|
Inhibitory activity against 5-lipoxygenase in guinea pig leukocyte at 30 uM
|
Cavia porcellus
|
22.7
%
|
|
Journal : J. Med. Chem.
Title : Acrylamide derivatives as antiallergic agents. 2. Synthesis and structure-activity relationships of N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(3-pyridyl)acryl amides.
Year : 1989
Volume : 32
Issue : 3
First Page : 583
Last Page : 593
Authors : Nishikawa Y, Shindo T, Ishii K, Nakamura H, Kon T, Uno H.
Abstract : A new series of 3-(3-pyridyl)acrylamides 16, 17, 19, and 26, and 5-(3-pyridyl)-2,4-pentadienamides 20-25 were prepared and evaluated for their antiallergic activity. Several of these compounds exhibited more potent inhibitory activities than the parent compound 1a [(E)-N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3- (3-pyridyl)acrylamide] against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase. Particularly, (E)-N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3- (6-methyl-3-pyridyl)acrylamide (17p) showed an ED50 value of 3.3 mg/kg po in the rat PCA test, which was one-fifth of ketotifen and oxatomide. As compared with ketotifen and oxatomide, compound 17p (AL-3264) possessed a better balance of antiallergic properties due to inhibition of chemical mediator release, inhibition of 5-lipoxygenase, and antagonism of histamine.
|
Inhibition of Human Immunodeficiency Virus Type 1 integrase (HIV-1 IN) in the disintegration reaction at a concentration of 25 uM
|
Human immunodeficiency virus 1
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships: analogues of the dicaffeoylquinic and dicaffeoyltartaric acids as potent inhibitors of human immunodeficiency virus type 1 integrase and replication.
Year : 1999
Volume : 42
Issue : 3
First Page : 497
Last Page : 509
Authors : King PJ, Ma G, Miao W, Jia Q, McDougall BR, Reinecke MG, Cornell C, Kuan J, Kim TR, Robinson WE.
Abstract : The dicaffeoylquinic acids (DCQAs) and dicaffeoyltartaric acids (DCTAs) are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase. They also inhibit HIV-1 replication at nontoxic concentrations. Since integrase is an excellent target for anti-HIV therapy, structure-activity relationships were employed to synthesize compounds with: (1) improved potency against HIV-1 integrase, (2) improved anti-HIV effect in tissue culture, and (3) increased selectivity as indicated by low cellular toxicity. Thirty-four analogues of the DCTAs and DCQAs were synthesized and tested for cell toxicity, anti-HIV activity, and inhibition of HIV-1 integrase. Seventeen of the 34 analogues had potent activity against HIV-1 integrase ranging from 0. 07 to >10 microM. Seventeen analogues that were synthesized or purchased had no inhibitory activity against integrase at concentrations of 25 microM. Of the biologically active analogues, 7 of the 17 inhibited HIV replication at nontoxic concentrations. The most potent compounds were D-chicoric acid, meso-chicoric acid, bis(3,4-dihydroxydihydrocinnamoyl)-L-tartaric acid, digalloyl-L-tartaric acid, bis(3,4-dihydroxybenzoyl)-L-tartaric acid, dicaffeoylglyceric acid, and bis(3, 4-dihydroxyphenylacetyl)-L-tartaric acid. Anti-HIV activity of the active compounds in tissue culture ranged from 35 to 0.66 microM. Structure-activity relationships demonstrated that biscatechol moieties were absolutely required for inhibition of integrase, while at least one free carboxyl group was required for anti-HIV activity. These data demonstrate that analogues of the DCTAs and the DCQAs can be synthesized which have improved activity against HIV integrase.
|
Inhibition of cyclooxygenase activity in sheep seminal vesicle was determined at 10E-4 M
|
Ovis aries
|
16.0
%
|
|
Journal : J. Med. Chem.
Title : 3,4-Dihydroxychalcones as potent 5-lipoxygenase and cyclooxygenase inhibitors.
