|
In vitro antiprotozoal activity against Giardia lamblia
|
Giardia intestinalis
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiparasitic activity of 2-(trifluoromethyl)-benzimidazole derivatives.
Year : 2001
Volume : 11
Issue : 2
First Page : 187
Last Page : 190
Authors : Navarrete-Vázquez G, Cedillo R, Hernández-Campos A, Yépez L, Hernädez-Luis F, Valdez J, Morales R, Cortés R, Hernández M, Castillo R.
Abstract : 2-(Trifluoromethyl)benzimidazole derivatives substituted at the 1-, 5-, and 6-positions have been synthesized and in vitro tested against the protozoa Giardia lamblia, Entamnoeha histolytica. and the helminth Trichinella spiralis. Results indicate that all the compounds tested are more active as antiprotozoal agents than Albendazole and Metronidazole. One compound (20) was as active as Albendazole against T. spiralis. These compounds were also tested for their effect on tubulin polymerization and none inhibited tubulin polymerization.
|
The compound was tested in vitro against the protozoa Giardia lamblia, for the inhibition of tubulin polymerization in rat brain
|
Giardia intestinalis
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiparasitic activity of 1H-benzimidazole derivatives.
Year : 2002
Volume : 12
Issue : 16
First Page : 2221
Last Page : 2224
Authors : Valdez J, Cedillo R, Hernández-Campos A, Yépez L, Hernández-Luis F, Navarrete-Vázquez G, Tapia A, Cortés R, Hernández M, Castillo R.
Abstract : Compounds 1-18 have been synthesized and tested in vitro against the protozoa Giardia lamblia, Entamoeba histolytica and the helminth Trichinella spiralis. Inhibition of rat brain tubulin polymerization was also measured and compared for each compound. Results indicate that most of the compounds tested were more active as antiprotozoal agents than Metronidazole and Albendazole. None of the compounds was as active as Albendazole against T. spiralis. Although only compounds 3, 9 and 15 (2-methoxycarbonylamino derivatives) inhibited tubulin polymerization, these were not the most potent antiparasitic compounds.
|
Inhibition of Co2+ loaded MetAP expressed in Escherichia coli at 10 uM
|
Escherichia coli
|
15.45
%
|
|
Journal : J. Med. Chem.
Title : Metal-mediated inhibition of Escherichia coli methionine aminopeptidase: structure-activity relationships and development of a novel scoring function for metal-ligand interactions.
Year : 2006
Volume : 49
Issue : 2
First Page : 511
Last Page : 522
Authors : Schiffmann R, Neugebauer A, Klein CD.
Abstract : We report the discovery of thiabendazole as a potent inhibitor (K(i) = 0.4 microM) of Escherichia coli methionine aminopeptidase (ecMetAP) and the synthesis and pharmacological evaluation of thiabendazole congeners with activity in the upper nanomolar range. Elucidation of the X-ray structure of ecMetAP in complex with thiabendazole and an unrelated inhibitor that was independently described by another group showed that that both compounds bind to an additional Co(II) ion at the entrance of the active site. This unexpected finding explains the inactivity of the compounds under in vivo conditions. It also allows us to discuss the structure-activity relationships of this series of compounds in a meaningful way, based upon docking runs with an auxiliary metal ion. We describe a new scoring function for the evaluation of metal-mediated inhibitor binding that, unlike the previously used scoring function implemented in the docking program, allows us to distinguish between active and inactive compounds. Finally, conclusions for the structure-based design of in vivo-active inhibitors of ecMetAP are drawn.
|
Antimicrobial activity against Giardia duodenalis WB
|
Giardia intestinalis
|
0.019
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Peroxide bond-dependent antiplasmodial specificity of artemisinin and OZ277 (RBx11160).
Year : 2007
Volume : 51
Issue : 8
First Page : 2991
Last Page : 2993
Authors : Kaiser M, Wittlin S, Nehrbass-Stuedli A, Dong Y, Wang X, Hemphill A, Matile H, Brun R, Vennerstrom JL.
Abstract : Using nonperoxidic analogs of artemisinin and OZ277 (RBx11160), the strong in vitro antiplasmodial activities of the latter two compounds were shown to be peroxide bond dependent. In contrast, the weak activities of artemisinin and OZ277 against six other protozoan parasites were peroxide bond independent. These data support the iron-dependent artemisinin alkylation hypothesis.
|
Antimicrobial activity against Giardia duodenalis G1
|
Giardia intestinalis
|
0.018
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Peroxide bond-dependent antiplasmodial specificity of artemisinin and OZ277 (RBx11160).
