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Thermolysis of 3-t-butyldimethylsiloxy-8-methyl-8-azabicyclo[3.2.1]oct-6-ene N-oxide (11) and (12) in butyronitrile gave 3-t-butyldimethylsiloxy-9-methyl-8-oxa-9-azabicyclo[3.2.2]non-6-ene (13) which upon reductive NO ring cleavage, hydrogenation, oxidation and deprotection yielded the 3-hydroxy analogue 8-methyl-8-azabicyclo[3.2.1]octane-1,3-diol ( 6a lrhar2 6b ) of the tropane alkaloid physoperuvine.

(+/-)-3alpha-hydroxy homoepibatidine 4 has been synthesized from the alkaloid scopolamine 5 and its properties as a nicotinic agonist assessed. While still binding strongly, the compound showed reduced agonist potency for the alpha(4)beta(2) nAChR compared with the parent compound epibatidine 1. Compound 4 also displayed generally similar binding and selectivity profiles at alpha(4)beta(2), alpha(2)beta(4), alpha(3)beta(4), and alpha(4)beta(4) nAChR subtypes to those for nicotine.

Extracts from the fruits of Capsicum frutescens Linn. were monitored for their mutagenic activities using the Micronucleus Test. The GC-MSD of the mutagenic fraction, FB4C4, gave 7 peaks. Repeated flash chromatography of FB4C4 gave 2 intractable mixtures, CF-1 and CF-2. CF-2 showed spectral properties comparable to those of natural capsaicin. Spectral analyses of CF-1 suggested that the major component is 3-acetamido-2-methyltetradecane. Results of the Micronucleus Test indicated that CF-1 is mutagenic.

Thermolysis of the 1-(2′-phenylcyclopropyl)tetrahydroisoquinoline N-oxide derivative 3b in butyronitrile/mesitylene gave the 1,3,4,5-tetrahydro-2,3-benzoxazepine derivative 4b and the 2,3,5,6-tetrahydro-10,11-dimethoxy-3-methyl-5-phenyl-1H-4,3-benzoxazecine 5b, the first representative of the 4,3-benzoxazecine system, in low yield. The structure of 5b was confirmed by X-ray crystallography. Thermolysis of the 1-cyclopropyltetrahydroisoquinoline N-oxide derivative 3a gave only the 2,3-benzoxazepine derivative 4a.

The novel cyclic peptoid 1, based upon a 1,1′-binaphthyl scaffold and a bridging tripeptide moiety, was synthesised utilising a ring-closing metathesis reaction, and was shown to possess anti-bacterial properties.

This article describes the compact synthesis of two isomeric dual-action hybrid antimicrobials where the 13-position of the antibacterial berberine has been linked via 3′- and 4′-methylene bridges to INF55 (5-nitro-2-phenylindole), an inhibitor of the bacterial NorA multidrug-resistance pump.

As part of a programme investigating antibacterial cyclic macrocycles containing a cationic amino acid with an internal aromatic hydrophobic scaffold, we previously reported a macrocycle anchored at the 3,3'-positions of a 1,1'-binaphthyl unit. This was prepared via key intermediates containing an internal allylglycine and an allyl-substituted binaphthyl unit for a subsequent ring-closing metathesis reaction. This paper presents some structure-activity relationship studies with additional macrocycles based on this lead compound against Staphylococcus aureus together with the antibacterial activity of two related acyclic compounds.

[2.31 Sigmatropic rearrangement of the N -ylides from the 1-vinyl and 1-(1-propenyl) tetrahydroisoquinolinium salts 3a and 3b at room temperature in acetonitrile gave high yields of the functionalised 3-benzazonine derivatives 6a (90%: E/Z = 19) and 6b (93%: E / Z = 2) respectively. The N -oxide analogues 4a and 4b gave the 2,3-benzoxazepines 8a and 8b . together with the first representative of the 4,3-benzoxazonine system, 9b , from 4b .

