Bar graphs showing the influence of heart rate on myocardial salvage (A), area at risk (B) and infarct size (C) in patients categorized in quintiles according to heart rate at hospital admission (details in the text).

<p>Bar graphs showing the influence of heart rate on myocardial salvage (A), area at risk (B) and infarct size (C) in patients categorized in quintiles according to heart rate at hospital admission (details in the text).</p

Synthesis and Biological Characterization of 3‑Substituted 1<i>H</i>‑Indoles as Ligands of GluN2B-Containing <i>N</i>‑Methyl‑d‑aspartate Receptors. Part 2

In the course of the identification of new indole derivatives targeting GluN2B-subunit-containing <i>N</i>-methyl-d-aspartate (NMDA) receptor, the (<i>N</i>-1<i>H</i>-indol-6-methanesulfonamide-3-yl)-2-(4-benzylpiperidin-1-yl)­ethanone (<b>10b</b>) was identified as a potent ligand for this NMDA receptor subunit. It displays very high binding affinity (IC₅₀ of 8.9 nmol) for displacement of [³H]­ifenprodil, thus showing improved potency with respect to the previously reported analogues as confirmed by functional assay. This finding was consistent with the docking pose of compound <b>10b</b> within the binding pocket localized in the GluN1-GluN2B subunit interface of NMDA receptor tetraheteromeric complex

Targeting Tyrosinase: Development and Structural Insights of Novel Inhibitors Bearing Arylpiperidine and Arylpiperazine Fragments

The inhibition of tyrosinase (Ty, EC 1.14.18.1) represents an efficient strategy of decreasing melanogenesis and skin hyperpigmentation. A combination of crystallographic and docking studies on two different tyrosinases, that from <i>Bacillus megaterium</i> (TyBm) and that from a mushroom (TyM), has contributed to increasing our knowledge about their structural information and translating that information to the most druggable human Ty (TyH) isozyme. In particular, we designed and synthesized a series of 1-(4-fluorobenzyl)­piperazine and 1-(4-fluorobenzyl)­piperidine derivatives showing inhibitory activities on TyM at micromolar ranges and more potency than that of the reference compound, kojic acid. The crystal structures of TyBm with inhibitor <b>3</b> (IC₅₀ value of 25.11 μM) and <b>16</b> (IC₅₀ value of 5.25 μM) were solved, confirming the binding poses hypothesized by in silico studies and revealing the main molecular determinants for the binding recognition of the inhibitors

Synthesis, Structure–Activity Relationship Studies, and X-ray Crystallographic Analysis of Arylsulfonamides as Potent Carbonic Anhydrase Inhibitors

A series of arylsulfonamides has been synthesized and investigated for the inhibition of some selected human carbonic anhydrase isoforms. The studied compounds showed significant inhibitory effects in the nanomolar range toward druggable isoforms (hCA VII, hCA IX, and hCA XIV) (<i>K</i>_i values from 4.8 to 61.7 nM), whereas they generally exhibited significant selectivity over hCA I and hCA II, that are ubiquitous and considered off-target isoforms. On the basis of biochemical data, we herein discussed structure–affinity relationships for this series of arylsulfonamides, suggesting a key role for alkoxy substituents in CA inhibition. Furthermore, X-ray crystal structures of complexes of two active inhibitors (<b>I</b> and <b>2a</b>) with hCA II allowed us to elucidate the main interactions between the inhibitor and specific amino acid residues within the catalytic site

Targeting Tyrosinase: Development and Structural Insights of Novel Inhibitors Bearing Arylpiperidine and Arylpiperazine Fragments

The inhibition of tyrosinase (Ty, EC 1.14.18.1) represents an efficient strategy of decreasing melanogenesis and skin hyperpigmentation. A combination of crystallographic and docking studies on two different tyrosinases, that from <i>Bacillus megaterium</i> (TyBm) and that from a mushroom (TyM), has contributed to increasing our knowledge about their structural information and translating that information to the most druggable human Ty (TyH) isozyme. In particular, we designed and synthesized a series of 1-(4-fluorobenzyl)­piperazine and 1-(4-fluorobenzyl)­piperidine derivatives showing inhibitory activities on TyM at micromolar ranges and more potency than that of the reference compound, kojic acid. The crystal structures of TyBm with inhibitor <b>3</b> (IC₅₀ value of 25.11 μM) and <b>16</b> (IC₅₀ value of 5.25 μM) were solved, confirming the binding poses hypothesized by in silico studies and revealing the main molecular determinants for the binding recognition of the inhibitors

Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides

On the basis of X-ray crystallographic studies of the complex of hCA II with 4-(3,4-dihydro-1<i>H</i>-isoquinoline-2-carbonyl)­benzenesulfonamide (<b>3</b>) (PDB code 4Z1J), a novel series of 4-(1-aryl-3,4-dihydro-1<i>H</i>-isoquinolin-2-carbonyl)­benzenesulfonamides (<b>23</b>–<b>33</b>) was designed. Specifically, our idea was to improve the selectivity toward druggable isoforms through the introduction of additional hydrophobic/hydrophilic functionalities. Among the synthesized and tested compounds, the (<i>R</i>,<i>S</i>)-4-(6,7-dihydroxy-1-phenyl-3,4-tetrahydroisoquinoline-1<i>H</i>-2-carbonyl)­benzenesulfonamide (<b>30</b>) exhibited a remarkable inhibition for the brain-expressed hCA VII (<i>K</i>_i = 0.20 nM) and selectivity over wider distributed hCA I and hCA II isoforms. By enantioselective HPLC, we solved the racemic mixture and ascertained that the two enantiomers (<b>30a</b> and <b>30b</b>) are equiactive inhibitors for hCA VII. Crystallographic and docking studies revealed the main interactions of these inhibitors into the carbonic anhydrase (CA) catalytic site, thus highlighting the relevant role of nonpolar contacts for this class of hCA inhibitors

Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication and provide a rationale to redesign antiretroviral treatment for feline AIDS-1

<p><b>Copyright information:</b></p><p>Taken from "Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication and provide a rationale to redesign antiretroviral treatment for feline AIDS"</p><p>http://www.retrovirology.com/content/4/1/79</p><p>Retrovirology 2007;4():79-79.</p><p>Published online 30 Oct 2007</p><p>PMCID:PMC2244644.</p><p></p>las' cat, and puma, respectively. The FIV-Fca clade is indicated by capital letters. The catalytic triad is marked by the black arrows. Blue arrows show the amino acids reported to confer significant cross-resistance to the major classes of IN strand transfer inhibitors. Small arrows show minor drug resistance mutations. Amino acid numbering refers to HIV-1 IN. The Pol IN CCD sequences aligned were from: immunodeficiency virus type-1 (HIV-1) [PDB: ]; simian immunodeficiency virus, host: macaque (SIV-mac) [PDB: ]; FIV-Fca: Petaluma (Pet) [REFSEQ: NP_040973.1], San Diego (SD) [Swiss-Prot: :], TM2 [GenBank: AAA43071], BM3070 [GenBank: AAM13444], C36 [GenBank: AAT12494]; FIV-Oma: Oma-3 [GenBank: AAU20798.1]; FIV-Pco: PLV-1695 [GenBank: ABB29307.1] and PLV-14 [GenBank: AAA67168.1]. M2 and M3 are local field isolates of FIV-Fca, clade B (Pistello et al., 1997, sequences being submitted to GenBank)

Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication and provide a rationale to redesign antiretroviral treatment for feline AIDS-4

<p><b>Copyright information:</b></p><p>Taken from "Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication and provide a rationale to redesign antiretroviral treatment for feline AIDS"</p><p>http://www.retrovirology.com/content/4/1/79</p><p>Retrovirology 2007;4():79-79.</p><p>Published online 30 Oct 2007</p><p>PMCID:PMC2244644.</p><p></p>ion was quantified by measuring p25 core antigen release in cell culture supernatants. Drug efficacy was assessed as percent decrease in p25 concentrations. Data points represent an average from three independent experiments following appropriate transformations to restore linearity. The solid line is the line best fitting the data points; the dashed curves represent the 95% confidence limits. The ECvalues (reported in the main text) were calculated by transposing onto a linear scale the intersection of the regression line (and 95% confidence limits) with the dotted line corresponding to 50% inhibition of viral replication

Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication and provide a rationale to redesign antiretroviral treatment for feline AIDS-5

<p><b>Copyright information:</b></p><p>Taken from "Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication and provide a rationale to redesign antiretroviral treatment for feline AIDS"</p><p>http://www.retrovirology.com/content/4/1/79</p><p>Retrovirology 2007;4():79-79.</p><p>Published online 30 Oct 2007</p><p>PMCID:PMC2244644.</p><p></p>ficant difference (< 0.01) between treatments (no treatment and 1 μM of L-870,810) at the different time points (12 and 24 h post-infection)

Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication and provide a rationale to redesign antiretroviral treatment for feline AIDS-2

<p><b>Copyright information:</b></p><p>Taken from "Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication and provide a rationale to redesign antiretroviral treatment for feline AIDS"</p><p>http://www.retrovirology.com/content/4/1/79</p><p>Retrovirology 2007;4():79-79.</p><p>Published online 30 Oct 2007</p><p>PMCID:PMC2244644.</p><p></p>ologue [PDB:]. The level of similarity was calculated by the Swiss PDB Viewer (SPDBV) software. The color scale is that adopted by SPDBV. The transferred strand of proviral DNA is shown in magenta. Similarity is maximal at the level of the INSTI binding site. The INSTI binding site (indicated by a circle) is that calculated by some of us in previous works [16,20]. Panels B-C: Docking of CHI1019 (panel B) and L-870,810 (panel C) at the catalytic cavity of FIV IN. The protein is shown as Connolly surface (in green). Ligands are shown in CPK (carbon backbone in magenta). The terminal dinucleotide of 3' processed proviral DNA is shown in CPK (carbon backbone in orange). Metals are shown as spheres (in gray). Images prepared using Pymol (see Ref. [50])