Year : 1993
Volume : 36
Issue : 24
First Page : 3904
Last Page : 3909
Authors : Sogawa S, Nihro Y, Ueda H, Izumi A, Miki T, Matsumoto H, Satoh T.
Abstract : A novel series of 3,4-dihydroxychalcones was synthesized to evaluate their effects against 5-lipoxygenase and cyclooxygenase. Almost all compounds exhibited potent inhibitory effects on 5-lipoxygenase with antioxidative effects, and some also inhibited cyclooxygenase. The 2',5'-disubstituted 3,4-dihydroxychalcones with hydroxy or alkoxy groups exhibited optimal inhibition of cyclooxygenase. We found that 2',5'-dimethoxy-3,4-dihydroxychalcone (37; HX-0836) inhibited cyclooxygenase to the same degree as flufenamic acid and 5-lipoxygenase, more than quercetin. Finally, these active inhibitors of 5-lipoxygenase inhibited arachidonic acid-induced mouse ear edema more than phenidone.
|
Percentage inhibition against release of beta-hexosaminidase from RBL-2H3 cells at 100 uM from control
|
Rattus norvegicus
|
5.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antiallergic principles from Alpinia galanga: structural requirements of phenylpropanoids for inhibition of degranulation and release of TNF-alpha and IL-4 in RBL-2H3 cells.
Year : 2003
Volume : 13
Issue : 19
First Page : 3197
Last Page : 3202
Authors : Matsuda H, Morikawa T, Managi H, Yoshikawa M.
Abstract : The 80% aqueous acetone extract of the rhizomes of Alpinia galanga was found to inhibit release of beta-hexosaminidase, as a marker of antigen-IgE-mediated degranulation in RBL-2H3 cells. Nine known phenylpropanoids and p-hydroxybenzaldehyde were isolated from the extract. Among them, 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate exhibited potent inhibitory activity with IC(50) values of 15 and 19 microM. From the effects of various related compounds, both the 1'- and 4-acetoxyl groups of 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate were essential for their strong activity, and the 2'-3' double bond enhanced the activity. In addition, 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate inhibited ear passive cutaneous anaphylaxis reactions in mice and the antigen-IgE-mediated TNF-alpha and IL-4 production, both of which participate in the late phase of type I allergic reactions, in RBL-2H3 cells.
|
Compound was evaluated for inhibition of xanthine oxidase
|
None
|
18.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antioxidant properties of nitrocaffeic acids
Year : 1996
Volume : 6
Issue : 4
First Page : 431
Last Page : 434
Authors : Grenier J, Cotelle N, Cotelle P, Catteau J
|
Compound was evaluated for hydroxyl radical (OH) scavenging activity
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antioxidant properties of nitrocaffeic acids
Year : 1996
Volume : 6
Issue : 4
First Page : 431
Last Page : 434
Authors : Grenier J, Cotelle N, Cotelle P, Catteau J
|
Percent inhibition of nitric oxide (NO) production in lipopolysaccharide activated mouse peritoneal macrophages at 100 uM of compound
|
Mus musculus
|
15.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-activity relationships of 1'S-1'-acetoxychavicol acetate for inhibitory effect on NO production in lipopolysaccharide-activated mouse peritoneal macrophages.
Year : 2005
Volume : 15
Issue : 7
First Page : 1949
Last Page : 1953
Authors : Matsuda H, Ando S, Morikawa T, Kataoka S, Yoshikawa M.