Year : 2007
Volume : 51
Issue : 8
First Page : 2991
Last Page : 2993
Authors : Kaiser M, Wittlin S, Nehrbass-Stuedli A, Dong Y, Wang X, Hemphill A, Matile H, Brun R, Vennerstrom JL.
Abstract : Using nonperoxidic analogs of artemisinin and OZ277 (RBx11160), the strong in vitro antiplasmodial activities of the latter two compounds were shown to be peroxide bond dependent. In contrast, the weak activities of artemisinin and OZ277 against six other protozoan parasites were peroxide bond independent. These data support the iron-dependent artemisinin alkylation hypothesis.
|
Anthelmintic activity against Nippostrongylus brasiliensis
|
Nippostrongylus brasiliensis
|
340.0
nM
|
|
Journal : J. Nat. Prod.
Title : New sesquiterpene derivatives from the red alga Laurencia scoparia. Isolation, structure determination, and anthelmintic activity.
Year : 2001
Volume : 64
Issue : 12
First Page : 1552
Last Page : 1555
Authors : Davyt D, Fernandez R, Suescun L, Mombrú AW, Saldaña J, Domínguez L, Coll J, Fujii MT, Manta E.
Abstract : Eleven sesquiterpenes (1-11) and one long chain aldehyde (12) have been isolated from the dichloromethane extract of the red alga Laurencia scoparia. Four of them are new natural products. Scopariol (1) is a new natural product with an unusual rearranged chamigrane-type structure. The other three are beta-chamigrenes: isorigidol (2), (+)-3-(Z)-bromomethylidene-10 beta-bromo-beta-chamigrene (3), and (-)-3-(E)-bromomethylidene-10 beta-bromo-beta-chamigrene (4). The in vitro activity of compounds 1-12 against the parasitant stage of Nippostrongylus brasiliensis (L4) has been studied.
|
Antiprotozoal activity against Giardia intestinalis IMSS:0981:1 trophozoites after 48 hrs
|
Giardia intestinalis
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and antiprotozoal activity of novel 1-methylbenzimidazole derivatives.
Year : 2009
Volume : 17
Issue : 4
First Page : 1724
Last Page : 1730
Authors : Valdez-Padilla D, Rodríguez-Morales S, Hernández-Campos A, Hernández-Luis F, Yépez-Mulia L, Tapia-Contreras A, Castillo R.
Abstract : In this paper are reported the synthesis and antiprotozoal activity in vitro of 24 1-methylbenzimidazole derivatives (13-36) substituted at position 2 with aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, ethoxycarbonyl, 1-hydroxyethyl and acetyl groups, some of them with chlorine atoms at the benzenoid ring. Compounds 13-36 were more active than metronidazole, the choice drug against Giardia intestinalis and most of them against Trichomonas vaginalis. The most active group of compounds for both parasites was that with a 2-ethoxycarbonyl group (16, 22, 28, 34), independently of the substitution pattern at the benzenoid ring.
|
Inhibition of Escherichia coli MetAP at 25 uM
|
Escherichia coli
|
35.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Subtype-selectivity of metal-dependent methionine aminopeptidase inhibitors.
Year : 2010
Volume : 20
Issue : 14
First Page : 4038
Last Page : 4044
Authors : Altmeyer MA, Marschner A, Schiffmann R, Klein CD.
Abstract : Inhibitors of methionine aminopeptidases (MetAPs) are treatment options for various pathological conditions. Several inhibitor classes have been described previously, but only few data on the subtype selectivity, which is of crucial importance for these enzymes, is available. We present a systematic study on the subtype- and species-selectivity of MetAP inhibitors that require the binding of an auxiliary metal ion. This includes, in particular, compounds based on the benzimidazole pharmacophore, but also hydroxyquinoline and picolinic acid derivatives. Our data indicates that a significant degree of selectivity can be attained with metal-dependent MetAP inhibitors.
|
Inhibition of Staphylococcus aureus MetAP at 25 uM
|
Staphylococcus aureus
|
10.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Subtype-selectivity of metal-dependent methionine aminopeptidase inhibitors.
Year : 2010
Volume : 20
Issue : 14
First Page : 4038
Last Page : 4044
Authors : Altmeyer MA, Marschner A, Schiffmann R, Klein CD.
