Moiety In Position Research Articles

Late‐Stage C–H Bond Arylation of Spirocyclic σ1 Ligands for Analysis of Complementary σ1 Receptor Surface

AbstractDirect C–H bond arylation in the α‐ and β‐positions of spirocyclic thiophenes containing various functional groups (amine, ether, acetal, lactone) was accomplished. Selective phenylation in the α‐position of the thiophene ring was achieved by using the catalytic system PdCl2/bipy/Ag2CO3. The introduction of phenyl moieties to the β‐position was performed with the catalytic system PdCl2/P[OCH(CF3)2]3/Ag2CO3. Even the five‐membered lactone 10 with an electron‐withdrawing carbonyl moiety directly attached to the thiophene ring was arylated. Spirocyclic thiophenes substituted with a phenyl moiety in position A (top position) or B (left position) display low nanomolar σ1 affinities (e.g., 4a: Ki = 1.6 nM; 5a: Ki = 2.4 nM), indicating an additional hydrophobic pocket on the complementary σ1 receptor protein. A phenyl moiety in position C (at the bottom position) is not tolerated by the σ1 receptor (e.g., 12: Ki = 483 nM). However, an additional phenyl moiety in position A is able to compensate at least partially the unfavorable effects of the phenyl moiety in position C.

Differential hepatoprotective mechanisms of rutin and quercetin in CCl4-intoxicated BALB/cN mice

To investigate the mechanisms underlying the protective effects of quercetin-rutinoside (rutin) and its aglycone quercetin against CCl(4)-induced liver damage in mice. BALB/cN mice were intraperitoneally administered rutin (10, 50, and 150 mg/kg) or quercetin (50 mg/kg) once daily for 5 consecutive days, followed by the intraperitoneal injection of CCl(4) in olive oil (2 mL/kg, 10% v/v). The animals were sacrificed 24 h later. Blood was collected for measuring the activities of ALT and AST, and the liver was excised for assessing Cu/Zn superoxide dismutase (SOD) activity, GSH and protein concentrations and also for immunoblotting. Portions of the livers were used for histology and immunohistochemistry. Pretreatment with rutin and, to a lesser extent, with quercetin significantly reduced the activity of plasma transaminases and improved the histological signs of acute liver damage in CCl(4)-intoxicated mice. Quercetin prevented the decrease in Cu/Zn SOD activity in CCl(4)-intoxicated mice more potently than rutin. However, it was less effective in the suppression of nitrotyrosine formation. Quercetin and, to a lesser extent, rutin attenuated the inflammation in the liver by down-regulating the CCl(4)-induced activation of nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α) and cyclooxygenase (COX-2). The expression of inducible nitric oxide synthase (iNOS) was more potently suppressed by rutin than by quercetin. Treatment with both flavonoids significantly increased NF-E2-related factor 2 (Nrf2) and heme oxygenase (HO-1) expression in injured livers, although quercetin was less effective than rutin at an equivalent dose. Quercetin more potently suppressed the expression of transforming growth factor-β1 (TGF-β1) than rutin. Rutin exerts stronger protection against nitrosative stress and hepatocellular damage but has weaker antioxidant and anti-inflammatory activities and antifibrotic potential than quercetin, which may be attributed to the presence of a rutinoside moiety in position 3 of the C ring.

Viable and straightforward approach to the preparation of water soluble pyrazol-5-one derivatives through glycoconjugation

The synthesis of water soluble pyrazol-5-one azo-dyes has been achieved. 6′-Aminolactosetriacetonide 9 was selected as the key building block to glyconjugate the pyrazole ring at its 3 position via a carboxamide or via a benzeneamide moiety in position 1 of the heterocycle. Diethyl-3-oxopentandionate 2 led eventually to a bicyclic compound, hampering the glyconjugation coupling process. The values of the molar extinction coefficients (ɛ) confirmed the tendency of pyrazolone azo dyes to exist in their tautomeric hydrazo form (especially in polar solvents); whereas the presence of substituents on the phenylazo group influenced the visible absorption maxima negligibly.