Abstract : 1'S-1'-Acetoxychavicol acetate from the rhizomes of Alpinia galanga inhibited nitric oxide (NO) production in lipopolysaccharide-activated mouse peritoneal macrophages with an IC(50) value of 2.3 microM. To clarify the structure-activity relationship of 1'S-1'-acetoxychavicol acetate, various natural and synthetic phenylpropanoids and synthetic phenylbutanoids were examined, and the following structural requirements were clarified. (1) The para or ortho substitution of the acetoxyl and 1-acetoxypropenyl groups at the benzene ring was essential. (2) The S configuration of the 1'-acetoxyl group was preferable. (3) The presence of the 3-methoxyl group and disappearance of the 2'-3' double bond by hydrogenation reduced the activity. (4) The substitution of acetyl groups with propionyl or methyl groups reduced the activity. (5) Lengthening of the carbon chain between the 1'- and 2'-positions reduced the activity.
|
Anti-inflammatory activity against carrageenan-induced edema in Sprague-Dawley rat paw after 3 hrs of 30 mg/kg, po
|
Rattus norvegicus
|
8.2
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases.
Year : 2006
Volume : 49
Issue : 5
First Page : 1668
Last Page : 1683
Authors : Rao PN, Chen QH, Knaus EE.
Abstract : A group of 1,3-diarylprop-2-yn-1-ones (13, 17, 23, 26 and 27) possessing a C-3 p-SO2Me COX-2 pharmacophore were designed, synthesized and evaluated as potential dual inhibitors of cyclooxygenase-1/2 (COX-1/2) and 5/15-lipoxygenases (5/15-LOX) that exhibit vivo antiinflammatory and analgesic activities. Among this class of compounds, 3-(4-methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-one (13h) was identified as a potent and selective inhibitor of COX-2 (COX-2 IC50 = 0.1 microM; SI = 300), being 5-fold more potent than rofecoxib (COX-2 IC50 = 0.5 microM; SI > 200). In a rat carrageenan-induced paw edema assay 13h exhibited moderate antiinflammatory activity (26% inhibition of inflammation) at 3 h after administration of a 30 mg/kg oral dose. A related dual COX-1/2 and 5/15-LOX inhibitor 3-(4-methanesulfonylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-one (13g, COX-1 IC50 = 31.5 microM; COX-2 IC50 = 1.0 microM; SI = 31.5; 5-LOX IC50 = 1.0 microM; 15-LOX IC50 = 3.2 microM) exhibited more potent antiinflammatory activity (ED50 = 90 mg/kg), being superior to the reference drug aspirin (ED50 = 129 mg/kg). Within this group of compounds 3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e) emerged as having an optimal combination of in vitro COX-1/2 and 5/15-LOX inhibitory effects (COX-1 IC50 = 9.2 microM; COX-2 IC50 = 0.32 microM; SI = 28; 5-LOX IC50 = 0.32 microM; 15-LOX IC50 = 0.36 microM) in conjunction with a good antiinflammatory activity (ED50 = 35 mg/kg) compared to the reference drug celecoxib (ED50 = 10.8 mg/kg) when administered orally. A molecular modeling study where 13e was docked in the COX-2 binding site indicated the C-1 p-i-Pr group was positioned within a hydrophobic pocket (Phe205, Val344, Val349, Phe381 and Leu534), and that this positioning of the i-Pr group facilitated orientation of the C-3 p-SO2Me COX-2 pharmacophore such that it inserted into the COX-2 secondary pocket (His90, Arg513, Ile517 and Val523). A related docking study of 13e in the 15-LOX binding site indicates that the C-3 p-SO2Me COX-2 pharmacophore was positioned in a region closer to the catalytic iron site where it undergoes a hydrogen bonding interaction with His541 and His366, and that the C-1 p-i-Pr substituent is buried deep in a hydrophobic pocket (Ile414, Ile418, Met419 and Ile593) near the base of the 15-LOX binding site.
|
Inhibitory activity against 4% NaCl-induced abdominal constriction in Sprague-Dawley rat after 30 min of 30 mg/kg, po
|
Rattus norvegicus
|
47.2
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases.
Year : 2006
Volume : 49
Issue : 5
First Page : 1668
Last Page : 1683
Authors : Rao PN, Chen QH, Knaus EE.