Abstract : Inhibitors of methionine aminopeptidases (MetAPs) are treatment options for various pathological conditions. Several inhibitor classes have been described previously, but only few data on the subtype selectivity, which is of crucial importance for these enzymes, is available. We present a systematic study on the subtype- and species-selectivity of MetAP inhibitors that require the binding of an auxiliary metal ion. This includes, in particular, compounds based on the benzimidazole pharmacophore, but also hydroxyquinoline and picolinic acid derivatives. Our data indicates that a significant degree of selectivity can be attained with metal-dependent MetAP inhibitors.
|
Inhibition of human MetAP2 expressed in baculovirus infected Sf9 cells at 25 uM
|
Homo sapiens
|
10.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Subtype-selectivity of metal-dependent methionine aminopeptidase inhibitors.
Year : 2010
Volume : 20
Issue : 14
First Page : 4038
Last Page : 4044
Authors : Altmeyer MA, Marschner A, Schiffmann R, Klein CD.
Abstract : Inhibitors of methionine aminopeptidases (MetAPs) are treatment options for various pathological conditions. Several inhibitor classes have been described previously, but only few data on the subtype selectivity, which is of crucial importance for these enzymes, is available. We present a systematic study on the subtype- and species-selectivity of MetAP inhibitors that require the binding of an auxiliary metal ion. This includes, in particular, compounds based on the benzimidazole pharmacophore, but also hydroxyquinoline and picolinic acid derivatives. Our data indicates that a significant degree of selectivity can be attained with metal-dependent MetAP inhibitors.
|
Antiprotozoal activity against Giardia intestinalis IMSS:0989:1 after 48 hrs
|
Giardia intestinalis
|
37.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological activity of 2-(trifluoromethyl)-1H-benzimidazole derivatives against some protozoa and Trichinella spiralis.
Year : 2010
Volume : 45
Issue : 7
First Page : 3135
Last Page : 3141
Authors : Hernández-Luis F, Hernández-Campos A, Castillo R, Navarrete-Vázquez G, Soria-Arteche O, Hernández-Hernández M, Yépez-Mulia L.
Abstract : A series of 2-(trifluoromethyl)-1H-benzimidazole derivatives (1a-1i) were synthesized via Phillips cyclocondensation of a substituted 1,2-phenylenediamine and trifluoroacetic acid. The synthesized compounds were evaluated in vitro against various protozoan parasites: Giardia intestinalis, Entamoeba histolytica, Trichomonas vaginalis and Leishmania mexicana, and they showed nanomolar activities against the first three protozoa tested. The compounds were also tested in vitro and in vivo against the nematode Trichinella spiralis. Compounds 1b, 1c and 1e had the most desirable in vitro antiparasitic profile against all parasites studied. In the in vivo model against T. spiralis, compounds 1b and 1e showed good activity against the adult phase at 75 mg/Kg. However, against the muscle larvae stage, only compound 1f exhibited in vivo antiparasitic efficacy.
|
Inhibition of tubulin in rabbit corneal cells by alamar blue assay
|
Oryctolagus cuniculus
|
700.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Molecular basis for resistance of acanthamoeba tubulins to all major classes of antitubulin compounds.
Year : 2008
Volume : 52
Issue : 3
First Page : 1133
Last Page : 1135
Authors : Henriquez FL, Ingram PR, Muench SP, Rice DW, Roberts CW.
Abstract : Tubulin is essential to eukaryotic cells and is targeted by several antineoplastics, herbicides, and antimicrobials. We demonstrate that Acanthamoeba spp. are resistant to five antimicrotubule compounds, unlike any other eukaryote studied so far. Resistance correlates with critical amino acid differences within the inhibitor binding sites of the tubulin heterodimers.
|
Antiprotozoan activity against Giardia intestinalis IMSS:0989:1 trophozoites compound treated for 48 hrs measured after 48 hrs washout period
|
Giardia intestinalis
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antiprotozoal activity of proton-pump inhibitors.
Year : 2011
Volume : 21
Issue : 24
First Page : 7351
Last Page : 7354
Authors : Pérez-Villanueva J, Romo-Mancillas A, Hernández-Campos A, Yépez-Mulia L, Hernández-Luis F, Castillo R.
Abstract : Parasitic diseases are still a major health problem in developing countries. In our effort to find new antiparasitic agents, in this Letter we report the in vitro antiprotozoal activity of omeprazole, lansoprazole, rabeprazole and pantoprazole against Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Molecular modeling studies were an important tool to highlight the potential antiprotozoal activity of these drugs. Experimental evaluations revealed a strong activity for all compounds tested. Rabeprazole and pantoprazole were the most active compounds, having IC(50) values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites.
|
Antiparasitic activity against Giardia duodenalis IMSS:0989 after 48 hrs
|
Giardia intestinalis
|
37.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Exploring the interplay of physicochemical properties, membrane permeability and giardicidal activity of some benzimidazole derivatives.
