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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.

BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and C(max) of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor.

This chapter reviews the significant developments in the metalation of furans and benzofurans and applications of the resulting metalated species in the past decade. New and interesting metalated furan and benzofuran derivatives and their novel reactions are featured. Topics encompass lithiation, magnesation and zincation, the use of boronated and other metalated furans and benzofurans in cross-coupling reactions, as well as the use of metalated furans and benzofurans in addition reactions. Examples of regioselective metalation are highlighted, and metalation of related furo heterocycles is also summarized.

Efforts to interfere with four key protein-protein interactions in the HIV-1 lifecycle with the goal of achieving clinically-relevant, orally administered HIV-1 therapies are reviewed. These four targets: the HIV-1 gp120/human CD4 interaction, the HIV-1 gp41 six-helix bundle formation, the human LEDGF/p75-integrase interaction, and HIV-1 protease dimerization each present unique challenges to the discovery of viable small molecule inhibitors. Background information from the literature is provided. A class of inhibitors which target gp120 from which an orally dosed member has been advanced into Phase II clinical studies as well as other small molecule approaches to disrupt the gp120/CD4 interaction are discussed. The unrealized efforts to find a small-molecule inhibitor of gp41 six-helix bundle formation that is suitable for clinical studies are described, including a summary of the work on effective, peptidic inhibitors that lack the properties needed for oral use. An overview of the progress to identify small molecule inhibitors of the LEDGF/HIV-1 p75-integrase interaction and the dimerization of the HIV-1 protease enzyme describes the preclinical compounds of greatest interest and discusses the rationale behind their design/activity.

The fully protected monomeric unit 19 of the marine macrodiolide, swinholide A (1), was obtained with > 97% ds by a Mukaiyama aldol reaction between 16 and 5, followed by a boron-mediated reduction to give the syn 1,3-diol 18. Deprotection gave (−)-pre-swinholide A (2), the putative biosynthetic precursor of 1.

A practical and convenient protocol has been developed for the acidic 1-ethyl-3-methylimidazolium chloroaluminate ionic liquid (generated from 1-ethyl-3-methylimidazolium chloride (EmimCl) and aluminium chloride ( X (AlCl 3 ), mole fraction X =0.67–0.75) promoted Friedel–Crafts acylation of indoles at room temperature. The simple experimental procedure provides 3-substituted indoles in good to high yields with less electron rich indole ring systems.

Three plantinum(II) complexes of biq (biq = 1,1′-biisoquinoline), [Pt(biq)Cl2], [Pt(biq)(py)3](ClO4)2 (py = pyridine) and [Pt(biq)(dapy)3](ClO4)2 [dapy = 4-(dimethylamino)pyridine] were prepared. Using 1H NMR spectroscopy and X-ray crystallography, biq in the former complex was found to be bidentate and in the two latter complexes monodentate. Dihedral angles between the two isoquinoline rings were determined to be 35.18° and 41.12° in [Pt(biq)Cl2] and 77.61° in [Pt(biq)(dapy)3](ClO4)2. The crystal structure of [Pt(biq)Cl2] is the first example of η2-μ1 biq complexes with a five-membered chelating ring. Weak intramolecular π-π stacking occurs in the solid phase of [Pt(biq)(dapy)3](ClO4)2.

The fully protected monomeric unit 19 of the marine macrodiolide, swinholide A (1), was obtained with > 97% ds by a Mukaiyama aldol reaction between 16 and 5, followed by a boron-mediated reduction to give the syn 1,3-diol 18. Deprotection gave (−)-pre-swinholide A (2), the putative biosynthetic precursor of 1.

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.

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.

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).

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 practical and convenient protocol has been developed for the acidic 1-ethyl-3-methylimidazolium chloroaluminate ionic liquid (generated from 1-ethyl-3-methylimidazolium chloride (EmimCl) and aluminium chloride ( X (AlCl 3 ), mole fraction X =0.67–0.75) promoted Friedel–Crafts acylation of indoles at room temperature. The simple experimental procedure provides 3-substituted indoles in good to high yields with less electron rich indole ring systems.

1-(4-Benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1a) has been characterized as an inhibitor of HIV-1 attachment that interferes with the interaction of viral gp120 with the host cell receptor CD4. In previous studies, the effect of indole substitution pattern on antiviral activity was probed. In this Letter, the effect of structural variation of the benzamide moiety is described, a study that reveals the potential or the phenyl moiety to be replaced by five-membered heterocyclic rings and a restricted tolerance for the introduction of substituents to the phenyl ring.

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.

A novel human coronavirus (CoV) has been identified as the etiological agent that caused the severe acute respiratory syndrome (SARS) outbreak in 2003. The spike (S) protein of this virus is a type I surface glycoprotein that mediates binding of the virus to the host receptor and the subsequent fusion between the viral and host membranes. Because of its critical role in viral entry, the S protein is an important target for the development of anti‐SARS CoV therapeutics and prophylactics. This article reviews the structure and function of the SARS CoV S protein in the context of its role in virus entry. Topics that are discussed include: the interaction between the S1 domain of the SARS spike protein and the cellular receptor, angiotensin converting enzyme 2 (ACE2), and the structural features of the ectodomain of ACE2; the antigenic determinants presented by the S protein and the nature of neutralizing monoclonal antibodies that are elicited in vivo; the structure of the 4,3‐hydrophobic heptad repeats HR1 and HR2 of the S2 domain and their interaction to form a six‐helical bundle during the final stages of fusion. Opportunities for the design and development of anti‐SARS agents based on the inhibition of receptor binding, the therapeutic uses of S‐directed monoclonal antibodies and inhibitors of HR1–HR2 complex formation are presented. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 4, 414–433, 2006

