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Weak Inhibitors (weak + inhibitor)
Selected AbstractsWeak inhibitors protect cholinesterases from strong inhibitors (paraoxon): in vitro effect of tiaprideJOURNAL OF APPLIED TOXICOLOGY, Issue 6 2005G. A. Petroianu Abstract Weak and reversible inhibitors of cholinesterases, when administered before potent organophosphorus inhibitors (pretreatment), have the ability, to a certain extent, to protect enzymes from inhibition. Such a protective effect was demonstrated in vitro for metoclopramide and ranitidine. The putative mode of protective action of these substances is, when administered in excess, competition for the active site of the enzyme with the more potent organophosphate. The present paper presents results using another benzamide with weak cholinesterase inhibitory properties: tiapride (TIA). The purpose of the study was to quantify in vitro the extent that TIA conferred protection, using paraoxon (POX) as an inhibitor, and to compare the results with existing data obtained using TIA as a protective agent against dichlorvos (DDVP). POX is a highly toxic non-neuropathic organophosphate. While the use of parathion (the inactive prodrug which is metabolically converted to POX) has been restricted in most countries, the organophosphate is still responsible for a large number of accidental or suicidal exposures. DDVP is a moderately toxic, non-neuropathic organophosphate. Red blood cell (RBC) acetylcholinesterase (AChE) activities in whole blood and butyrylcholinesterase (BChE) activities in human plasma were measured photometrically in the presence of different POX and TIA concentrations and the IC50 was calculated. Determinations were repeated in the presence of increasing TIA concentrations. The IC50 of POX increases with the TIA concentration in a linear manner. The protective effect of tiapride on cholinesterase could be of practical relevance in the pretreatment of organophosphate poisoning. It is concluded that in vivo testing of TIA as an organophosphate protective agent is warranted. Copyright © 2005 John Wiley & Sons, Ltd. [source] Interferon and ribavirin therapy does not select for resistance mutations in hepatitis C virus polymeraseJOURNAL OF VIRAL HEPATITIS, Issue 8 2008C. L. Ward Summary., Ribavirin has a minor and transient effect on hepatitis C virus (HCV) replication and has been suggested to select a novel mutation, F415Y, in the RNA-dependent RNA polymerase of subtype 1a viruses. Twenty-nine patients with chronic hepatitis C (subtyped by INNO LiPA as 1a, 17; 1b, 11; 1a/1b, 1) who were nonresponders to interferon-based therapies were identified retrospectively and screened at Baseline, week 24 of treatment, and 24 weeks post-treatment. Selection of resistance mutations, including at amino acid position 415 of the polymerase, was investigated. Using clonal sequencing and pyrosequencing of the NS5B gene, we screened for the F415Y resistance mutation among patients who received combination therapy with ribavirin and interferon ,. Of the 15 subtype 1a patients treated with interferon plus ribavirin, only one had the F415Y change at week 24, and an F/Y mixture was still present 24 weeks after therapy. Four additional patients in this group had the F415Y change 24 weeks post-therapy. The NS5B genes were sequenced in order to identify amino acid changes associated with ribavirin therapy, but no evidence was found that ribavirin selects for particular amino acids in the RNA-dependent RNA polymerase. Ribavirin, a weak inhibitor of HCV replication, does not select for resistance mutations in the sequence of the HCV RNA polymerase. [source] Distribution and characterization of hemolytic activity by an oral anaerobe from the Streptococcus milleri groupMOLECULAR ORAL MICROBIOLOGY, Issue 2 2004T. Yamaguchi Some oral anaerobes from the Streptococcus milleri strain group were found to secrete human specific hemolytic toxin, which was detected when bacteria were cultured in Todd-Hewitt broth and Brain Heart Infusion broth. The toxin elicited by the Streptococcus intermedius strain was partially fractionated by ammonium sulfate precipitation. Preincubation with glutathione