Year : 2012
Volume : 52
First Page : 193
Last Page : 204
Authors : Hernández-Covarrubias C, Vilchis-Reyes MA, Yépez-Mulia L, Sánchez-Díaz R, Navarrete-Vázquez G, Hernández-Campos A, Castillo R, Hernández-Luis F.
Abstract : This study evaluated the relationship between the physicochemical properties, membrane permeability and in vitro giardicidal activity of twenty nine benzimidazole derivatives (1-7n). The retention time data from reverse phase high performance chromatography (RP-HPLC) were used to estimate aqueous solubility and lipophilicity of these compounds. The apparent permeability was determined using Caco-2 cell monolayer. The calculation of some descriptors, such as Clog P, PSA, was performed using ACD labs software. For benzimidazole derivatives with NHCOOCH(3), CH(3), NH(2), SH and SCH(3) groups at the 2-position, a quadratic type of regression model was obtained with giardicidal activity and aqueous solubility or lipophilicity. On the other hand, giardicidal activity of 2-(trifluoromethyl)-1H-benzimidazole derivatives was influenced by lipophilicity, hydrogen bond donors and molecular volume but it was not determined by their apparent permeability in Caco-2 cell line.
|
Inhibition of mouse Ido2 transfected in HEK293T cells using L-tryptophan as substrate assessed as kynurenine formation at 20 uM after 45 mins by spectrophotometric analysis relative to control
|
Mus musculus
|
55.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.
Year : 2012
Volume : 22
Issue : 24
First Page : 7641
Last Page : 7646
Authors : Bakmiwewa SM, Fatokun AA, Tran A, Payne RJ, Hunt NH, Ball HJ.
Abstract : The kynurenine pathway is responsible for the breakdown of the majority of the essential amino acid, tryptophan (Trp). The first and rate-limiting step of the kynurenine pathway can be independently catalysed by tryptophan 2,3-dioxygenase (Tdo2), indoleamine 2,3-dioxygenase 1 (Ido1) or indoleamine 2,3-dioxygenase 2 (Ido2). Tdo2 or Ido1 enzymatic activity has been implicated in a number of actions of the kynurenine pathway, including immune evasion by tumors. IDO2 is expressed in several human pancreatic cancer cell lines, suggesting it also may play a role in tumorigenesis. Although Ido2 was originally suggested to be a target of the chemotherapeutic agent dextro-1-methyl-tryptophan, subsequent studies suggest this compound does not inhibit Ido2 activity. The development of selective Ido2 inhibitors could provide valuable tools for investigating its activity in tumor development and normal physiology. In this study, a library of Food and Drug Administration-approved drugs was screened for inhibition of mouse Ido2 enzymatic activity. A number of candidates were identified and IC(50) values of each compound for Ido1 and Ido2 were estimated. The Ido2 inhibitors were also tested for inhibition of Tdo2 activity. Our results showed that compounds from a class of drugs used to inhibit proton pumps were the most potent and selective Ido2 inhibitors identified in the library screen. These included tenatoprazole, which exhibited an IC(50) value of 1.8μM for Ido2 with no inhibition of Ido1 or Tdo2 activity detected at a concentration of 100μM tenatoprazole. These highly-selective Ido2 inhibitors will be useful for defining the distinct biological roles of the three Trp-catabolizing enzymes.
|
Antiprotozoal activity against trophozoite stage of Giardia intestinalis IMSS:0981:1 assessed as growth inhibition after 48 hrs by haemocytometric analysis
|
Giardia intestinalis
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiprotozoal activity of novel 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives.
Year : 2013
Volume : 23
Issue : 14
First Page : 4221
Last Page : 4224
Authors : Pérez-Villanueva J, Hernández-Campos A, Yépez-Mulia L, Méndez-Cuesta C, Méndez-Lucio O, Hernández-Luis F, Castillo R.
Abstract : A series of 19 new 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives was synthesized starting from the properly substituted 1,2-phenylendiamine. These compounds have hydrogen or methyl at position 1; while hydrogen, chlorine, ethoxy or methoxycarbonyl group is at position 5 and/or 6. The novel compounds were tested against protozoa Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Experimental evaluations revealed strong activity for all tested compounds, having IC50 values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
102.72
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
95.9
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
DNDI: Cytotoxicity in Vitro, 72 hour, in rat skeletal myoblast cells
|
Rattus norvegicus
|
410.0
nM
|
|
Title : Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning
Authors : Kaiser M, Mäser P, Tadoori LP, Ioset JR, Brun R.