Marine organisms produce a fascinating range of structurally diverse secondary metabolites, which often possess unusual and sometimes unexpected biological activities. This structural diversity makes these marine natural products excellent molecular probes for the investigation of biochemical pathways. Recently, a number of novel and stereochemically complex macrolides, having a large macrolactone (22- to 44-membered) ring, that interact with the actin cycloskeleton have been isolated from different marine sources. Actin, like tubulin, is a major component of the cytoskeleton and has important cellular functions. Although the details of these interactions are still under investigation, these marine macrolides are becoming increasingly important as novel molecular probes to help elucidate the cellular functions of actin. Owing to their potent antitumor activities, these compounds, for example the aplyronines, also have potential for preclinical development in cancer chemotherapy. Their appealing molecular structures, with an abundance of stereochemistry, and biological significance, coupled with the extremely limited availability from the marine sources, have stimulated enormous interest in the synthesis of these compounds. This review summarizes the biological properties of these unusual marine natural products and features the recently completed total syntheses of swinholide A, scytophycin C, aplyronine A, mycalolide A--all of these being potent cytotoxic agents that target actin--and a diastereoisomer of ulapualide A. Rather than detailing each individual step of these multistep total syntheses, the different synthetic strategies, key reactions, and methods adopted for controlling the stereochemistry are compared.

Publisher Summary This chapter reviews papers that were published in 2006 on the reactions and syntheses of furans, benzofurans, and their derivatives. Like 2005, many new naturally occurring molecules containing tetrahydrofuran and dihydrofuran rings were identified in 2006. Several examples reported in 2006 demonstrate that 2-substituted furans underwent spirocyclization at the 2-position. The reaction of a furan tethered at the 2-position to an iminium ion gave a spiro-2,5-dihydrofuran derivative as the sole diastereoisomer. This spirocyclization that proceeded irrespective of the length of the carbon linker was employed to construct the ABC tricyclic core of manzamine A. Spirocyclization was also the reaction pathway under radical conditions if furan was tethered to a radical precursor at the 2-position. When furans were tethered to silyl enol ethers at the 2-position, spiroannulation also occurred at the 2-position under electrochemical conditions. Furan that was loaded on a soluble dendritic polyglycerol support could be efficiently oxidized electrochemically to a 2,5-dihydro-2,5-dimethoxyfuran, which served as an intermediate in the synthesis of a pyrrole library.

A survey of isosteric replacements of the phosphonoalanine side chain coupled with a process of conformational constraint of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of hepatitis C virus (HCV) NS3 serine protease resulted in the identification of novel series of active compounds with extended side chains. However, Zn(2+)-dependent HCV NS3 inhibition was relatively insensitive to the structural variations examined but dependent on the presence of negatively charged functionality. This result was interpreted in the context of an initial electrostatic interaction between protease and inhibitor that is subsequently consolidated by Zn(2+), with binding facilitated by the featureless active site and proximal regions of the HCV NS3 protein.

Reaction of [ReO2(PPh3)2I] and [ReNCl2(PPh3)2] with 2,2′ : 6′,2″ : 6″,2‴-quaterpyridine (L) in methanol gave [ReO(L)(OMe)2]ClO4 and [ReN(L)(PPh3)Cl]ClO4 respectively. The structures determined by X-ray crystallography revealed seven-co-ordination around rhenium with ReO and ReN distances of 1.666(4) and 1.647(6)A respectively. Intense metal-to-ligand charge-transfer transitions in the visible region and reversible ReVI–ReV redox couples have been observed for both complexes in acetonitrile.

Corrigendum to ‘‘Inhibitors of HIV-1 attachment. Part 3: A preliminary survey of the effect of structural variation of the benzamide moiety on antiviral activity’’ [Bioorg. Med. Chem. Lett. 19 (2009) 5136] Nicholas A. Meanwell *, Owen B. Wallace , Henry Wang , Milind Deshpande , Bradley C. Pearce , Ashok Trehan , Kap-Sun Yeung , Zhilei Qiu , J. J. Kim Wright , Brett A. Robinson , Yi-Fei Gong , Hwei-Gene Heidi Wang , Timothy P. Spicer , Wade S. Blair , Pei-Yong Shi , Pin-fang Lin b Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States

Hepatitis C virus NS3 serine protease (HCV-Pr) is an extensively studied enzyme for drug intervention. The target presented serious challenges in early screening efforts, however, wish the lack of prominent active site features rendering traditional nonpeptidic serine protease inhibitor motifs and high-throughput screening campaigns ineffectual. In contrast, the peptidomimetic structure-based design approach has proven uccessful in the discovery of potent inhibitors of HCV Pr. Subsequent rational design efforts have led to the identification of an inhibitor that demonstrates efficacy in man, validating the years of research. This review summarizes why HCV Pr provides a viable drug discovery target despite the many obstacies, and details the breakthroughs in protein production and essay development that have facilitated inhibitor advances. The latest inhibitors in preclinical and clinical research and development are also presented, along with a discussion of how the recent HCV Pr clinical candidate chalienges much of the dogma surrounding peptidomimetic design. In addition, future issues such as resistance, genotype coverage and HIV-HCV coinfected individuals are considered.