Novel coumarins and 2-thioxo-coumarins as inhibitors of the tumor-associated carbonic anhydrases IX and XII

A series of coumarins incorporating tert-butyl-dimethylsilyloxy- or allyoxy- moieties in positions 4-, 6 or 7 of the heterocyclic ring have been synthesized and then converted to the corresponding 2-thioxo-coumarins. Other derivatives incorporating hydroxyethyloxy-, tosylethoxy- and 2-fluroethyloxy- moieties in position 7 of the coumarin ring were synthesized together with derivatives of 4-methyl-7-amino coumarin incorporating acetamido, 3,5-dimethylphenylureido- and tert-butyloxycarbonylamido functionalities. All these compounds were assayed as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The human (h) cytosolic isoforms hCA I and II were weakly inhibited (hCA I) or not inhibited at all (hCA II) by these (thioxo)coumarins whereas the tumor-associated transmembrane isoforms hCA IX and XII were inhibited with efficiencies from the submicromolar to the low micromolar range by many of these derivatives. The structure–activity relationship for these classes of less investigated CA inhibitors are delineated, with the potential of using them as leads to obtain isoform-selective inhibitors with excellent affinity for CA IX and XII (validated antitumor targets) which do not significantly inhibit the cytosolic offtarget isoforms hCA I and II.

Equilibrium and NMR Relaxometric Studies on the s-Triazine-Based Heptadentate Ligand PTDITA Showing High Selectivity for Gd3+ Ions

A complete potentiometric and NMR relaxometric solution study on the heptadentate 2,2',2″,2'″-[(6-piperidinyl-1,3,5-triazine-2,4-diyl)dihydrazin-2-yl-1-ylidene]tetraacetic acid (PTDITA) ligand has been carried out. This ligand is based on the 1,3,5-triazine ring with two hydrazine-N,N-diacetate groups in positions 2 and 4 and a piperidine moiety in position 6. The introduction of the triazine ring into the ligand backbone is expected to modify its flexibility and then to affect the stability of the corresponding complexes with transition-metal and lanthanide ions. Thermodynamic stabilities have been determined by pH potentiometry, UV spectrophotometry, and (1)H NMR spectroscopy for formation of the complexes with Mg(2+), Ca(2+), Cu(2+), Zn(2+), La(3+), Gd(3+), and Lu(3+) ions. PTDITA shows a good binding affinity for Gd(3+) (logK = 18.49, pGd = 18.6) and an optimal selectivity for Gd(3+) over the endogenous Ca(2+), Zn(2+), and Cu(2+) (K(sel) = 6.78 × 10(7)), which is 3 orders of magnitude higher that that reported for Gd(DTPA) (K(sel) = 2.85 × 10(4)). This is mainly due to the lower stability of the Cu(II)- and Zn(II)(PTDITA) complexes compared to the corresponding DTPA complexes, which suggests an important role of the triazine ring on the selectivity for the Gd(3+) ion. The relaxometric properties of Gd(PTDITA) have been investigated in aqueous solution by measuring the (1)H relaxivity as a function of the pH, temperature, and magnetic field strength (nuclear magnetic relaxation dispersion profile). Variable-temperature (17)O NMR data have provided direct information on the kinetic parameters for exchange of the coordinated water molecules. A simultaneous fit of the data suggests that the high relaxivity value (r(1) = 10.2 mM(-1) s(-1)) is a result of the presence of two inner-sphere water molecules along with the occurrence of relatively slow rotation and electronic relaxation. The water residence lifetime, (298)τ(M) = 299 ns, is quite comparable to that of clinically approved magnetic resonance imaging contrast agents. The displacement of the inner-sphere water molecules by bidentate endogeneous anions (citrate, phosphate, and carbonate) has also been evaluated by (1)H relaxometry. In general, the binding interaction is markedly weak, and only in the case of citrate, a ca. 35% decrease in relaxivity was observed in the presence of 60 equiv of the anion. Phosphate and carbonate also interact with the paramagnetic ion, likely as monodentate ligands, but formation of the ternary complex is accompanied by a modest increase of r(1) due to the contribution of second-sphere water molecules.