Abstract : A group of 1,3-diarylprop-2-yn-1-ones (13, 17, 23, 26 and 27) possessing a C-3 p-SO2Me COX-2 pharmacophore were designed, synthesized and evaluated as potential dual inhibitors of cyclooxygenase-1/2 (COX-1/2) and 5/15-lipoxygenases (5/15-LOX) that exhibit vivo antiinflammatory and analgesic activities. Among this class of compounds, 3-(4-methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-one (13h) was identified as a potent and selective inhibitor of COX-2 (COX-2 IC50 = 0.1 microM; SI = 300), being 5-fold more potent than rofecoxib (COX-2 IC50 = 0.5 microM; SI > 200). In a rat carrageenan-induced paw edema assay 13h exhibited moderate antiinflammatory activity (26% inhibition of inflammation) at 3 h after administration of a 30 mg/kg oral dose. A related dual COX-1/2 and 5/15-LOX inhibitor 3-(4-methanesulfonylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-one (13g, COX-1 IC50 = 31.5 microM; COX-2 IC50 = 1.0 microM; SI = 31.5; 5-LOX IC50 = 1.0 microM; 15-LOX IC50 = 3.2 microM) exhibited more potent antiinflammatory activity (ED50 = 90 mg/kg), being superior to the reference drug aspirin (ED50 = 129 mg/kg). Within this group of compounds 3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e) emerged as having an optimal combination of in vitro COX-1/2 and 5/15-LOX inhibitory effects (COX-1 IC50 = 9.2 microM; COX-2 IC50 = 0.32 microM; SI = 28; 5-LOX IC50 = 0.32 microM; 15-LOX IC50 = 0.36 microM) in conjunction with a good antiinflammatory activity (ED50 = 35 mg/kg) compared to the reference drug celecoxib (ED50 = 10.8 mg/kg) when administered orally. A molecular modeling study where 13e was docked in the COX-2 binding site indicated the C-1 p-i-Pr group was positioned within a hydrophobic pocket (Phe205, Val344, Val349, Phe381 and Leu534), and that this positioning of the i-Pr group facilitated orientation of the C-3 p-SO2Me COX-2 pharmacophore such that it inserted into the COX-2 secondary pocket (His90, Arg513, Ile517 and Val523). A related docking study of 13e in the 15-LOX binding site indicates that the C-3 p-SO2Me COX-2 pharmacophore was positioned in a region closer to the catalytic iron site where it undergoes a hydrogen bonding interaction with His541 and His366, and that the C-1 p-i-Pr substituent is buried deep in a hydrophobic pocket (Ile414, Ile418, Met419 and Ile593) near the base of the 15-LOX binding site.
|
Inhibitory activity against 4% NaCl-induced abdominal constriction in Sprague-Dawley rat after 60 min of 30 mg/kg, po
|
Rattus norvegicus
|
58.3
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases.
Year : 2006
Volume : 49
Issue : 5
First Page : 1668
Last Page : 1683
Authors : Rao PN, Chen QH, Knaus EE.
