Fleetamine (3-O-α-d-glucopyranosyl-swainsonine): the synthesis of a hypothetical inhibitor of endo-α-mannosidase

3-O-α-d-Glucopyranosyl-swainsonine was originally proposed¹⁷ as a potential inhibitor of the mammalian enzyme endo-α-mannosidase, but its synthesis has not been reported. Herein we report the total synthesis of this enigmatic compound, utilizing a halide-ion catalysed glycosylation of a swainsonine lactam with a glucosyl iodide donor as the key step. The resulting inhibitor was evaluated as an inhibitor of human endo-α-mannosidase, and as a ligand for bacterial orthologs from Bacteroides thetaiotaomicron and Bacteroides xylanisolvens, including active-centre variants, although no evidence for binding or inhibition was observed. The surprising lack of binding was rationalized by using structural alignment with an endo-α-mannosidase inhibitor complex, which identified deleterious interactions with the swainsonine piperidine ring and an essential active site residue.     

Corrosion inhibition of mild steel by Laurus nobilis leaves extract as green inhibitor

The efficiency of Laurus nobilis leaves?? extract as a corrosion inhibitor for mild steel in acidic medium (1?M H₂SO₄) was investigated by use of the electrochemical techniques potentiodynamic polarization, electrochemical impedance spectroscopy, and polarization resistance measurements. According to the experimental results, L. nobilis extract acts as a good corrosion inhibitor. In the presence of the inhibitor, corrosion potential shifted toward a more negative value than for the blank solution. Inhibitor efficiency increased with increasing inhibitor concentration, as expected. According to the potentiodynamic polarization results the corrosion of mild steel increased with increasing temperature both in the presence and absence of the inhibitor. The activation energy (E _a) of the corrosion process was calculated from the variation of corrosion current density with temperature.     

Looking glass inhibitors: synthesis of a potent naringinase inhibitor l-DIM [1,4-dideoxy-1,4-imino-l-mannitol], the enantiomer of DIM [1,4-dideoxy-1,4-imino-d-mannitol] a potent α-d-mannosidase inhibitor

The synthesis of l-DIM [1,4-dideoxy-1,4-imino-l-mannitol] and of 1,4-imino-d-glycero-l-talo-heptitol from d-glycero-d-gulo-heptono-1,4-lactone depends on the use of pentan-3-one to form two five ring ketals as described by Burke, rather than the formation of one five ring and one six ring ketal formed with acetone. l-DIM, the enantiomer of the potent α-d-mannosidase inhibitor DIM [1,4-dideoxy-1,4-imino-d-mannitol] is a good inhibitor of naringinase (an α-l-rhamnosidase) with a K_i of 3.63 μM. 1,4-Imino-d-glycero-l-talo-heptitol is a moderate inhibitor of naringinase.     

Trypsin Inhibitor from Edible Mushroom Pleurotus floridanus Active against Proteases of Microbial Origin

Protease inhibitors can be versatile tools mainly in the fields of medicine, agriculture and food preservative applications. Fungi have been recognized as sources of protease inhibitors, although there are only few such reports on mushrooms. This work reports the purification and characterization of a trypsin inhibitor from the fruiting body of edible mushroom Pleurotus floridanus (PfTI) and its effect on the activity of microbial proteases. The protease inhibitor was purified up to 35-fold by DEAE-Sepharose ion exchange column, trypsin-Sepharose column and Sephadex G100 column. The isoelectric point of the inhibitor was 4.4, and its molecular mass was calculated as 37 kDa by SDS-PAGE and 38.3 kDa by MALDI-TOF. Inhibitory activity confirmation was by dot-blot analysis and zymographic activity staining. The specificity of the inhibitor toward trypsin was with Ki of 1.043?×?10^?10 M. The inhibitor was thermostable up to 90 °C with maximal stability at 30 °C, active over a pH range of 4–10 against proteases from Aspergillus oryzae, Bacillus licheniformis, Bacillus sp. and Bacillus amyloliquefaciens. Results indicate the possibility of utilization of protease inhibitor from P. floridanus against serine proteases.     