In this study a series of isatin-based, pH-sensitive aryl imine derivatives with differing aromatic substituents and substitution patterns were synthesised and their acid-catalysed hydrolysis evaluated. These derivatives were functionalised at the C3 carbonyl group of a potent N-substituted isatin cytotoxin and were stable at physiological pH but readily cleaved at pH 4.5. Observed rates of hydrolysis for the embedded imine-acid moiety were in the order para-phenylpropionic acid>phenylacetic acid (para>meta)>benzoic acid (meta>para). The ability to fine-tune hydrolysis rates in this way has potential implications for optimising imine linked, tumour targeting cytotoxin-protein conjugates.

The synthesis of eleven novel antibacterial agents is reported. The structures are based on a C 2 -symmetric binaphthyl scaffold which holds two identical chains consisting of a short linker, a basic amino acid and a small hydrophobic side chain. Antibacterial activity is revealed for a number of derivatives down to an MIC of 2 μg/mL (2 μM) against Staphylococcus aureus – comparable to vancomycin, and an MIC of 31 μg/mL (31 μM) against some vancomycin-resistant enterococcal strains.

Photolysis of 1-( chloroacetyl )-8,9-dimethoxy-2,3,5,6-tetrahydropyrrolo[2,1-a] isoquinoline (4a) and 1-( chloroacetyl )-9,10-dimethoxy-3,4,6,7-tetrahydro-2H-benzo[a] quinolizine (4b) in acidified water/ acetonitrile each gave mixtures of two products: 10,11-dimethoxy-1,4,5,6,7,8-hexahydro-3,6-methano-2H-3-benzazecine-7,13-dione (5) plus crude 7,8-dimethoxy-1,2,4,5,9,10-hexahydrobenzo [de] pyrrolo [3,2,1-ij] isoquinoline-9,10-dione (6); and 12-hydroxy-11-methoxy- 1,2,4,5,6,7,8,9-octahydro-3,7-methano-3-benzazacycloundecine-8,14-dione (7) and 8,9-dimethoxy-2,3,5,6,10,11-hexahydro-1H-benzo[de] pyrido [3,2,1ij ]quinoline-10,11-dione (8), respectively. The structures of (5), (7) and (8) were confirmed by X-ray crystallographic studies.

ESI mass spectrometry was used to assess the binding of 13-substituted, 5-nitro-2-phenylindolyl- and 2-naphthalenyl-based berberine derivatives to inter- and intramolecular G-quadruplex DNA molecules. In contrast with the parent berberine, the compounds showed selectivity for quadruplex over duplex DNA and stabilised the quadruplex structure. They represent a new class of quadruplex DNA-selective ligands.

Thermolysis of 3-t-butyldimethylsiloxy-8-methyl-8-azabicyclo[3.2.1]oct-6-ene N-oxide (11) and (12) in butyronitrile gave 3-t-butyldimethylsiloxy-9-methyl-8-oxa-9-azabicyclo[3.2.2]non-6-ene (13) which upon reductive NO ring cleavage, hydrogenation, oxidation and deprotection yielded the 3-hydroxy analogue 8-methyl-8-azabicyclo[3.2.1]octane-1,3-diol ( 6a lrhar2 6b ) of the tropane alkaloid physoperuvine.

The objective of this research was to synthesize isoquino[2,1-c][1,3]benzodiazepine from papaverine alkaloid. Functional Group Interconversion (FGI) and Carbon -Nitrogen bond connection approach was investigated. Papaverine (1) was nitrated by HNO3 to compound (2) and followed by reduction with Sn and HCl to afford aminonorlaudanosine (3). Formation of cyclic benzodiazepine (4) was achieved by reaction of (3) with CS2. Products of reactions were confirmed by Nuclear Magnetic Resonances (n.m.r), Mass Spectrum, and Fourier Transform Infra Red (FTIR). Keywords: isoquino[2,1-c][1,3]benzodiazepine, papaverine

Baenzigeride A, a new rearranged clerodane diterpene and baenzigeride A glucoside, baenzigeroside A, have been isolated from the stems of Tinospora baenzigeri . The structures were established on the basis of the spectroscopic data.

This paper describes the synthesis of a novel cyclic peptoid 11, structurally comprising a tripeptide moiety linked through a carbazole scaffold. In a key step, a ring-closing metathesis reaction was used giving efficientaccess to a new class of cyclic peptoids.