Abstract : A group of 1,3-diarylprop-2-yn-1-ones (13, 17, 23, 26 and 27) possessing a C-3 p-SO2Me COX-2 pharmacophore were designed, synthesized and evaluated as potential dual inhibitors of cyclooxygenase-1/2 (COX-1/2) and 5/15-lipoxygenases (5/15-LOX) that exhibit vivo antiinflammatory and analgesic activities. Among this class of compounds, 3-(4-methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-one (13h) was identified as a potent and selective inhibitor of COX-2 (COX-2 IC50 = 0.1 microM; SI = 300), being 5-fold more potent than rofecoxib (COX-2 IC50 = 0.5 microM; SI > 200). In a rat carrageenan-induced paw edema assay 13h exhibited moderate antiinflammatory activity (26% inhibition of inflammation) at 3 h after administration of a 30 mg/kg oral dose. A related dual COX-1/2 and 5/15-LOX inhibitor 3-(4-methanesulfonylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-one (13g, COX-1 IC50 = 31.5 microM; COX-2 IC50 = 1.0 microM; SI = 31.5; 5-LOX IC50 = 1.0 microM; 15-LOX IC50 = 3.2 microM) exhibited more potent antiinflammatory activity (ED50 = 90 mg/kg), being superior to the reference drug aspirin (ED50 = 129 mg/kg). Within this group of compounds 3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e) emerged as having an optimal combination of in vitro COX-1/2 and 5/15-LOX inhibitory effects (COX-1 IC50 = 9.2 microM; COX-2 IC50 = 0.32 microM; SI = 28; 5-LOX IC50 = 0.32 microM; 15-LOX IC50 = 0.36 microM) in conjunction with a good antiinflammatory activity (ED50 = 35 mg/kg) compared to the reference drug celecoxib (ED50 = 10.8 mg/kg) when administered orally. A molecular modeling study where 13e was docked in the COX-2 binding site indicated the C-1 p-i-Pr group was positioned within a hydrophobic pocket (Phe205, Val344, Val349, Phe381 and Leu534), and that this positioning of the i-Pr group facilitated orientation of the C-3 p-SO2Me COX-2 pharmacophore such that it inserted into the COX-2 secondary pocket (His90, Arg513, Ile517 and Val523). A related docking study of 13e in the 15-LOX binding site indicates that the C-3 p-SO2Me COX-2 pharmacophore was positioned in a region closer to the catalytic iron site where it undergoes a hydrogen bonding interaction with His541 and His366, and that the C-1 p-i-Pr substituent is buried deep in a hydrophobic pocket (Ile414, Ile418, Met419 and Ile593) near the base of the 15-LOX binding site.
|
Inhibitory activity against tyrosinase at 100uM
|
Homo sapiens
|
10.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Analogues of N-hydroxycinnamoylphenalkylamides as inhibitors of human melanocyte-tyrosinase.
Year : 2006
Volume : 16
Issue : 8
First Page : 2252
Last Page : 2255
Authors : Okombi S, Rival D, Bonnet S, Mariotte AM, Perrier E, Boumendjel A.
Abstract : Melanin play a major role in human skin protection and their biosynthesis is vital. Due to their color, they contribute to the skin pigmentation. Tyrosinase is a key enzyme involved in the first stage of melanin synthesis, catalyzing the transformation of tyrosine to l-dopaquinone. The aim of the present study was to study molecules able to inhibit melanin synthesis through inhibition of tyrosinase and their potential use in treating pigmentation-related disorders. We targeted amides obtained from coupling p-hydroxycinnamic acid derivatives with phenylalkylamines. The biological activity was evaluated on human melanocytes by an assay which measures tyrosine-catalyzed L-Dopa oxidation. The most active amides were: trans-N-caffeoyltyramine, N-dihydrocaffeoyltyramine, and trans-N-dihydro-p-hydroxycinnamoyltyramine which induce complete inhibition at 0.1mM. At the latter concentration, kojic acid, which was used as the reference inhibitor, was inactive.
|
Inhibition of heme-dependent lipid peroxidation
|
None
|
22.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacochemical evaluation of novel aryl-acetic acid inhibitors of lipoxygenase, antioxidants, and anti-inflammatory agents.
Year : 2007
Volume : 15
Issue : 17
First Page : 5819
Last Page : 5827
Authors : Pontiki E, Hadjipavlou-Litina D.
Abstract : Lipoxygenase catalyzes the first two steps of the transformation of arachidonic acid into leukotrienes which are implicated in host defense reactions. It is well known that many acids possess potent anti-inflammatory activity. Taking into account that compounds bearing a thienyl, naphthyl, pyrollyl, and 2,4-di-tert-butyl-phenol moieties possess anti-inflammatory activity which is related to their capacity to transfer electrons and to scavenge reactive oxygen species, we synthesized some new aryl-acetic acids and we explored their ability to inhibit soybean lipoxygenase, to present antioxidant and anti-inflammatory activities, and to interact with glutathione. The compounds have shown important antioxidant activity, medium anti-inflammatory activity, and very good inhibition of soybean lipoxygenase. Compound 3-(3,5-di-tert-butyl-2-hydroxy-phenyl)-2-phenyl-acrylic acid (1i) showed significant in vitro LO inhibition (IC(50) 65 microM). The results are discussed in terms of structural and physicochemical characteristics of the compounds. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity are experimentally determined by RPTLC method.
|
Superoxide radical scavenging activity at 0.1 mM
|
None
|
48.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacochemical evaluation of novel aryl-acetic acid inhibitors of lipoxygenase, antioxidants, and anti-inflammatory agents.