Phenylphenalenones and related natural products from Wachendorfia thyrsiflora L.

Phytochemical studies of different plant parts and root cultures of Wachendorfia thyrsiflora (Haemodoraceae) resulted in 24 phenylphenalenones and related compounds, which were elucidated by means of nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Among them, one new 9-phenylphenalenone, two new phenylphenalenone O-glycosides carrying the sugar moiety in position 4 of the 9-phenylphenalenone skeleton and two new 7-phenyl-benzoisochromenone-6- O-glucosides were identified.

Exploitation of an additional hydrophobic pocket of σ1 receptors: Late-stage diverse modifications of spirocyclic thiophenes by C–H bond functionalization

The hypothesis that the σ(1) receptor will tolerate an additional aryl moiety in position 1 of the spirocyclic system was based on spirocyclic pyrazole derivatives, pharmacophore models of σ(1) receptor ligands and DFT calculations. The strategy of introducing the aryl residue at the final step of the synthesis allowed the preparation of a large set of diverse ligands for the exploitation of the hydrophobic pocket of the σ(1) receptor protein. The catalyst system PdCl(2)/2,2'-bipyridyl/Ag(2)CO(3) is able to introduce various aryl groups onto the α-positions of spirocyclic thiophene derivatives 5 and 6 to afford the target aryl-appended spirocyclic thiophenes 3 and 4. Although the σ(1) affinity of the 1-phenyl substituted spirocyclic thiophenes 3a and 4a is slightly reduced compared with the σ(1) affinity of the non-arylated compounds 5 and 6, both compounds represent very potent σ(1) receptor ligands (3a: K(i) = 4.5 nM; 4a: K(i) = 1.0 nM). This result indicates that an aryl moiety in position 1 is well tolerated by the σ(1) receptor protein. The substitution pattern of the additional phenyl moiety has only weak effects on the σ(1) affinity. Even ligands 3f and 4h with extended naphthyl residue show high σ(1) affinity. However, decrease of σ(1) affinity by extension of the π-system to a biphenylyl substituent (4j: K(i) = 30 nM) indicates that the biphenylyl residue is too large for the primary hydrophobic binding pocket of the σ(1) receptor.

Molecular Determinants of Potent P2X2 Antagonism Identified by Functional Analysis, Mutagenesis, and Homology Docking

P2X2 receptors are members of the ATP-gated P2X family of cation channels, and they participate in neurotransmission in sympathetic ganglia and interneurons. Here, we identified 7,7'-(carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-methyl-phenylene)carbonylimino))bis(1-methoxy-naphthalene-3,6-disulfonic acid) tetrasodium salt (NF770) as a nanomolar-potent competitive P2X2 receptor antagonist within a series of 139 suramin derivatives. Three structural determinants contributed to the inhibition of P2X2 receptors by NF770: 1) a "large urea" structure with two symmetric phenylenecarbonylimino groups; 2) attachment of the naphthalene moiety in position 7,7'; and 3) the specific position of two sulfonic acid groups (3,3'; 6,6') and of one methoxy group (1,1') at the naphthalene moiety. This structure-activity relationship was interpreted using a rat P2X2 homology model based on the crystal structure of the closed zebrafish P2X4 receptor. Docking of the suramin derivatives into the modeled ATP-binding pocket provides a uniform explanation for the observed differences in inhibitory potencies. Changes in the chemical structure that increase the inhibitory potency of the suramin derivatives improved the spatial orientation within the ATP-binding pocket to allow for stronger polar interactions of functional groups with Gly72, Glu167, or Arg290. Gly72 is responsible for the orientation of the methoxy group close to Arg290 or Glu167. Combined mutational and functional analysis confirmed that residues Gly72 and Glu167 are as important for ATP binding as Arg290, the ATP-binding role of which has been shown in previous studies. The in silico prediction of Gly72 and Glu167 as ATP-binding residues strongly supports the validity of our homology docking.