A compact synthesis of 15 new binaphthyl-based dicationic tripeptoids and one biphenyl based dicationic tripeptoid is described. Fourteen of these tripeptoids resulted from variation of the C-2' ether substituent of the binaphthyl unit. An O-iso-butyl ether binaphthyl derivative was found to be the most active against Staphylococcus aureus (MIC 1.95 μg/mL). The biphenyl analogue also showed good activity against S. aureus (MIC 1.95 μg/mL). These compounds, however, were less active against four vancomycin-resistant strains of enterococci (VRE) than some of our previously developed compounds that had an O-iso-pentyl ether substituent on the binaphthyl unit and a C-2 L-Leu moiety.

A urokinase targeting conjugate of 2′-deoxy-5-fluorouridine (5-FUdr) was synthesized and tested for tumor-cell selective cytotoxicity in vitro. The 5-FUdr prodrug 2′-deoxy-5-fluoro-3′-O-(3-carboxypropanoyl)uridine (5-FUdrsuccOH) containing an ester-labile succinate linker was attached to the specific urokinase inhibitor plasminogen activator inhibitor type II (PAI-2) and was found to preferentially kill urokinase-over expressing cancer cells. Up to 7 molecules of 5-FUdr were incorporated per PAI-2 molecule without affecting protein activity. This is the first time a small organic cytotoxin has been conjugated to PAI-2.

An efficient synthesis of 29 new binaphthyl-based neutral, and mono- and di-cationic, peptoids is described. Some of these compounds had antibacterial activities with MIC values of 1.9-3.9microg/mL against Staphylococcus aureus. One peptoid had a MIC value of 6microg/mL against a methicillin-resistant strain of S. aureus (MRSA) and a MIC value of 2microg/mL against vancomycin-resistant strains of enterococci (VRE).

The alkaloidal components of the Bhutanese medicinal plant Corydalis calliantha Long, which is used for the treatment of malaria, have been assessed. Four known alkaloids, protopine (1), scoulerine (2), cheilanthifoline (3) and stylopine (4) are reported from this plant for the first time. The protopine alkaloid, protopine, and the tetrahydroprotoberine alkaloid, cheilanthifoline, showed promising in vitro antiplasmodial activities against Plasmodium falciparum, both wild type (TM4) and multidrug resistant (K1) strains with IC(50) values in the range of 2.78-4.29 microM. Such activity had not been demonstrated previously for cheilanthifoline. The results thus support, at a molecular level, the clinical use of this plant in the Bhutanese traditional medicine and identified cheilanthifoline as a potential new antimalarial drug lead.

An efficient synthesis of four new acyclic and four new cyclic binaphthyl-based cationic peptoids is described. These compounds had anti-bacterial activities with MIC values of 4–62 μg/mL against Staphylococcus aureus.

A compact three-step synthesis of a new fused bisindole system isomeric with the heterocyclic skeleton present in the marine natural product iheyamine A has been achieved. The structure of the synthetic product was confirmed by a single-crystal X-ray structure.

Betulinic acid, oleanolic acid and ursolic acid have been modified at the C-3 position to cinnamate-based esters and in vitro antimycobacterial activity against Mycobacterium tuberculosis H(37)Ra has been determined. The results indicated that modification of the parent structures of betulinic acid, oleanolic acid and ursolic acid to the p-coumarate and, in the case of the latter two triterpenes, the ferulate ester analogues resulted in high antimycobacterial activity. Structure-activity relationships within the lupane, oleanane and ursane analogues and between these triterpenes are discussed.

Betulinic acid, oleanolic acid and ursolic acid have been modified at the C-3 position to cinnamate-based esters and in vitro antimycobacterial activity against Mycobacterium tuberculosis H(37)Ra has been determined. The results indicated that modification of the parent structures of betulinic acid, oleanolic acid and ursolic acid to the p-coumarate and, in the case of the latter two triterpenes, the ferulate ester analogues resulted in high antimycobacterial activity. Structure-activity relationships within the lupane, oleanane and ursane analogues and between these triterpenes are discussed.