Year : 2007
Volume : 15
Issue : 17
First Page : 5819
Last Page : 5827
Authors : Pontiki E, Hadjipavlou-Litina D.
Abstract : Lipoxygenase catalyzes the first two steps of the transformation of arachidonic acid into leukotrienes which are implicated in host defense reactions. It is well known that many acids possess potent anti-inflammatory activity. Taking into account that compounds bearing a thienyl, naphthyl, pyrollyl, and 2,4-di-tert-butyl-phenol moieties possess anti-inflammatory activity which is related to their capacity to transfer electrons and to scavenge reactive oxygen species, we synthesized some new aryl-acetic acids and we explored their ability to inhibit soybean lipoxygenase, to present antioxidant and anti-inflammatory activities, and to interact with glutathione. The compounds have shown important antioxidant activity, medium anti-inflammatory activity, and very good inhibition of soybean lipoxygenase. Compound 3-(3,5-di-tert-butyl-2-hydroxy-phenyl)-2-phenyl-acrylic acid (1i) showed significant in vitro LO inhibition (IC(50) 65 microM). The results are discussed in terms of structural and physicochemical characteristics of the compounds. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity are experimentally determined by RPTLC method.
|
Inhibition of Jurkat cell activation assessed as blocking of T-cell antigen receptor-induced IL-2 expression at 10 uM by luciferase assay
|
Homo sapiens
|
2.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : The structure-activity relationship of the series of non-peptide small antagonists for p56lck SH2 domain.
Year : 2007
Volume : 15
Issue : 11
First Page : 3938
Last Page : 3950
Authors : Park SH, Oh HS, Kang MA, Cho H, Prasad JB, Won J, Lee KH.
Abstract : The antagonists for the SH2 domain are regarded as novel therapeutic candidates for cancer, autoimmune disease, and chronic inflammatory disease. Previously, we identified rosmarinic acid (alpha-o-caffeoyl-3,4-dihydroxyphenyl-lactic acid; RosA) from Prunella vulgaris as an antagonist for the p56lck SH2 domain by screening natural products. RosA not containing phosphotyrosine surrogate had a considerable inhibitory activity for T-cell antigen receptor (TCR)-induced interleukin (IL)-2 expression, and subsequent T-cell proliferation in vitro cell assay. To investigate the structure-activity relationship of RosA and to identify a novel p56lck SH2 antagonist with more potent in vitro T-cell inhibitory activity, we synthesized several analogs of RosA by using rational design. All synthesized compounds were tested in vitro binding activity for the SH2 domain and in vitro T-cell inhibitory activity. All four hydroxyl groups of RosA were essential for binding with the p56lck SH2 domain and T-cell inhibitory activity. Unexpectedly, conformationally less constrained analogs 4 and 9 showed a more potent binding affinity for the SH2 domain than that of RosA, and chirality of the analog did not play an important role in protein binding. We successfully identified several RosA analogs with a more potent T-cell inhibitory activity than that of RosA. Overall results revealed important structural requirements of the p56lck SH2 antagonists for in vitro T-cell inhibitory activity and in vitro protein binding activity.
|
Inhibition of beta amyloid 25-35 fibril formation at 10 uM
|
None
|
15.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New polyphenols active on beta-amyloid aggregation.
Year : 2008
Volume : 18
Issue : 2
First Page : 828
Last Page : 831
Authors : Rivière C, Richard T, Vitrac X, Mérillon JM, Valls J, Monti JP.