Synthesis of 2-acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc] from d-glucuronolactone: the first sub-micromolar inhibitor of α-N-acetylgalactosaminidases

2-Acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc], prepared in 20% overall yield from d-glucuronolactone, is the first potent competitive sub-micromolar inhibitor of α-N-acetyl-galactosaminidases (K_i 0.081 μM from chicken liver, K_i 0.136 μM from Charonia lampas). DGJNAc is a good competitive—whereas the enantiomer l-DGJNAc is a very weak but non-competitive—inhibitor of β-hexosaminidases.     

Corrosion inhibition of steel in molar HCl by triphenyltin2–thiophene carboxylate

The effect of triphenyltin2–thiophene carboxylate (TTC) on the corrosion of steel in hydrochloric acid medium was studied using gravimetric, electrochemical polarisation and electrochemical impedance spectroscopy (EIS) measurements. The percentage inhibition efficiency was found to increase with increasing concentration of inhibitor to reach 97% at 10^?3 M. Polarisation study shows that TTC is an efficient inhibitor and acts as a mixed-type inhibitor. EIS results indicate the increase of resistance transfer (R_T) and the decrease of double layer capacitance (C_dl) with TTC concentration. Triphenyltin2–thiophene carboxylate molecules lead to the formation of a protective layer on the surface of steel. The inhibitor is adsorbed on the steel surface according to Langmuir isotherm.     

Enantioselective Synthesis of Cyclopentyltetrahydrofuran (Cp-THF), an Important High-Affinity P2-Ligand for HIV-1 Protease Inhibitors

A convenient optically active synthesis of (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan, a high-affinity nonpeptidyl ligand for HIV-1 protease inhibitor 2, is described. The synthesis utilizes commercially available (1R,5S)-(+)-2-oxabicyclo[3.3.0]oct-6-en-3-one as the starting material and oxymercuration or bromohydrin reaction as the key step. Enantiopure ligand was converted to protease inhibitor 2.     

A fluorescence turn-on method for real-time monitoring of protease activity based on the electron transfer between a fluorophore labeled oligonucleotide and cytochrome c

A new continuous fluorescence turn-on assay for protease activity and inhibitor screening has been developed. A fluorophore labeled single stranded DNA (FAM-DNA) and cytochrome c (cyt c) were employed. The fluorescence of the FAM-DNA was efficiently quenched when binding to cyt c, through the electron transfer between the FAM fluorophore and the heme cofactor of cyt c. In the presence of a protease, such as trypsin, cyt c was digested into small peptide fragments. The FAM-DNA was released, which resulted in the recovery of the FAM fluorescence. The rate of the cyt c digestion could be reduced via the addition of an inhibitor. As a result, reduced degree of the fluorescence recovery was obtained. The limit of detection of our assay is 1 nM trypsin and the IC₅₀ values are 3.23 μg mL⁻¹ and 0.303 μg mL⁻¹ for the inhibitor from egg white and the inhibitor from soybean, respectively. Our method could be used for the sensing of protease activity for various biochemical applications, and for the screening of protease inhibitors as drugs for the treatment of various related diseases.     

Multivalent calixarene-based C-fucosyl derivative: a new Pseudomonas aeruginosa biofilm inhibitor

The first example of multivalent conjugate in which four α-l-C-fucosyl units are clustered by means of a calix[4]arene platform was designed as a new potential Pseudomonas aeruginosa biofilm inhibitor. The anti-biofilm activity of the synthesized compound (6) against PAO1 strain was assayed and it was found to be dose-dependent. The presence of the fucose cluster improves the biofilm inhibitor efficiency as proven by the lower inhibitor activity of the analogous glycyl-calix[4]arene derivative (3) lacking in the fucose moieties.     