Azepines and their benz-fused derivatives have commanded a considerable amount of synthetic interest. This is particularly true of the latter systems because of their continuing pharmacological significance. Ring synthesis by ring construction is the dominant general approach, although a number of new ring transformation strategies have been developed. Amongst the ring construction strategies a flowering of methods based on ring closing metathesis is evident for type c and type d processes. There is scope also for extension of this methodology to type b processes. A novel zirconium-mediated approach to substituted azepanes has been described and this reaction has considerable further synthetic potential. The synthetic power of sequential reactions has also been demonstrated, for example in the synthesis of tetrahydro-1H-1-benzazepine derivatives. A single crystal X-ray structure of the first reported 2-azatropone is also a significant development.

The 1,3-oxazepines and 1,3-thiazepines and their benz-fused derivatives have attracted some synthetic interest. Ring synthesis by ring construction is still an important avenue to these heterocycles. Typical of this approach are C–C bond formations to complete the heterocyclic ring using palladium-based methodology or metal complex-mediated ring closing metathesis to benz-fused oxazepines. There is much scope for extension of these metal-ion based ring cyclization approaches to oxazepines. The formation of C–O and C–S bonds underpin other cyclization approaches to 1,3-oxazepines and thiazepines respectively. The first route to a 1,3-selenazepane derivative was also described with ring cyclization after amine addition to a isoselenocyanate precursor. The Baeyer–Villiger ring expansion reaction still attracts some research attention, while other ring expansion methodologies to 1,3-oxazepines have been described, including a potentially adaptable insertion approach in 1,2-oxazines involving a cobalt carbonyl complex and carbon monoxide. This insertion reaction has considerable potential for further chemical and pharmacological exploration of this structural space.

This review collates and analyses recent work done on dual action approaches to tackling the mounting health problem of resistance by human pathogenic bacteria to antibacterial agents. In particular the areas reviewed include the use of two drugs in combination, dual action prodrugs, and dual action drugs (or hybrid drugs).

Reaction of primary aromatic amines with peroxidic tetrahydrofuran (THF) in the presence of hydrogen and 10% palladium on carbon catalyst results in THF ring opening to give 4-N-arylamino-1-butanols in good yield. The reaction mechanism is believed to involve a free-radical sequence resulting in an imino alcohol subsequently reduced to product.

Negative ion electrospray ionization mass spectrometry (ESI-MS) was used to compare the binding affinities and stoichiometries of the alkaloid berberine, a 13-substituted indolyl berberine derivative, SS14, and the chemotherapeutic agent, daunomycin, for 16-mer double-stranded (ds) DNA (D1 and D2) and for an 8-mer tetrameric quadruplex, Q1 (d(TTGGGGGT)4). Under the experimental conditions presented here, ESI mass spectra of Q1 showed that the major ions were from Q1 with three ammonium ions bound in the structure. Ions from Q1 with four ammonium ions were of lower abundance. In agreement with other work, there were multiple binding sites on the dsDNA and the quadruplex for daunomycin and berberine. The binding of SS14 to both dsDNA and Q1 was less extensive. Although the binding affinity of SS14 for Q1 was modest, this compound showed a clear preference for Q1 DNA over D1 or D2 DNA. Berberine and daunomycin bound with greater affinity to both types of DNA secondary structure, with the former showing a slight preference for Q1 over D1 while the latter showed a slight preference for D1 over Q1. While at least five berberine molecules bound to Q1, this quadruplex could accommodate only two SS14 molecules. These investigations show that SS14 is a promising lead compound for drugs that may selectively bind quadruplex over duplex DNA. Copyright © 2007 John Wiley & Sons, Ltd.

Fractionation of the aerial parts of Chromolaena odorata afforded a new flavonoid, 5,7-dihydroxy-6,4'-dimethoxyflavanone, in addition to 14 known flavonoid compounds, six of which had not been isolated previously from this plant. The structure of the new compound was determined by spectroscopic methods particularly 2D-NMR analysis.