Abstract : New polyphenol classes have been tested against amyloid-beta peptide aggregation. We have identified four novel polyphenols which could be efficient fibril inhibitors in Alzheimer's disease: malvidin and its glucoside and curculigosides B and D. We suggest that molecules with the particular C(6)-linkers-C(6) structure could be potent inhibitors. From the results reported for the flavan-3-ol family, their anti-amyloidogenic effects against whole peptides (1-40 and 1-42) could involve several binding sites.
|
Inhibition of COX2 at 100 uM by scintillation proximity assay
|
None
|
32.0
%
|
|
Journal : J. Nat. Prod.
Title : Screening of ubiquitous plant constituents for COX-2 inhibition with a scintillation proximity based assay.
Year : 2002
Volume : 65
Issue : 11
First Page : 1517
Last Page : 1521
Authors : Huss U, Ringbom T, Perera P, Bohlin L, Vasänge M.
Abstract : A rapid semi-homogeneous cyclooxygenase-2 (COX-2) enzymatic assay using scintillation proximity assay (SPA) technology was developed, and 49 ubiquitous plant secondary metabolites were screened for inhibition of COX-2-catalyzed prostaglandin E(2) (PGE(2)) biosynthesis. Assay conditions were optimized with respect to reaction time, amount of antibody, radiolabeled PGE(2), and SPA beads, and the kinetic parameter, K(m), was estimated. The assay was validated with two natural triterpenoids, ursolic and oleanolic acid, known to inhibit COX-2, as well as with four synthetic COX inhibitors, NS-398, rofecoxib, indomethacin, and aspirin. Plant metabolites of different biosynthetic origin representing several substance classes, including alkaloids, anthraquinones, flavonoids, phenylpropanes, steroids, and terpenes, were screened for inhibition of COX-2-catalyzed PGE(2) production. Of these 49 plant metabolites, eugenol, pyrogallol, and cinnamaldehyde (with IC(50) values of 129, 144, and 245 microM, respectively) were found to inhibit COX-2. This study showed that a COX-2-catalyzed PGE(2) assay using SPA is suitable for screening natural compounds with respect to COX-2 inhibition.
|
Inhibition of HIV reverse transcriptase at 200 ug/ml
|
Human immunodeficiency virus
|
0.0
%
|
|
Journal : J. Nat. Prod.
Title : Saniculoside N from Sanicula europaea L.
Year : 1997
Volume : 60
Issue : 11
First Page : 1170
Last Page : 1173
Authors : Arda N, Gören N, Kuru A, Pengsuparp T, Pezzuto JM, Qiu SX, Cordell GA.
Abstract : Extracts from the aerial parts of Sanicula europaea L. were investigated for their anti-HIV activity, and the 50% ethanolic extract was shown to exhibit the highest activity. A new triterpene saponin glycoside, 21 beta-(angeloyloxy)-3-O-[beta-D-arabinopyranosyl(1-->4)-beta- D-glucopyranosyl (1-->3)-beta-D-glucuronopyranosyl propyl ester]-3 beta,15,16,22 alpha,28 beta-pentahydroxy-delta(12)-oleanene, saniculoside N (1), in addition to the known phenolic acids, rosmarinic acid (2), and caffeic acid (3) were isolated as major components. Rosmarinic acid was established as the principal active substance.
|
Antioxidant activity assessed as DPPH free radical scavenging activity relative to control
|
None
|
3.2
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Vanillic acid glycoside and quinic acid derivatives from Gardeniae Fructus.
Year : 2006
Volume : 69
Issue : 4
First Page : 600
Last Page : 603
Authors : Kim HJ, Kim EJ, Seo SH, Shin CG, Jin C, Lee YS.