or cysteine showed significant inhibiting effects; however, no effects were seen with dithiothreitol or ,-mercaptoethanol, and cholesterol was a weak inhibitor. Five kinds of protease inhibitor had no effect on the hemolytic activity, and rabbit preimmune and immune sera against the bacterial cells showed weak inhibition at a similar level. Digestion with trypsin, chymotrypsin, proteinase-K, subtilisin and pronase-P brought about a rise in activity, followed by a decrease during long-term incubation. Other enzymes tested showed no effects. Further, the presence of the intermedilysin gene in the portion with hemolytic activity was not identified by polymerase chain reaction. [source] Structural studies of a baboon (Papio sp.) plasma protein inhibitor of cholesteryl ester transferasePROTEIN SCIENCE, Issue 8 2000Garry W. Buchko Abstract A 38-residue protein associated with cholesteryl ester transfer inhibition has been identified in baboons (Papio sp.). The cholesteryl ester transfer inhibitor protein (CETIP) corresponds to the N-terminus of baboon apoC-I. Relative to CETIP, baboon apoC-I is a weak inhibitor of baboon cholesteryl ester transferase (CET). To study the structural features responsible for CET inhibition, CETIP was synthesized by solid-phase methods. Using sodium dodecyl sulfate (SDS) to model the lipoprotein environment, the solution structure of CETIP was probed by optical and 1HNMR spectroscopy. Circular dichroism data show that the protein lacks a well-defined structure in water but, upon the addition of SDS, becomes helical (56%). A small blue shift of 8 nm was observed in the intrinsic tryptophan fluorescence of CETIP in the presence of saturating amounts of SDS, suggesting that tryptophan-23 is not buried deeply in the lipid environment. The helical nature of CETIP in the presence of SDS was confirmed by upfield 1H, secondary shifts and an average solution structure determined by distance geometry/simulated annealing calculations using 476 NOE-based distance restraints. The backbone (N , C, , C, = O ) root-mean-square deviation of an ensemble of 17 out of 25 calculated structures superimposed on the average structure was 1.06 ± 0.30 Å using residues V4-P35 and 0.51 ± 0.17 Å using residues A7-S32. Although the side-chain orientations fit the basic description of a class A amphipathic helix, both intramolecular salt bridge formation and "snorkeling" of basic side chains toward the polar face play minor, if any, roles in stabilizing the lipid-bound amphipathic structure. Conformational features of the calculated structures for CETIP are discussed relative to models of CETIP inhibition of cholesteryl ester transferase. [source] Norbornane Mimics of Distorted , - D -Glucopyranosides , Inhibitors of , - D -Glucopyranosidases?HELVETICA CHIMICA ACTA, Issue 4 2006Stephan Buser Abstract The racemic gluco -configured norbornanes 4 and 16 were prepared and tested as inhibitors of ,- glucosidases. The known alcohol 5 was deprotected to provide the triol 6. Silylation (,,7), monobenzoylation (,,8/9), and oxidation provided the regioisomeric ketones 10 and 11. Reduction of 10 gave the desired endo -alcohol 13, albeit in low yield, while reduction of the isomeric ketone 11 provided mostly the altro -configured endo -alcohol 12. The alcohol 13 was desilylated to 14. Debenzoylation to 15 followed by hydrogenolytic deprotection gave the amino triol 4 that was reductively aminated to the benzylamine 16. The amino triols 4 and 16 proved weak inhibitors of the , -glucosidase from Caldocellum saccharolyticum (4: IC50,=,5.6,mm; 16:IC50,=,3.3,mm) and from sweet,almonds (16:IC50,=,5.5,mm). A comparison of 4 with the manno -configured norbornane 3 shows that 3 is a better inhibitor of snail , -mannosidase than 4 is of ,- glucosidases, in keeping with earlier results suggesting that these , -glycosidases enforce a different conformational itinerary. [source] Synthesis of 2-Azabicyclo[3.2.2]nonane-Derived Monosaccharide Mimics and Their Evaluation as Glycosidase InhibitorsHELVETICA CHIMICA ACTA, Issue 3 2006Stephan Buser Abstract The racemic 2-azabicyclo[3.2.2]nonanes 5 and 18 were synthesized and tested as , -glycosidase