7,8-Disubstituted- but not 6,7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II in the low nanomolar/subnanomolar range

Two series of disubstituted coumarins incorporating ether and acetyl/propionyl moieties in positions 6,7- and 7,8- of the heterocyclic ring were synthesized investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). All these coumarins were very weak or ineffective as inhibitors of the housekeeping, offtarget isoforms CA I and II. The 6,7-disubstituted series showed ineffective inhibition also for the transmembrane tumor-associated isoforms CA IX and XII, whereas the corresponding isomeric 7,8-disubstituted coumarins showed nanomolar/subnanomolar inhibition of CA IX/XII. The nature and position of the groups substituting the coumarin ring in the 7,8-positions greatly influenced CA inhibitory properties, with C1-C4 alkyl ethers being the most effective inhibitors.

Antimicrobial investigations on synthetic p-tolylazo derivatives of thienopyrimidinone based on an ortho funtionalized thiophene nucleus

New derivatives of thieno[2,3- d ]pyrimidin-4-one, 4a-c, and 6 were respectively synthezised based on thiophene derivative, 2c, ortho -disposed amino and ester groups. Carbohydrazide, bearing 7, was obtained by hydrazinolysis of 3-ethoxycabonylmethyl derivative, 4c. Compounds 4b and 7 were used to build up two series of novel 3-substituted-methylthieno[2,3- d ]pyrimidin-4-ones, 7-11, and their corresponding 3-substituted-amino analogues 12, 15a,b, 18, which were of significant interest for biological study. The new thieno[2,3- d ]pyrimidin-4-one derivatives, with various groups in position 3, were screened for their preliminary antimicrobial activity against a representative panel of Gram-positive and Gram-negative bacteria as well as fungi strains. The compounds tested displayed different levels of antibacterial and antifungal effects, with the assays carried out on six pathogenic bacteria and six pathogenic fungi. Of these compounds, the 3-unsubstituted-thieno[2,3- d ]pyrimidin-4(3 H )-one, 4a, showed the lowest effect on pathogenic bacteria, while the corresponding 3-substituted analogues produced inhibitory effects against bacteria similar or superior to the reference drug Tetracycline. For those derivatives of thieno[2,3- d ]pyrimidin-4-one in which the 3-position contains a methylene moiety, it has been observed that the antibacterial effect was in general found to be significantly higher than the corresponding analogues with a substituted-amino moiety in position 3. Despite promising in vitro antibacterial activity of the new thienopyrimidin-4-ones, only compounds 7, 10 and 11, among the compounds tested, exhibited some kind of antifungal activity. The detailed synthesis and biological screening data were reported.

Synthesis, crystal structures and electrochemistry of ferrocenyl-substituted 1,3,4-oxadiazoles

Two ferrocenyl-substituted 1,3,4-oxadiazoles, 2-ferrocenyl-1,3,4-oxadiazole (1) and 2,5-diferrocenyl-1,3,4-oxadiazole (2), have been prepared from the corresponding hydrazides, (ferrocenecarbonyl)hydrazine (3) and 1,2-bis(ferrocenecarbonyl)hydrazine (4), and characterized by conventional spectroscopic methods (IR, NMR, MS) and elemental analyses. The solid-state structures of 1, 2 and 4 have been determined by single-crystal X-ray diffraction analysis. The redox behavior of 1 and 2 was studied by electrochemical methods. Compound 1 underwent a reversible one-electron oxidation attributed to the ferrocene/ ferrocenium couple (Eo′ = +0.28 V vs ferrocene/ferrocenium). On the other hand, compound 2 showed two closely separated anodic waves corresponding to two consecutive redox changes, indicating some degree of electronic communication between the ferrocenyl moieties in positions 2 and 5 at the 1,3,4-oxadiazole ring.