Interactions of a Low Molecular Weight Inhibitor from Streptomyces sp. MBR04 with Human Cathepsin D: Implications in Mechanism of Inactivation

Cathepsin D, a lysosomal aspartic protease, is of potential interest as a target for drug design due to its implication in breast and ovarian cancer. The article reports a low molecular weight cathepsin D inhibitor from Streptomyces sp. MBR04. The M_r of the inhibitor was 1,078 Da as determined by MALDI-TOF, and the amino acid analysis showed the presence of Asp, Asp, Gly, Ala, Lys, Leu, Tyr, Trp residues. The steady-state kinetic interactions revealed reversible, competitive, slow-tight-binding nature of the inhibitor with an IC₅₀ and K _i values of 3.2 and 2.5 nM, respectively. The binding of the inhibitor with the enzyme and the subsequent conformational changes were monitored by exploiting the intrinsic fluorescence of the surface exposed Trp-54 residue. Based on the fluorescence and circular dichroism studies, we demonstrate that the inhibitor binds to the active site of cathepsin D and causes inactivation. All these kinetic, thermodynamic, and quenching studies suggest that the newly isolated peptidic inhibitor could be a potential scaffold to study and can be used to develop new potent therapeutic lead molecule for the development of drugs. The inhibitor will be significant as a potential lead molecule to target cathepsin D.     

Kinetics of radical copolymerization—IX: Investigation of the effect of molecule inhibitors in copolymerization—2 copolymerization of acrylonitrile and methyl acrylate in solution

Inhibition kinetic measurements were carried out with p-nitrosodiphenylamine as a molecule inhibitor in acrylonitrile-methyl acrylate copolymerization in solution. The effect of dilution on the stoichiometry of inhibition (μ) was studied at various initial monomer compositions. The value of μ for the investigated inhibitor depends on the solvent concentration (s). The relationship between μ and s was interpreted in terms of the hot radical theory.     

Evaluation of the inhibitive effect of essential oil of Lavandula multifida L., on the corrosion behavior of C38 steel in 0.5 M H2SO4 medium

The essential oil of the aerial parts of Lavandula multifida L., collected in Errachidia region (three samples) in southeast Morocco, was extracted by hydrodistillation and analyzed by GC and GC-MS. The oil was predominated by carvacrol (57.9–59.0%). L. multifida oil was tested as corrosion inhibitor of C38 steel in 0.5 M H₂SO₄ using weight loss measurements, electrochemical polarization, and EIS methods. The results obtained by measurements of weight loss showed that inhibition efficiency increases with inhibitor concentration to attain 72.2% at 2 g/l of oil at 298 K. Polarization curves revealed that L. multifida oil acts as mixed type inhibitor. The temperature effect on the corrosion behavior of steel in 0.5 M H₂SO₄ without and with the inhibitor at 2 g/l was studied in the temperature range from 303 and 343 K. The adsorption of inhibitor on the C38 steel surface was found to be a spontaneous process and to obey Langmuir’s adsorption isotherm. The associated activation energy has been determined.     

Study of noncovalent enzyme—inhibitor complexes and metal binding stoichiometry of matrilysin by electrospray ionization mass spectrometry

Electrospray ionization mass spectrometry (ESI-MS) was used to study the noncovalent metallo-enzyme—inhibitor complexes of matrilysin (a matrix metalloproteinase of mass 18,720 u) under gentle experimental conditions and to determine the metal ion association stoichiometries in both the free enzyme and the complexes. The metal association stoichiometries of the free matrilysin were found to be highly sensitive to solution pH changes. At pH 2.2 the enzyme existed as metal-free apo-matrilysin and was not capable of binding an inhibitor. At pH 4.5–7.0 the enzyme associated specifically with zinc and calcium cations and became active in inhibitor binding. Although the stoichiometries of the metal cofactors varied (zero to two zinc and/or calcium ions) in the free enzyme dependent on solution pH, the predominant form of the enzyme—inhibitor complexes in the pH range of 4.5–7.0, in contrast, always had the metal association stoichiometry of 2Zn + 2Ca, which was the same stoichiometry the most active free metallo-enzyme had at the optimal pH of 7. At the activity onset pH of 4.5 matrilysin existed mostly as apo-enzyme (but in a conformation different from the denatured one at pH 2.2) and bound to an inhibitor slowly (time constant ～ 2.5 min) to form the noncovalent metallo-enzyme—inhibitor complex. Of the two inhibitors studied, the one with the higher solution binding constant also produced larger ion signals for the noncovalent complex in the solvent-free gas phase, which pointed to the feasibility of the use of ESI-MS for inhibitor screening studies.     