inhibitors. The intramolecular Diels,Alder reaction of the masked o -benzoquinone generated from 2-(allyloxy)phenol (6) gave the , -keto acetal 7 which was reduced with SmI2 to the hydroxy ketone 8. Dihydroxylation, isopropylidenation (,,12), and Beckmann rearrangement provided lactam 15. N -Benzylation of this lactam, reduction to the amine 17, and deprotection provided the amino triol 19 which was debenzylated to the secondary amine 5. Both 5 and 19 proved weak inhibitors of snail , -mannosidase (IC50,>,10,mM), Caldocellum saccharolyticum , -glucosidase (IC50,>,10,mM), sweet almond , -glucosidase (IC50,>,10,mM), yeast , -glucosidase (5: IC50,>,10,mM; 19: IC50,=,1.2,mM), and Jack bean , -mannosidase (no inhibition detected). [source] Synthesis of N -Acetylglucosamine-Derived Nagstatin Analogues and Their Evaluation as Glycosidase InhibitorsHELVETICA CHIMICA ACTA, Issue 1 2005Miroslav Terinek The gluco -configured analogue 15 of nagstatin (1) and the methyl ester 14 were synthesized via condensation of the thionolactams 17 or 18 with the , -amino ester 19. The silyl ethers 20 and 21 resulting from 17 were desilylated to 22 and 23; these alcohols were directly obtained by condensing 18 and 19. The attempted substitution of the C(8)OH group of 22 by azide under Mitsunobu conditions led unexpectedly to the deoxygenated , -azido esters 24. The desired azide 25 was obtained by treating the manno -configured alcohol 23 with diphenyl phosphorazidate. The azide was transformed to the debenzylated acetamido ester 14 that was hydrolyzed to the nagstatin analogue 15. The imidazole-2-acetates 14 and 15 are nanomolar inhibitors of the N -acetyl- , -glucosaminidases from Jack beans and from bovine kidney, submicromolar to micromolar inhibitors of the , -glucosidase from Caldocellum saccharolyticum, and rather weak inhibitors of the snail , -mannosidase. In all cases, the ester was a stronger inhibitor than the corresponding acid. As expected from their gluco -configuration, both imidazopyridines 14 and 15 are stronger inhibitors of the , - N -acetylglucosaminidase from bovine kidney than nagstatin. [source] Synthesis of Monosaccharide-Derived Spirocyclic Cyclopropylamines and Their Evaluation as Glycosidase InhibitorsHELVETICA CHIMICA ACTA, Issue 9 2003Christian Blüchel The glucose-, mannose-, and galactose-derived spirocyclic cyclopropylammonium chlorides 1a,1d, 2a,2d and 3a,3d were prepared as potential glycosidase inhibitors. Cyclopropanation of the diazirine 5 with ethyl acrylate led in 71% yield to a 4,:,5,:,1,:,20 mixture of the ethyl cyclopropanecarboxylates 7a,7d, while the Cu-catalysed cycloaddition of ethyl diazoacetate to the exo -glycal 6 afforded 7a,7d (6,:,2,:,5,:,3) in 93,98% yield (Scheme,1). Saponification, Curtius degradation, and subsequent addition of BnOH or t- BuOH led in 60,80% overall yield to the Z- or Boc-carbamates 11a,11d and 12a,12d, respectively. Hydrogenolysis of 11a,11d afforded 1a,1d, while 12a,12d was debenzylated to 13a,13d prior to acidic cleavage of the N -Boc group. The manno - and galacto -isomers 2a,2d and 3a,3d, respectively, were similarly obtained in comparable yields (Schemes,2 and 4). Also prepared were the differentially protected manno- configured esters 24a,24d; they are intermediates for the synthesis of analogous N -acetylglucosamine-derived cyclopropanes (Scheme,3). The cyclopropylammonium chlorides 1a,1d, 2a,2d and 3a,3d are very weak inhibitors of several glycosidases (Tables,1 and 2). Traces of Pd compounds, however, generated upon catalytic debenzylation, proved to be strong inhibitors. PdCl is, indeed, a reversible, micromolar inhibitor for the ,- glucosidases from C. saccharolyticum and sweet almonds (non-competitive), the , -galactosidases from bovine liver and from E. coli (both non-competitive), the , -galactosidase from Aspergillus niger (competitive), and an irreversible inhibitor of the , -glucosidase from yeast and the , -galactosidase from coffee beans. The cyclopropylamines derived from 1a,1d or 3a,3d significantly enhance the inhibition of the ,- glucosidase from C. saccharolyticum by PdCl, lowering the Ki value from 40,,M (PdCl) to 0.5,,M for a 1,:,1 mixture of PdCl and 1d. A