Abstract : In this study, a set of 100 registered drugs with drug repositioning potential for neglected tropical diseases was assembled. The compound collection was systematically screened against protozoan parasites, namely T. b. rhodesiense, L. donovani, T. cruzi and P. falciparum. Several drugs and drug classes exhibited in vitro activity and selectivity against one of the protozoan parasites. The results offer opportunities for drug repurposing and the identified compound classes could also be a starting point for new drug discovery projects. See also publication: Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning. PLoS One. 2015 10(8): e0135556.
|
PubChem BioAssay. Increased HeLa cells with 2N DNA content-IC50. (Class of assay: confirmatory)
|
None
|
65.6
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. RKO viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
165.33
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. Decreased HeLa cell count-IC50. (Class of assay: confirmatory)
|
None
|
37.7
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. HCT116 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
111.8
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. VEGF stimulated ADSC/ECFC co-culture CD31-stained tube area decrease-IC50. (Class of assay: confirmatory)
|
None
|
355.4
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. Colo320 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
502.0
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. Increased HeLa cells with 4N DNA content-IC50. (Class of assay: confirmatory)
|
None
|
61.2
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. DLD-1 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
108.48
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. GSK3B-pretreated HCT116 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
157.93
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. Increased chromatin condensation in HeLa cells-IC50. (Class of assay: confirmatory)
|
None
|
61.5
nM
|
|
Title : PubChem BioAssay data set
|
Antiparasitic activity against trophozoite stage of Giardia intestinalis IMSS:0989:1 after 48 hrs
|
Giardia intestinalis
|
37.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, antiprotozoal activity, and chemoinformatic analysis of 2-(methylthio)-1H-benzimidazole-5-carboxamide derivatives: Identification of new selective giardicidal and trichomonicidal compounds.
Year : 2017
Volume : 137
First Page : 211
Last Page : 220
Authors : Flores-Carrillo P, Velázquez-López JM, Aguayo-Ortiz R, Hernández-Campos A, Trejo-Soto PJ, Yépez-Mulia L, Castillo R.
Abstract : A series of twelve new 2-(methylthio)-1H-benzimidazole-5-carboxamide derivatives (1-12) were synthesized and their antiparasitic activity was tested in vitro against Giardia intestinalis, Trichomonas vaginalis and Entamoeba histolytica. Experimental evaluations showed IC50 values within the nanomolar range for all tested compounds, some showing higher activity than metronidazole and albendazole. A chemoinformatic study was used to compare the structure-activity relationship of the synthesized carboxamides with those of 91 previously studied benzimidazoles, and with some Nitazoxanide-N-methylbenzimidazole hybrids recently synthetized by our group. Compounds 1 and 3 were identified as prominent selective compounds against T. vaginalis and G. intestinalis, respectively, while compound 4 was found to be of broad spectrum against the three protozoans.
|
Cytotoxicity against human PC3MLN4 cells assessed as reduction in cell viability after 48 hrs by cyquant reagent based fluorescence spectrometric assay
|
Homo sapiens
|
580.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and anticancer activity of novel water soluble benzimidazole carbamates.
Year : 2018
Volume : 144
First Page : 372
Last Page : 385
Authors : Cheong JE, Zaffagni M, Chung I, Xu Y, Wang Y, Jernigan FE, Zetter BR, Sun L.
Abstract : Metastases account for more than 90% of all cancer deaths and respond poorly to most therapies. There remains an urgent need for new therapeutic modalities for the treatment of advanced metastatic cancers. The benzimidazole methylcarbamate drugs, commonly used as anti-helmitics, have been suggested to have anticancer activity, but progress has been stalled by their poor water solubility and poor suitability for systemic delivery to disseminated cancers. We synthesized and characterized the anticancer activity of novel benzimidazoles containing an oxetane or an amine group to enhance solubility. Among them, the novel oxetanyl substituted compound 18 demonstrated significant cytotoxicity toward a variety of cancer cell types including prostate, lung, and ovarian cancers with strong activity toward highly aggressive cancer lines (IC50: 0.9-3.8 μM). Compound 18 achieved aqueous solubility of 361 μM. In a mouse xenograft model of a highly metastatic human prostate cancer, compound 18 (30 mg/kg) significantly inhibited the growth of established tumors (T/C: 0.36) without noticeable toxicity.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
3.05
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
1.87
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
3.18
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
1.7
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
18.94
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
2.62
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
42.52
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
23.24
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Antiparasitic activity against Nippostrongylus brasiliensis L4
|
Nippostrongylus brasiliensis
|
340.0
nM
|
|
Journal : MedChemComm
Title : Synthesis of bicyclic 1,4-thiazepines as novel anti-<i>Trypanosoma brucei brucei</i> agents.