Selectivity between N-1 and N-7 nucleosides: regioselective synthesis of BMK-Y101, a potent cdk7 and 9 inhibitor

BMK-Y101 is a new pyrrolo[2,3-d]pyrimidine-based potent cdk7 and 9 inhibitor, which is characterized by an intriguing structural feature of N-1 nucleoside, departing from previously reported N-7 nucleoside Cdk inhibitor, xylocydine. Though N-1 nucleosides have appeared in the literature, they have often been considered as kinetic products and thus intermediates of N-7 glycosylation. In the course of the synthetic studies of xylocydine derivatives, we have developed a highly regioselective method to obtain the N-1 nucleoside. The origin of the selectivity is apparently based on the reactivity of the silylated nucleobase and the stability of the resulting N-1 nucleoside. The choice of BSA as a silylating agent was critical in securing the N-1 nucleoside, BMK-Y101. On the other hand, proper selection of reaction conditions promoting transglycosylation provides an efficient route to N-7 nucleosides.     

Ethanol extracts of Hemidesmus indicus leaves as eco-friendly inhibitor of mild steel corrosion in H2SO4 medium

The inhibitory action of an extract of Hemidesmus indicus leaves as a potential corrosion inhibitor for steel in H₂SO₄ solutions was examined using conventional mass loss, gasometric techniques, electrochemical polarisations and electrochemical impedance spectroscopy. The results revealed that the extract of Hemidesmus indicus leaves performed well as an inhibitor for the corrosion of the metal employed in an accelerating medium. The inhibition efficiencies for all the experimental techniques employed increased with increasing the concentration of the plant extract but decreased with a rise in temperature. Both the cathodic hydrogen evolution and the anodic dissolution of mild steel were inhibited, hence the active molecule of the extract studied acted as a mixed-type corrosion inhibitor.     

Inhibition of copper corrosion in acid solution by N-1-naphthylethylenediamine dihydrochloride monomethanolate: experimental and theoretical study: part-1

Inhibition of corrosion of copper in 2M HNO₃ by N-1-naphthylethylenediamine dihydrochloride monomethanolate (N-NEDHME) has been studied by use of weight loss, electrochemical polarization, and electrochemical impedance spectroscopy (EIS) measurements. The result obtained reveal that this organic compound is a very good inhibitor and its inhibition efficiency increases with increasing concentration, reaching 94% at 10^?3?M at 303?K. The potentiodynamic polarization study indicated that this compound acts as a cathodic type corrosion inhibitor. EIS results indicate that the change in the impedance properties (R _t and C _dl) with concentration of inhibitor was because of the formation of a protective layer on the surface of copper. Quantum chemical calculations using DFT at the B3LYP/6-31G* level of theory was further used to calculate some electronic properties of the molecule in order to ascertain any correlation between the inhibitive effect and molecular structure of N-NEDHME. The effect of temperature between 303 and 343?K and calculation of activation data will be discussed in Part 2.     

Experimental and theoretical studies of acridine orange as corrosion inhibitor for copper protection in acidic media

The corrosion process commonly limits the use of copper in practical applications. The use of corrosion inhibitors is one of the effective methods to reduce the corrosion rate of copper. In this research, the inhibition effect of acridine orange (3,6-bis(dimethylamine)acridine) (AcO) for the protection of copper in 0.5 ?M ?H₂SO₄ solution was studied. For this aim, the change of open circuit potential with exposure time (E_ocp-t), electrochemical impedance spectroscopy (EIS), linear polarization resistance (LPR), anodic and cathodic potentiodynamic polarization measurements (PP) and chronoamperometry (CA) techniques were used. Some quantum chemical parameters (E_HOMO, E_LUMO and dipole moment) were calculated and discussed. The AcO film formed over the copper surface was examined by SEM, EDX, AFM and contact angle measurements. The electrochemical data showed that AcO is an effective corrosion inhibitor even at low concentrations (ranging between 99.1% and %99.4 ?at concentrations from 0.01 ?mM to 1 ?mM). The corrosion rate of copper decreases in the presence of the inhibitor by reducing both anodic and cathodic rates, which is depended on its concentration. This compound behaves as mixed-type corrosion inhibitors with predominantly cathodic type. Its adsorption on the copper surface obeys Langmuir adsorption isotherm. The value of adsorption equilibrium constant (K_ads) and the standard free energy of adsorption were ΔG_ads 1.298 x 10³ ?M^?1 and -27.71 ?kJ/mol in the case of 0.5 ?M ?H₂SO₄ solution containing 1.0 ?mM AcO, which shows the adsorption is high and spontaneous. The adsorbed inhibitor film over the metal increase contact angle of the surface, which suggests the more hydrophobic properties of the surface are increasing coming from the orientation of hydrophobic sites to the electrolyte. The zero charge potential (E_pzc) studies showed that the surface charge of the metal is positive in the corrosive media containing the inhibitor. Quantum chemical calculations showed that the binding of inhibitor molecules to the metal surface takes place through N atoms of the inhibitor.     