similar effect is shown by cyclopropylamine, but not by several other amines. [source] Dual effect of DL -homocysteine and S -adenosylhomocysteine on brain synthesis of the glutamate receptor antagonist, kynurenic acidJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2005E. Luchowska Abstract Increased serum level of homocysteine, a sulfur-containing amino acid, is considered a risk factor in vascular disorders and in dementias. The effect of homocysteine and metabolically related compounds on brain production of kynurenic acid (KYNA), an endogenous antagonist of glutamate ionotropic receptors, was studied. In rat cortical slices, DL -homocysteine enhanced (0.1,0.5 mM) or inhibited (concentration inducing 50% inhibition [IC50] = 6.4 [5.5,7.5] mM) KYNA production. In vivo peripheral application of DL -homocysteine (1.3 mmol/kg intraperitoneally) increased KYNA content (pmol/g tissue) from 8.47 ± 1.57 to 13.04 ± 2.86 (P < 0.01; 15 min) and 11.4 ± 1.72 (P < 0.01; 60 min) in cortex, and from 4.11 ± 1.54 to 10.02 ± 3.08 (P < 0.01; 15 min) in rat hippocampus. High concentrations of DL -homocysteine (20 mM) applied via microdialysis probe decreased KYNA levels in rabbit hippocampus; this effect was antagonized partially by an antagonist of group I metabotropic glutamate receptors, LY367385. In vitro, S -adenosylhomocysteine acted similar to but more potently than DL -homocysteine, augmenting KYNA production at 0.03,0.08 mM and reducing it at ,0.5 mM. The stimulatory effect of S -adenosylhomocysteine was abolished in the presence of the L -kynurenine uptake inhibitors L -leucine and L -phenyloalanine. Neither the N -methyl- D -aspartate (NMDA) antagonist CGS 19755 nor L -glycine influenced DL -homocysteine- and S -adenosylhomocysteine-induced changes of KYNA synthesis in vitro. DL -Homocysteine inhibited the activity of both KYNA biosynthetic enzymes, kynurenine aminotransferases (KATs) I and II, whereas S -adenosylhomocysteine reduced only the activity of KAT II. L -Methionine and L -cysteine, thiol-containing compounds metabolically related to homocysteine, acted only as weak inhibitors, reducing KYNA production in vitro and inhibiting the activity of KAT II (L -cysteine) or KAT I (L -methionine). The present data suggest that DL -homocysteine biphasically modulates KYNA synthesis. This seems to result from conversion of compound to S -adenosylhomocysteine, also acting dually on KYNA formation, and in part from the direct interaction of homocysteine with metabotropic glutamate receptors and KYNA biosynthetic enzymes. It seems probable that hyperhomocystemia-associated brain dysfunction is mediated partially by changes in brain KYNA level. © 2004 Wiley-Liss, Inc. [source] Synthesis of lipophilic 2-oxoamides based on ,-aminobutyric and ,-aminovaleric analogues and their activity against phospholipase A2JOURNAL OF PEPTIDE SCIENCE, Issue 10 2007Panagiota Moutevelis-Minakakis Abstract A variety of lipophilic 2-oxoamides based on ,-aminobutyric and ,-aminovaleric analogues were synthesized. 2-oxoamides containing a tetrazole, a thioethyl or a thioacetyl group are weak inhibitors of GIVA cPLA2, while derivatives containing a methyl tetrazole, a diethyl phosphonate or a thioethyl group are weak inhibitors of GV sPLA2. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [source] Nitric Oxide Synthase Inhibition by Pentacycloundecane Conjugates of Aminoguanidine and TryptamineARCHIV DER PHARMAZIE, Issue 2 2009Dennis K. Wilkes Abstract This paper describes the synthesis and in-vitro activity of pentacycloundecane-conjugated aminoguanidine and tryptamine analogues on nitric oxide synthase (NOS) using rat brain homogenate. Both aminoguanidine and tryptamine-derived NOS inhibitors show selectivity towards the inducible and neuronal isoforms of the NOS enzyme, but are weak inhibitors and complete inhibition of the enzyme occurs only at high millimolar concentrations. In view of the increased NOS inactivation observed with alkyl substitution of these structures, the present study aimed to evaluate the effect of the pentacycloundecane cage moiety as an alkyl substituent on the in vitro NOS inhibition of aminoguanidine and tryptamine