Year : 2019
Volume : 10
Issue : 8
First Page : 1481
Last Page : 1487
Authors : Vairoletti F, Medeiros A, Fontán P, Meléndrez J, Tabárez C, Salinas G, Franco J, Comini MA, Saldaña J, Jancik V, Mahler G, Saiz C.
Abstract : 1,4-Thiazepines derivatives are pharmacologically important heterocycles with different applications in medicinal chemistry. In the present work, we describe the preparation of new bicyclic thiazolidinyl-1,4-thiazepines <b>3</b> by reaction between azadithiane compounds and Michael acceptors. The reaction scope was explored and the yields were optimized. The activity of the new compounds was evaluated against <i>Nippostrongylus brasiliensis</i> and <i>Caenorhabditis elegans</i> as anthelmintic models and <i>Trypanosoma brucei brucei.</i> The most active compound was <b>3l</b>, showing an EC<sub>50</sub> = 2.8 ± 0.7 μM against <i>T. b. brucei</i> and a selectivity index >71.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
4.415
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.38
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.38
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Antigiardial activity against Giardia duodenalis GS/M-83-H7 (ATCC 50581) incubated for 3 days by fluorescence method
|
Giardia intestinalis
|
55.0
nM
|
|
Journal : J Med Chem
Title : Anti-Giardia Drug Discovery: Current Status and Gut Feelings.
Year : 2020
Volume : 63
Issue : 22.0
First Page : 13330
Last Page : 13354
Authors : Riches A,Hart CJS,Trenholme KR,Skinner-Adams TS
Abstract : Giardia parasites are ubiquitous protozoans of global importance that impact a wide range of animals including humans. They are the most common enteric pathogen of cats and dogs in developed countries and infect ∼1 billion people worldwide. While Giardia infections can be asymptomatic, they often result in severe and chronic diseases. There is also mounting evidence that they are linked to postinfection disorders. Despite growing evidence of the widespread morbidity associated with Giardia infections, current treatment options are limited to compound classes with broad antimicrobial activity. Frontline anti-Giardia drugs are also associated with increasing drug resistance and treatment failures. To improve the health and well-being of millions, new selective anti-Giardia drugs are needed alongside improved health education initiatives. Here we discuss current treatment options together with recent advances and gaps in drug discovery. We also propose criteria to guide the discovery of new anti-Giardia compounds.
|
Antigiardial activity against Giardia duodenalis WB (ATCC 30957) incubated for 3 days by fluorescence method
|
Giardia intestinalis
|
55.0
nM
|
|
Journal : J Med Chem
Title : Anti-Giardia Drug Discovery: Current Status and Gut Feelings.
Year : 2020
Volume : 63
Issue : 22.0
First Page : 13330
Last Page : 13354
Authors : Riches A,Hart CJS,Trenholme KR,Skinner-Adams TS
Abstract : Giardia parasites are ubiquitous protozoans of global importance that impact a wide range of animals including humans. They are the most common enteric pathogen of cats and dogs in developed countries and infect ∼1 billion people worldwide. While Giardia infections can be asymptomatic, they often result in severe and chronic diseases. There is also mounting evidence that they are linked to postinfection disorders. Despite growing evidence of the widespread morbidity associated with Giardia infections, current treatment options are limited to compound classes with broad antimicrobial activity. Frontline anti-Giardia drugs are also associated with increasing drug resistance and treatment failures. To improve the health and well-being of millions, new selective anti-Giardia drugs are needed alongside improved health education initiatives. Here we discuss current treatment options together with recent advances and gaps in drug discovery. We also propose criteria to guide the discovery of new anti-Giardia compounds.
|
Antigiardial activity against Giardia duodenalis G1 incubated for 3 days by fluorescence method
|
Giardia intestinalis
|
55.0
nM
|
|
Journal : J Med Chem
Title : Anti-Giardia Drug Discovery: Current Status and Gut Feelings.