Curcumin Inhibits the Sortase A Activity of the Streptococcus mutans UA159

Streptococcus mutans (S. mutans) forms part of the commensal microflora and is deemed to be the major pathogen responsible for the generation of dental caries. The enzyme, sortase A enzyme, modulates the surface properties and cariogenicity of S. mutans. Curcumin has been reported to be an inhibitor of Staphylococcus aureus sortase A. In this study, inhibition of a purified S. mutans UA159 sortase A by curcumin was evaluated. Curcumin exerted strong inhibitory activity with a half maximal inhibitory concentration (IC₅₀) of 10.2?±?0.7 μM which was lower than the minimum inhibitory concentration of 175 μM and the minimum bactericidal concentration of 350 μM. These results indicated that curcumin is a S. mutans UA159 sortase A inhibitor and therefore represents as a promising anticaries agent.     

Synthesis and kinetic evaluation of 4-deoxy-4-phosphonomethyl-d-erythronate, the first hydrolytically stable and potent competitive inhibitor of ribose-5-phosphate isomerase

4-deoxy-4-Phosphonomethyl-d-erythronate, an isosteric and hydrolytically stable analogue of the known ribose-5-phosphate isomerase inhibitor 4-deoxy-4-phospho-d-erythronate, was obtained by a 14-step synthesis from d-arabinose through an highly improved synthesis of the precursor 5-deoxy-5-phosphonomethyl-d-arabinose. The title compound appears as the first stable and potent competitive inhibitor of the enzyme catalyzed isomerization of ribose-5-phosphate to d-ribulose-5-phosphate (K_i=74 μM, K_m/K_i=100), exhibiting only a 3-fold weaker inhibitory activity than its phosphate analogue.     

Performance of Waterborne Polyurethanes in Inhibition of Gas Hydrate Formation and Corrosion: Influence of Hydrophobic Fragments

The design of new dual-function inhibitors simultaneously preventing hydrate formation and corrosion is a relevant issue for the oil and gas industry. The structure-property relationship for a promising class of hybrid inhibitors based on waterborne polyurethanes (WPU) was studied in this work. Variation of diethanolamines differing in the size and branching of N-substituents (methyl, n-butyl, and tert-butyl), as well as the amount of these groups, allowed the structure of polymer molecules to be preset during their synthesis. To assess the hydrate and corrosion inhibition efficiency of developed reagents pressurized rocking cells, electrochemistry and weight-loss techniques were used. A distinct effect of these variables altering the hydrophobicity of obtained compounds on their target properties was revealed. Polymers with increased content of diethanolamine fragments with n- or tert-butyl as N-substituent (WPU-6 and WPU-7, respectively) worked as dual-function inhibitors, showing nearly the same efficiency as commercial ones at low concentration (0.25 wt%), with the branched one (tert-butyl; WPU-7) turning out to be more effective as a corrosion inhibitor. Commercial kinetic hydrate inhibitor Luvicap 55 W and corrosion inhibitor Armohib CI-28 were taken as reference samples. Preliminary study reveals that WPU-6 and WPU-7 polyurethanes as well as Luvicap 55 W are all poorly biodegradable compounds; BOD_t/COD_cr (ratio of Biochemical oxygen demand and Chemical oxygen demand) value is 0.234 and 0.294 for WPU-6 and WPU-7, respectively, compared to 0.251 for commercial kinetic hydrate inhibitor Luvicap 55 W. Since the obtained polyurethanes have a bifunctional effect and operate at low enough concentrations, their employment is expected to reduce both operating costs and environmental impact.