compounds. Comparison of the IC50 values of aminoguanidine (IC50 = 2.306×10,3 M) and 8-imino- N -guanidino-pentacyclo-undecane 2 (IC50 = 8.803×10,5 M) revealed a more than 26-fold increase in potency. The ability of tryptamine to inhibit NOS activity was also markedly improved by the various pentacycloundecane substituents. The compounds, 3-hydroxy-4-[3-(2-aminoethyl)indole]-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane 4 and 8-[3-(2-aminoethyl) indole]-pentacyclo[5.4.02,6.03,10.05,9]undecane 7 showed the best activity of the tryptamine analogues with a more than 3-fold increase in nitric oxide synthase inhibition. The results confirmed that the pentacycloundecane structure substantially enhanced the NOS inhibitory potency as observed for the six new NOS inhibitors. [source] New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosisBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2006Alessia Ligresti We previously reported that the compound O-2093 is a selective inhibitor of the reuptake of the endocannabinoid anandamide (AEA). We have now re-examined the activity of O-2093 in vivo and synthesized four structural analogs (O-2247, O-2248, O-3246, and O-3262), whose activity was assessed in: (a) binding assays carried out with membranes from cells overexpressing the human CB1 and CB2 receptors; (b) assays of transient receptor potential of the vanilloid type-1 (TRPV1) channel functional activity (measurement of [Ca2+]i); (c) [14C]AEA cellular uptake and hydrolysis assays in rat basophilic leukaemia (RBL-2H3) cells; (d) the mouse ,tetrad' tests (analgesia on a hot plate, immobility on a ,ring', rectal hypothermia and hypolocomotion in an open field); and (e) the limb spasticity test in chronic relapsing experimental allergic encephalomyelitis (CREAE) mice, a model of multiple sclerosis (MS). O-2093, either synthesized by us or commercially available, was inactive in the ,tetrad' up to a 20 mg kg,1 dose (i.v.). Like O-2093, the other four compounds exhibited low affinity in CB1 (Ki from 1.3 to >10 ,M) and CB2 binding assays (1.3 Inhibition of Histidine Ammonia Lyase by Heteroaryl-alanines and AcrylatesCHEMISTRY & BIODIVERSITY, Issue 5 2006Adrian Katona Abstract Histidine ammonia lyase (HAL) catalyzes the elimination of ammonia from the substrate to form (E)-urocanate. The interaction between HAL and acrylic acids or alanines substituted with heteroaryl groups in the , -position was investigated. These proved to be strong competitive inhibitors when the heteroaryl groups were furanyl, thiophenyl, benzofuranyl, and benzothiophenyl, carrying the alanyl or acrylic side chains either in 2 or 3 positions, with Ki values between 18 and 139,,M. The exception was (furan-3-yl)alanine which was found to be inert. Tryptophan and 1-methyltryptophan, as well as the corresponding acrylates (=prop-2-enoates), are strong mixed inhibitors of HAL. Theoretically, L -histidine can be dissected into 4-methyl-1H -imidazole and glycine. Whereas these two compounds separately are only very weak inhibitors of HAL, equimolar amounts of both show a Ki value of 1.7±0.09,mM which is to be compared with the Km value of 15.6,mM for the normal reaction. We conclude that 5-methyl-1H -imidazole and glycine mimic the substrate and occupy the active site of HAL in a similar orientation. [source] Thiazolopyrimidine Inhibitors of 2-Methylerythritol 2,4-Cyclodiphosphate Synthase (IspF) from Mycobacterium tuberculosis and Plasmodium falciparumCHEMMEDCHEM, Issue 7 2010Julie Abstract A library of 40,000 compounds was screened for inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) protein from Arabidopsis thaliana using a photometric assay. A thiazolopyrimidine derivative resulting from the high-throughput screen was found to inhibit the IspF proteins of Mycobacterium tuberculosis, Plasmodium falciparum, and A.,thaliana with IC50 values in the micromolar range. Synthetic efforts afforded derivatives that inhibit IspF protein from M.,tuberculosis and P.,falciparum with IC50 values in the low micromolar range. Several compounds act as weak inhibitors in the P.,falciparum red blood cell assay. [source]
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