Synthesis and antiproliferative activity of 2,4-disubstituted 6-aryl-7 H-pyrrolo[3,2- d]pyrimidin-7-one 5-oxides

A series of 2,4-disubstituted 6-aryl-7 H-pyrrolo[3,2- d]pyrimidin-7-one 5-oxides were synthesized and in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, HBL-100, HeLa, SW1573, T-47D, and WiDr. The most potent analog induced considerably growth inhibition in the range 0.35–2.0 μM. Cell cycle studies in the breast and lung cancer cells revealed arrest in the G 2/M compartment. The results showed that the title compounds bearing alkylamino or dialkylamino moieties in position 2 of the pyrimidine ring are more active than those bearing hydrogen or methylthio groups.

6-Methoxy-N-alkyl Isatin Acylhydrazone Derivatives as a Novel Series of Potent Selective Cannabinoid Receptor 2 Inverse Agonists: Design, Synthesis, and Binding Mode Prediction

Recently, we discovered and reported a series of N-alkyl isatin acylhydrazone derivatives that are potent CB2 agonists. Here, we describe a novel series of selective CB2 inverse agonists resulting from introduction of a methoxy moiety in position 6 of the isatin scaffold. These novel 6-methoxy-N-alkyl isatin acylhydrazone derivatives exhibited high CB2 functional activity and selectivity at human CB2. Compound 16 (MDA77) had high activity (EC(50) = 5.82 nM) at CB2 and no activity at CB1. Compound 15 (MDA55) (K(i) = 89.9 nM, EC(50) = 88.2 nM at CB2) inhibited the effect of compound 1 (MDA7), a selective CB2 agonist, in an animal model of neuropathic pain. The molecular modeling study presented here represents a first study of CB2 based on the structure of beta(2)-adrenergic receptor. A ligand-based homology model of the CB2 binding site was developed, and on the basis of our results, we propose a general binding mode for this class of inverse agonists with CB2.

Pyrido[1,2-a]pyrimidin-4-one Derivatives as a Novel Class of Selective Aldose Reductase Inhibitors Exhibiting Antioxidant Activity

2-Phenyl-pyrido[1,2-a]pyrimidin-4-one derivatives bearing a phenol or a catechol moiety in position 2 were tested as aldose reductase (ALR2) inhibitors and exhibited activity levels in the micromolar/submicromolar range. Introduction of a hydroxy group in position 6 or 9 gave an enhancement of the inhibitory potency (compare 18, 19, 28, and 29 vs 13 and 14). Lengthening of the 2-side chain to benzyl determined a general reduction in activity. The lack or the methylation of the phenol or catechol hydroxyls gave inactive (10-12, 21, 22, 25-27) or scarcely active (15, 17, 20) compounds, thus demonstrating that the phenol or catechol hydroxyls are involved in the enzyme pharmacophoric recognition. Moreover, all the pyridopyrimidinones displayed significant antioxidant properties, with the best activity shown by the catechol derivatives. The theoretical binding mode of the most active compounds obtained by docking simulations into the ALR2 crystal structure was fully consistent with the structure-activity relationships in the pyrido[1,2-a]pyrimidin-4-one series.

Synthesis and in vitro binding studies of substituted piperidine naphthamides. Part I: Influence of the substitution on the basic nitrogen and the position of the amide on the affinity for D 2L, D 4.2, and 5-HT 2A receptors

A series of 1- and 2-naphthamides has been prepared and tested for in vitro binding to D 2L, D 4.2, and 5-HT 2A receptors. Different compounds display selectivity for D 4.2 and 5-HT 2A receptors versus D 2L receptors. N-(1-Arylalkyl-piperidin-4-yl) carboxamides have higher affinities than the corresponding N-(4-arylalkylamino-piperidin-1-yl) carboxamide analogues. A benzyl moiety in position 1 of the piperidine in the 2-naphthamide series ( 2) appears to be the best choice for a favorable interaction with D 4.2 and 5-HT 2A receptors. Increasing the linker length between the phenyl ring and the basic nitrogen led to a decreased affinity for these receptors. In the 1-naphthamide series, the most potent D 4.2 ligand ( 7) possesses a phenylpropyl moiety while its affinity for 5-HT 2A receptors is strongly reduced. All compounds with significant affinity for D 4.2 and 5-HT 2A receptors were antagonists.