Year : 2020
Volume : 63
Issue : 22.0
First Page : 13330
Last Page : 13354
Authors : Riches A,Hart CJS,Trenholme KR,Skinner-Adams TS
Abstract : Giardia parasites are ubiquitous protozoans of global importance that impact a wide range of animals including humans. They are the most common enteric pathogen of cats and dogs in developed countries and infect ∼1 billion people worldwide. While Giardia infections can be asymptomatic, they often result in severe and chronic diseases. There is also mounting evidence that they are linked to postinfection disorders. Despite growing evidence of the widespread morbidity associated with Giardia infections, current treatment options are limited to compound classes with broad antimicrobial activity. Frontline anti-Giardia drugs are also associated with increasing drug resistance and treatment failures. To improve the health and well-being of millions, new selective anti-Giardia drugs are needed alongside improved health education initiatives. Here we discuss current treatment options together with recent advances and gaps in drug discovery. We also propose criteria to guide the discovery of new anti-Giardia compounds.
|
Antigiardial activity against Giardia duodenalis Ah1 incubated for 3 days by fluorescence method
|
Giardia intestinalis
|
55.0
nM
|
|
Journal : J Med Chem
Title : Anti-Giardia Drug Discovery: Current Status and Gut Feelings.
Year : 2020
Volume : 63
Issue : 22.0
First Page : 13330
Last Page : 13354
Authors : Riches A,Hart CJS,Trenholme KR,Skinner-Adams TS
Abstract : Giardia parasites are ubiquitous protozoans of global importance that impact a wide range of animals including humans. They are the most common enteric pathogen of cats and dogs in developed countries and infect ∼1 billion people worldwide. While Giardia infections can be asymptomatic, they often result in severe and chronic diseases. There is also mounting evidence that they are linked to postinfection disorders. Despite growing evidence of the widespread morbidity associated with Giardia infections, current treatment options are limited to compound classes with broad antimicrobial activity. Frontline anti-Giardia drugs are also associated with increasing drug resistance and treatment failures. To improve the health and well-being of millions, new selective anti-Giardia drugs are needed alongside improved health education initiatives. Here we discuss current treatment options together with recent advances and gaps in drug discovery. We also propose criteria to guide the discovery of new anti-Giardia compounds.
|
Antigiardial activity against Giardia duodenalis Ah2 incubated for 3 days by fluorescence method
|
Giardia intestinalis
|
55.0
nM
|
|
Journal : J Med Chem
Title : Anti-Giardia Drug Discovery: Current Status and Gut Feelings.
Year : 2020
Volume : 63
Issue : 22.0
First Page : 13330
Last Page : 13354
Authors : Riches A,Hart CJS,Trenholme KR,Skinner-Adams TS
Abstract : Giardia parasites are ubiquitous protozoans of global importance that impact a wide range of animals including humans. They are the most common enteric pathogen of cats and dogs in developed countries and infect ∼1 billion people worldwide. While Giardia infections can be asymptomatic, they often result in severe and chronic diseases. There is also mounting evidence that they are linked to postinfection disorders. Despite growing evidence of the widespread morbidity associated with Giardia infections, current treatment options are limited to compound classes with broad antimicrobial activity. Frontline anti-Giardia drugs are also associated with increasing drug resistance and treatment failures. To improve the health and well-being of millions, new selective anti-Giardia drugs are needed alongside improved health education initiatives. Here we discuss current treatment options together with recent advances and gaps in drug discovery. We also propose criteria to guide the discovery of new anti-Giardia compounds.
|
Antigiardial activity against Giardia duodenalis Ac1 incubated for 3 days by fluorescence method
|
Giardia intestinalis
|
55.0
nM
|
|
Journal : J Med Chem
Title : Anti-Giardia Drug Discovery: Current Status and Gut Feelings.
Year : 2020
Volume : 63
Issue : 22.0
First Page : 13330
Last Page : 13354
Authors : Riches A,Hart CJS,Trenholme KR,Skinner-Adams TS
Abstract : Giardia parasites are ubiquitous protozoans of global importance that impact a wide range of animals including humans. They are the most common enteric pathogen of cats and dogs in developed countries and infect ∼1 billion people worldwide. While Giardia infections can be asymptomatic, they often result in severe and chronic diseases. There is also mounting evidence that they are linked to postinfection disorders. Despite growing evidence of the widespread morbidity associated with Giardia infections, current treatment options are limited to compound classes with broad antimicrobial activity. Frontline anti-Giardia drugs are also associated with increasing drug resistance and treatment failures. To improve the health and well-being of millions, new selective anti-Giardia drugs are needed alongside improved health education initiatives. Here we discuss current treatment options together with recent advances and gaps in drug discovery. We also propose criteria to guide the discovery of new anti-Giardia compounds.
|
Antigiardial activity against Giardia duodenalis Ac2 incubated for 3 days by fluorescence method
|
Giardia intestinalis
|
55.0
nM
|
|
Journal : J Med Chem
Title : Anti-Giardia Drug Discovery: Current Status and Gut Feelings.