The adsorption of Al(III) from aqueous solutions onto chitosan was studied in a batch system. The isotherms and the kinetics of adsorption with respect to the initial Al(III) concentration and temperature were investigated. Langmuir and Freundlich adsorption models were applied to describe the experimental isotherms. Equilibrium data fitted very well to the Langmuir model in the entire concentration range (5-40 mg/L). The negative values of free energy (DeltaG degrees ) and enthalpy (DeltaH degrees ) for the adsorption of Al(III) onto chitosan indicated that the adsorption process is a spontaneous and exothermic one. Two simplified kinetic models, based on pseudo first-order and pseudo second-order equations, were tested to describe the adsorption mechanism. The pseudo second-order kinetic model resulted in an activation energy of 56.4 kJ/mol. It is suggested that the overall rate of Al(III) ion adsorption is likely to be controlled by the chemical process. The values of the enthalpy (DeltaH(#)) and entropy (DeltaS(#)) of activation were 53.7 kJ/mol and -164.4 J/molK, respectively. The free energy of activation (DeltaG(#)) at 30 degrees C was 103.5 kJ/mol.

A range of substituted 1H-indole-2,3-diones (isatins) were synthesized using standard procedures and their cytotoxicity evaluated against the human monocyte-like histiocytic lymphoma (U937) cell line in vitro. SAR studies identified C(5), C(6), and C(7) substitution greatly enhanced activity with some di- and tri-halogenated isatins giving IC(50) values

The alkaloid 1,3,7-trimethylguanine was isolated from the ascidian Eudistoma maculosum, and differences in the NMR spectroscopic data for this compound compared with data in the literature are due to ammonium salt formation.

In order to develop structure–activity relationships and to provide access to antibacterial agents for dual action studies, a variety of aryl group-substituted 2-aryl-5-nitro-1 H -indoles were synthesized and the activity of the compounds assessed as inhibitors of the NorA multidrug resistance pump in the bacterium Staphylococcus aureus . The NorA protein from the major facilitator superfamily of efflux pumps confers resistance to a variety of structurally dissimilar antimicrobials such as norfloxacin, ethidium bromide, berberine and acriflavin. The compound [4-benzyloxy-2-(5-nitro-1 H -2-yl)-phenyl]-methanol was the most potent pump inhibitor.

Publisher Summary This chapter describes seven-membered ring heteroatoms, with an emphasis on nitrogen, oxygen and sulfur. Systems of pharmacological interest or significance, and on future directions, are also discussed. While activity in this particular area has not been especially high, a number of interesting preparations and reactions are described in the chapter. A study of the rearrangement-ring expansion and rearrangement-ring opening reactions of stereoisomeric tetrahydropyrans with zinc acetate has been undertaken—for example, the oxepane 113 was obtained from 112 in moderate yield, together with a small amount of the ring opened product 114. The first total synthesis of the marine natural product (+)-rogioloxepane A containing a reduced oxepine ring has also been reported. New conditions for the Baeyer–Villiger oxidation continue to be explored including selenium-catalyzed oxidation with aqueous hydrogen peroxide and tin–zeolite as a chemoselective heterogeneous catalyst.

From analysis by gas chromatography/mass spectrometry (GC/MS), the presence of either 2,4,5-tribromo-1H-imidazole (1) or 3,4,5-tribromo-1H-pyrazole (2) was tentatively identified in lipophilic extracts from the egg masses of three muricid molluscs. Synthesis of these compounds, followed by comparison of the GC retention times and fragmentation patterns from electron impact MS, with those of the natural products, indicated that it was 2,4,5-tribromo-1H-imidazole rather than the pyrazole. This imidazole is likely to be responsible for some of the antimicrobial activity observed in the egg extracts. This is the first report of this compound from a natural source.

A range of 3,6,6-trisubstituted nortropane derivatives based upon 6 β -phenyltropane-3 β ,6 α -diol have been synthesised from 6 β -hydroxytropinone, including some novel related tricyclic hemi-ketal and tricyclic ketal compounds. Derivatives were assessed for pharmacological affinity and selectivity at α 1 -adrenergic receptors, and 6 β -phenyl-8-azabicyclo[3.2.1]octan-3-spiro-2′-(1′,3′-dioxolane)-6-ol, a novel lead compound selective for the alpha 1D -adrenergic receptor, is reported.