Synthesis of novel σ-receptor ligands from methyl α- d-mannopyranoside

For the first time a monosaccharide (methyl α- d-mannopyranoside) has been used as starting material for the synthesis of novel σ-receptor ligands. The hept-3-ulopyranoside dimethyl ketals 14 and 15 were obtained from the nitrile 7 via two synthetic routes. After selective hydrolysis of the ketone dimethyl acetal, various amino substituents were introduced into position 3. High σ 1-receptor affinity and selectivity was attained with equatorially arranged amino substituents in position 3 and a dichlorophenylacetamide moiety in position 7. The anomeric mixture of dimethylamines 26α/ β displayed the highest σ 1-receptor affinity ( K i = 21 nM) within this small series of test compounds.

A New Synthesis of Thiazole Derivatives via Ring Transformation of 6‐Imino‐6H‐1,3‐thiazine Hydroperchlorates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

First Synthesis of 1,3-Alternate 25,27-Dialkyloxy-5,17-diarylcalix[4]arenes-crown-6 as New Cesium Selective Extractants by Suzuki Cross-coupling Reaction

The synthesis of new 25,27-dialkyloxy-5,17-diarylcalix[4]arenes-crown-6 1a–f in 1,3-alternate conformation by Suzuki cross-coupling reaction is reported. Their conformation was determined using 1H, 13C, 2D NMR and ROESY analysis, and X-ray crystallography. Extraction experiments using a two-phase solvent method involving sodium, potassium or cesium picrate showed good extraction of the cesium cation. The X-ray crystal structures of 1,3-alternate 25,27-dipropoxy-5,17-diphenylcalix[4]arene-crown-6 ether 1a and its cesium picrate complex were established. Solid-state data were used to determine the complexation behavior of these new ligands. The efficiency of calixarenes 1a–f for cesium ion extraction could be ascribed to the rigidity and flatness linkages caused by the aryl groups at the lower rim of the aromatic moieties in the calixarene skeleton. In addition, the introduction of these aromatic moieties in positions 5 and 17 enhanced the solubility of the metal complexes in organic media.

A new group of potential antituberculotics: hydrochlorides of piperidinylalkyl esters of alkoxy-substituted phenylcarbamic acids.

A group of 31 of alkoxy-substituted phenylcarbamic acids with the alkoxy group in ortho, meta or para position, and methyl or ethoxymethyl attached to the ethylene moiety in position 1, including both basic ethyl esters and derivatives branched on ethylene, were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, and M. avium. To describe the structure-antimycobacterial activity relationships (QSARs), an approach based on a combination of the Free-Wilson analysis was used to express the influence of the substituents on the ethylene group as well as the position of the alkoxy groups on the phenyl ring and of the hydrophobicity of alkyls. In vitro antimycobacterial activity becomes higher with increasing hydrophobic properties of the alkoxy groups. The para- and meta-substituted derivatives were more active than the ortho-substituted ones. Substitution of ethylene in position 1 by methyl increased the activity against M. tuberculosis, a similar substitution by ethoxymethyl increased the activity against M. kansasii. The most active compounds were piperidinyl-1-(ethoxymethyl)ethylesters of heptoxyphenylcarbamic acids.

Synthesis of New Hexahydro‐ and Octahydropyrido[1,2‐c]pyrimidine Derivatives with an Arylpiperazine Moiety as Ligands for 5‐HT1A and 5‐HT2A Receptors. Part 2.

AbstractFor Abstract see ChemInform Abstract in Full Text.