a complex U-shaped template to achieve a molecular U-turn and assemble the large-sized cyclophane transition state for the remote C-H activation, a synthetically useful phenyl nitrile functional group could also direct remote meta-C-H activation. This reaction provides a useful method for the modification of biaryl compounds because the nitrile group can be readily converted to amines, acids, amides, or other heterocycles. Notably, the remote meta-selectivity of biphenylnitriles could not be expected from previous results with a macrocyclophane nitrile template. DFT computational studies show that a ligand-containing Pd-Ag heterodimeric transition state (TS) favors the desired remote meta-selectivity. Control experiments demonstrate the directing effect of the nitrile group and exclude the possibility of non-directed meta-C-H activation. Substituted 2-pyridone ligands were found to be key in assisting the cleavage of the meta-C-H bond in the concerted metalation-deprotonation (CMD) process.

During a medicinal chemistry campaign to identify inhibitors of the hepatitis C virus nonstructural protein 5B (RNA-dependent RNA polymerase), a bicyclo[1.1.1]pentane was introduced into the chemical scaffold to improve metabolic stability. The inhibitors bearing this feature, 5-(3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-4-fluorophenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (1) and 5-(3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (2), exhibited low turnover in incubations with liver S9 or hepatocytes (rat, human), with hydroxylation of the bicyclic moiety being the only metabolic pathway observed. In subsequent disposition studies using bile-duct-cannulated rats, the metabolite profiles of bile samples revealed, in addition to multiple products of bicyclopentane-oxidation, unexpected metabolites characterized by molecular masses that were 181 Da greater than those of 1 or 2. Further LC/MSn and NMR analysis of the isolated metabolite of 1 demonstrated the presence of a phosphocholine (POPC) moiety bound to the methine carbon of the bicyclic moiety through an ester bond. The POPC conjugate of the NS5B inhibitors was assumed to result from two sequential reactions: hydroxylation of the bicyclic methine to a tertiary alcohol and addition of POPC by CDP-choline: 1,2-diacylglycerol cholinephosphotransferase, an enzyme responsible for the final step in the biosynthesis of phosphatidylcholine. However, this pathway could not be recapitulated using CDP-choline-supplemented liver S9 or hepatocytes due to inadequate formation of the hydroxylation product in vitro. The observation of this unexpected pathway prompted concerns about the possibility that 1 and 2 might interfere with routine phospholipid synthesis. These results demonstrate the participation in xenobiotic metabolism of a process whose function is ordinarily limited to the synthesis of endogenous compounds.

[Image: see text] In solving the P-gp and BCRP transporter-mediated efflux issue in a series of benzofuran-derived pan-genotypic palm site inhibitors of the hepatitis C virus NS5B replicase, it was found that close attention to physicochemical properties was essential. In these compounds, where both molecular weight (MW >579) and TPSA (>110 Å(2)) were high, attenuation of polar surface area together with weakening of hydrogen bond acceptor strength of the molecule provided a higher intrinsic membrane permeability and more desirable Caco-2 parameters, as demonstrated by trifluoroacetamide 11 and the benchmark N-ethylamino analog 12. In addition, the tendency of these inhibitors to form intramolecular hydrogen bonds potentially contributes favorably to the improved membrane permeability and absorption. The functional group minimization that resolved the efflux problem simultaneously maintained potent inhibitory activity toward a gt-2 HCV replicon due to a switching of the role of substituents in interacting with the Gln414 binding pocket, as observed in gt-2a NS5B/inhibitor complex cocrystal structures, thus increasing the efficiency of the optimization. Noteworthy, a novel intermolecular S=O···C=O n → π* type interaction between the ligand sulfonamide oxygen atom and the carbonyl moiety of the side chain of Gln414 was observed. The insights from these structure–property studies and crystallography information provided a direction for optimization in a campaign to identify second generation pan-genotypic NS5B inhibitors.

We herein report the first example of a 2-pyridone accelerated non-directed C−H cyanation with an arene as the limiting reagent. This protocol is compatible with a broad scope of arenes, including advanced intermediates, drug molecules, and natural products. A kinetic isotope experiment (kH/kD = 4.40) indicates that the C–H bond cleavage is the rate-limiting step. Also, the reaction is readily scalable, further showcasing the synthetic utility of this method.

Electron deficient, bivalent sulfur atoms have two areas of positive electrostatic potential, a consequence of the low-lying σ* orbitals of the C-S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, π-systems. Intramolecular interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a molecule. Although a well-documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramolecular hydrogen-bonding interaction, appears to be underappreciated by the medicinal chemistry community. In this Perspective, we discuss the theoretical basis for sulfur σ* orbital interactions and illustrate their importance in the context of drug design and organic synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermolecular interactions between ligand C-S σ* orbitals and proteins are illustrated.