Year : 2020
Volume : 63
Issue : 22.0
First Page : 13330
Last Page : 13354
Authors : Riches A,Hart CJS,Trenholme KR,Skinner-Adams TS
Abstract : Giardia parasites are ubiquitous protozoans of global importance that impact a wide range of animals including humans. They are the most common enteric pathogen of cats and dogs in developed countries and infect ∼1 billion people worldwide. While Giardia infections can be asymptomatic, they often result in severe and chronic diseases. There is also mounting evidence that they are linked to postinfection disorders. Despite growing evidence of the widespread morbidity associated with Giardia infections, current treatment options are limited to compound classes with broad antimicrobial activity. Frontline anti-Giardia drugs are also associated with increasing drug resistance and treatment failures. To improve the health and well-being of millions, new selective anti-Giardia drugs are needed alongside improved health education initiatives. Here we discuss current treatment options together with recent advances and gaps in drug discovery. We also propose criteria to guide the discovery of new anti-Giardia compounds.
|
Antigiardial activity against Giardia duodenalis Ec1 incubated for 3 days by fluorescence method
|
Giardia intestinalis
|
55.0
nM
|
|
Journal : J Med Chem
Title : Anti-Giardia Drug Discovery: Current Status and Gut Feelings.
Year : 2020
Volume : 63
Issue : 22.0
First Page : 13330
Last Page : 13354
Authors : Riches A,Hart CJS,Trenholme KR,Skinner-Adams TS
Abstract : Giardia parasites are ubiquitous protozoans of global importance that impact a wide range of animals including humans. They are the most common enteric pathogen of cats and dogs in developed countries and infect ∼1 billion people worldwide. While Giardia infections can be asymptomatic, they often result in severe and chronic diseases. There is also mounting evidence that they are linked to postinfection disorders. Despite growing evidence of the widespread morbidity associated with Giardia infections, current treatment options are limited to compound classes with broad antimicrobial activity. Frontline anti-Giardia drugs are also associated with increasing drug resistance and treatment failures. To improve the health and well-being of millions, new selective anti-Giardia drugs are needed alongside improved health education initiatives. Here we discuss current treatment options together with recent advances and gaps in drug discovery. We also propose criteria to guide the discovery of new anti-Giardia compounds.
|
Antigiardial activity against Giardia duodenalis Ec2 incubated for 3 days by fluorescence method
|
Giardia intestinalis
|
55.0
nM
|
|
Journal : J Med Chem
Title : Anti-Giardia Drug Discovery: Current Status and Gut Feelings.
Year : 2020
Volume : 63
Issue : 22.0
First Page : 13330
Last Page : 13354
Authors : Riches A,Hart CJS,Trenholme KR,Skinner-Adams TS
Abstract : Giardia parasites are ubiquitous protozoans of global importance that impact a wide range of animals including humans. They are the most common enteric pathogen of cats and dogs in developed countries and infect ∼1 billion people worldwide. While Giardia infections can be asymptomatic, they often result in severe and chronic diseases. There is also mounting evidence that they are linked to postinfection disorders. Despite growing evidence of the widespread morbidity associated with Giardia infections, current treatment options are limited to compound classes with broad antimicrobial activity. Frontline anti-Giardia drugs are also associated with increasing drug resistance and treatment failures. To improve the health and well-being of millions, new selective anti-Giardia drugs are needed alongside improved health education initiatives. Here we discuss current treatment options together with recent advances and gaps in drug discovery. We also propose criteria to guide the discovery of new anti-Giardia compounds.
|
Giardicidal activity against Giardia intestinalis WB ATCC 30957 incubated for 48 hrs by hemocytometric counting method
|
Giardia intestinalis
|
47.0
nM
|
|
|
Giardicidal activity against metronidazole-resistant Giardia intestinalis incubated for 48 hrs by hemocytometric counting method
|
Giardia intestinalis
|
54.0
nM
|
|
|
Giardicidal activity against Giardia intestinalis IMSS isolate incubated for 48 hrs by hemocytometric counting method
|
Giardia intestinalis
|
37.0
nM
|
|
|
Giardicidal activity against albendazole-resistant Giardia intestinalis incubated for 48 hrs by hemocytometric counting method
|
Giardia intestinalis
|
137.0
nM
|
|
|
Giardicidal activity against nitazoxanide-resistant Giardia intestinalis incubated for 48 hrs by hemocytometric counting method
|
Giardia intestinalis
|
277.0
nM
|
|