Pd-catalyzed β-C-H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C-H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary to direct β-C-H activation, albeit this system was not compatible with carboxylic acids containing α-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the N-methoxyamide auxiliary, leading to a significant improvement of β-arylation of carboxylic acid derivatives, especially α-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules, and chiral bis(oxazoline) ligands.

Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.

Pd-catalyzed C-H functionalizations promoted by transient directing groups remain largely limited to C-H arylation only. Herein, we report a diverse set of ortho-C(sp

The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase via binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 (43) as a preclinical candidate.

The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.

An efficient, one-pot Friedel–Crafts acylation/hydrolysis reaction promoted by the acidic ionic liquid 1-ethyl-3-methylimidazolium chloroaluminate (generated from 1-ethyl-3-methylimidazolium chloride (EmimCl) and aluminum chloride (X(AlCl3), mole fraction X = 0.75) for the formation of 3-glyoxylic acid derivatives of electron-deficient, substituted 4- and 6-azaindoles is described.

This article summarizes the significant developments and new discoveries in both the virology and antiviral research associated with the severe acute respiratory syndrome coronavirus (SARS CoV) that were reported in 2005 and 2006. Areas reviewed include genomic studies and the identification of bat-SARS CoV, spike protein and host cell entry, nucleocapsid protein, accessory proteins, non-structural proteins of the replicase complex, viral proteases and their inhibitors, and clinical treatment of SARS with ribavirin.

This article summarizes key aspects of progress made during 2004 toward the design, discovery and development of antiviral agents for clinical use. Important developments in the identification, characterization and clinical utility of inhibitors of human immunodeficiency virus; the hepatitis viruses, hepatitis B, hepatitis C; the herpes family of viruses, herpes simplex viruses 1 and 2, varicella zoster virus, Epstein-Barr virus and human cytomegalovirus; the respiratory viruses, influenza, respiratory syncytial virus, human metapneumovirus, picornaviruses, measles and the severe acute respiratory syndrome coronavirus; human papilloma virus; rotavirus; Ebola virus and West Nile virus, are reviewed.

A convenient and efficient one step, base-catalyzed synthesis of 3,5-disubstituted 1,2,4-triazoles by the condensation of a nitrile and a hydrazide is presented. A diverse range of functionality and heterocycles are tolerated under the reaction conditions developed, and the reactivity of the nitrile partner is relatively insensitive to electronic effects.

Marine Organismen produzieren eine faszinierende Vielfalt von Sekundarmetaboliten unterschiedlicher Struktur mit haufig ungewohnlichen und manchmal unerwarteten biologischen Wirkungen. Ihre strukturelle Diversitat macht diese marinen Naturstoffe zu ausgezeichneten Testverbindungen fur die Untersuchung biochemischer Mechanismen. Kurzlich wurden aus verschiedenen marinen Organismen mehrere neue, stereochemisch komplexe Makrolide mit grosem Lactonring (22- bis 44-gliedrig) isoliert, die mit dem Actin-Cytoskelett wechselwirken. Actin ist wie Tubulin ein Hauptbestandteil des Cytoskeletts und hat wichtige zellulare Funktionen. Auch wenn die Einzelheiten dieser Wechselwirkungen noch untersucht werden, erhalten diese marinen Makrolide zunehmend Bedeutung als neue Testverbindungen zur Aufklarung der zellularen Wirkungen von Actin. Wegen ihrer starken Antitumorwirkung kommen diese Verbindungen, z. B. die Aplyronine, fur Anwendungen in der vorklinischen Entwicklung der Krebs-Chemotherapie infrage. Ihre interessanten Molekulstrukturen mit einer Fulle von Stereozentren und ihre biologische Bedeutung haben angesichts ihres auserst begrenzten Vorkommens in marinen Organismen ein enormes Interesse an der Synthese dieser Verbindungen geweckt. Dieser Aufsatz gibt einen Uberblick uber die biologischen Eigenschaften dieser ungewohnlichen Naturstoffe und schildert die kurzlich beendeten Totalsynthesen von Swinholid A, Scytophycin C, Aplyronin A, Mycalolid A – alle sind stark cytotoxische Actin-bindende Wirkstoffe – und eines Diastereomers von Ulapualid A. Dabei wird nicht jeder Einzelschritt dieser vielstufigen Totalsynthesen detailliert beschrieben, vielmehr werden unterschiedliche Synthesestrategien, Schlusselreaktionen und Methoden zur Steuerung der Stereochemie verglichen.

Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.

Scytophycin C (1) was synthesised in 8 steps from the fully protected seco acid 2 . Key steps include: ( i ) a high yielding macrolactonisation reaction of 15 followed by regioselective isomerisation of the undesired, 24-membered macrolide, 18 → 16 ; ( ii ) the chemoselective oxidation steps, 16 → 6 and 7 → 8; ( iii ) the P 2 O 5 -promoted condensation of 8 with HN(Me)CHO to install the N -methyl vinylformamide moiety in 1 .

A stereocontrolled synthesis of the C 1 C 32 seco acid derivative 9 for scytophycin C ( 1 ) was completed in 14 steps (18.2% yield, 85% ds) from aldehyde ( S )- 18 . Key steps include: ( i ) the asymmetric crotylboration of ( S )- 18 to give homoallylic alcohol 15 ; ( ii ) the boron-mediated aldol construction of aldehyde 14 from ( S )- 17 ; ( iii ) the Ba(OH) 2 -promoted HWE reaction, 13 + 14 → 31 ; ( iv ) the highly stereocontrolled Mukaiyama aldol coupling between silyl enol ether 33 and aldehyde 11 to give adduct 10 ; ( v ) the chemoselective reduction at C 17 of ketone 10 to produce 1,3- syn -diol 34 .

4-Thiomethylbenzisothiazolone-1,1-dioxides were synthesized via the corresponding 4-methylbenzisothiazolone-1,1-dioxides by a regioselective benzylic bromination, followed by conversion of the bromide to the thiol moiety under mild and neutral reaction conditions using 1-(2-hydroxyethyl)-4,6-diphenylpyridine-2-thione (HDPT).

4-Hydroxymethylbenzisothiazolone-1,1-dioxide could be facilely synthesised via a highly regioselective Diels-Alder cycloaddition between furfuryl alcohol and 2-( tert -butyl)-isothiazolone-1,1-dioxide, followed by aromatization of the adduct under basic conditions. A secondary effect from intramolecular hydrogen bonding is found also to influence the regioselectivity of the cycloaddition. Unequivocal proof of the regiochemistry of the Diels-Alder reaction is provided by X-ray crystallography and ab initio calculations showed electronic and steric effects on transition structure asynchronicity.

This review covers work published in the calendar year 2012. References to new, naturally occurring furans, dihydrofurans, and tetrahydrofurans are given. New methods for the ring synthesis of furans, dihydrofurans, and tetrahydrofurans, and benzofurans are discussed. Novel reaction chemistry of furans, dihydrofurans, and tetrahydrofurans, and benzofurans is covered.

Direct blockade of the cardiac potassium channel encoded by the KCNH2 gene, the human ether-a-go-go related gene (hERG) product, has been recognized for some time as a potential liability that is typically assessed by electrophysiological testing during preclinical profiling of drug candidates. However, inhibition of hERG protein trafficking has emerged as a potential mechanism of interfering with channel function that can only be detected by a very different screening paradigm that relies on extended incubation of hERG-expressing cells with candidate compounds. In this chapter, the background biochemical pharmacology underlying hERG protein trafficking is discussed and those compounds that have been shown to interfere with hERG channel expression on the cell surface together with insights into their mechanism of action are summarized. Assays that have recently been developed to detect hERG trafficking inhibitors are also described.

Because HIV relies on host cell machinery for infection, replication and transmission, future anti-HIV therapeutic agents that target the interactions between viral components and host cell proteins, such as actin, are likely to emerge.

Swinholide A and isoswinholide A were synthesised in 7 steps from the fully protected seco acid 4 . Key steps include: ( i) bimolecular acylation, 7 + 10 → 12 , ( ii ) selective hydrolysis of the methyl ester, 16 → 17 , and ( iii ) regioselective macrolactonisation. 17 → 18 . The monomeric lactone analogues 2 and 5 were prepared by regioselective macrolactonisation of the seco acid 6 , where the ring size was controlled by variation of the reaction conditions.

Two coupling strategies for (−)-pre-swinholide A were devised based on the analysis in Scheme 1. In the first route, a boron-mediated aldol reaction between the ethyl ketone 19 and the aldehyde 3 was used to construct the C15-C16 bond with moderate diastereoselectivity. In the second route, a Mukaiyama aldol reaction between the methyl ketone 54 and the aldehyde 4 introduced the C18-C19 bond with complete stereocontrol.

7-(2H-Tetrazol-5-yl)-1H-indole 3 was found to be a potent inhibitor of HIV-1 attachment but the compound lacked oral bioavailability in rats. The cause of the low exposure was believed to be poor absorption attributed to the acidic nature of the tetrazole moiety and, in an effort to address this liability, three more lipohilic tetrazole analogs, N-acetoxymethyl 4, N-pivaloyloxymethyl 5, and N-methyl 6, were evaluated as potential oral prodrugs in rats. Prodrug 5 was ineffective in improving the plasma concentration of 3 in vivo but compound 4 provided a 15-fold enhancement of the plasma concentration of 3. Most interestingly, oral dosing of analog 6 afforded a substantial increase in the plasma concentration of the parent in rats when compared to dosing of parent. This represents a novel example of a methyl tetrazole that acts as a prodrug for a free NH tetrazole-containing compound.

As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a primary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory activity against M- and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmacokinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest exposure.