Abstract : Bioassay-directed chromatographic fractionation of an ethyl acetate extract of Gardenia jasminoides (Gardeniae Fructus) afforded a new vanillic acid 4-O-beta-d-(6'-sinapoyl)glucopyranoside (1) and five new quinic acid derivatives, methyl 5-O-caffeoyl-3-O-sinapoylquinate (2), ethyl 5-O-caffeoyl-3-O-sinapoylquinate (3), methyl 5-O-caffeoyl-4-O-sinapoylquinate (4), ethyl 5-O-caffeoyl-4-O-sinapoylquinate (5), and methyl 3,5-di-O-caffeoyl-4-O-(3-hydroxy-3-methyl)glutaroylquinate (6), together with three known quinic acid derivatives, two flavonoids, two iridoids, and two phenolic compounds. The structures of new compounds were elucidated by the aid of spectroscopic methods. These compounds were assessed for antioxidant activity using three different cell-free bioassay systems and for HIV-1 integrase inhibitory activity. Five new quinic acid derivatives showed potent DPPH radical scavenging, superoxide anion scavenging, and lipid peroxidation inhibition activities. These new quinic acid derivatives also exhibited HIV-1 integrase inhibitory activity.
|
Antioxidant activity assessed as superoxide anion scavenging activity by xanthine oxidase oxidation system relative to control
|
None
|
0.5
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Vanillic acid glycoside and quinic acid derivatives from Gardeniae Fructus.
Year : 2006
Volume : 69
Issue : 4
First Page : 600
Last Page : 603
Authors : Kim HJ, Kim EJ, Seo SH, Shin CG, Jin C, Lee YS.
Abstract : Bioassay-directed chromatographic fractionation of an ethyl acetate extract of Gardenia jasminoides (Gardeniae Fructus) afforded a new vanillic acid 4-O-beta-d-(6'-sinapoyl)glucopyranoside (1) and five new quinic acid derivatives, methyl 5-O-caffeoyl-3-O-sinapoylquinate (2), ethyl 5-O-caffeoyl-3-O-sinapoylquinate (3), methyl 5-O-caffeoyl-4-O-sinapoylquinate (4), ethyl 5-O-caffeoyl-4-O-sinapoylquinate (5), and methyl 3,5-di-O-caffeoyl-4-O-(3-hydroxy-3-methyl)glutaroylquinate (6), together with three known quinic acid derivatives, two flavonoids, two iridoids, and two phenolic compounds. The structures of new compounds were elucidated by the aid of spectroscopic methods. These compounds were assessed for antioxidant activity using three different cell-free bioassay systems and for HIV-1 integrase inhibitory activity. Five new quinic acid derivatives showed potent DPPH radical scavenging, superoxide anion scavenging, and lipid peroxidation inhibition activities. These new quinic acid derivatives also exhibited HIV-1 integrase inhibitory activity.
|
Antioxidant activity assessed as inhibition of 2,2'-azobis(2-amidinopropane)dihydrochloride-induced lipid peroxidation at 3.125 ug/ml by ferric thiocyanate system relative to control
|
None
|
54.1
%
|
|
Journal : J. Nat. Prod.
Title : Vanillic acid glycoside and quinic acid derivatives from Gardeniae Fructus.
Year : 2006
Volume : 69
Issue : 4
First Page : 600
Last Page : 603
Authors : Kim HJ, Kim EJ, Seo SH, Shin CG, Jin C, Lee YS.
Abstract : Bioassay-directed chromatographic fractionation of an ethyl acetate extract of Gardenia jasminoides (Gardeniae Fructus) afforded a new vanillic acid 4-O-beta-d-(6'-sinapoyl)glucopyranoside (1) and five new quinic acid derivatives, methyl 5-O-caffeoyl-3-O-sinapoylquinate (2), ethyl 5-O-caffeoyl-3-O-sinapoylquinate (3), methyl 5-O-caffeoyl-4-O-sinapoylquinate (4), ethyl 5-O-caffeoyl-4-O-sinapoylquinate (5), and methyl 3,5-di-O-caffeoyl-4-O-(3-hydroxy-3-methyl)glutaroylquinate (6), together with three known quinic acid derivatives, two flavonoids, two iridoids, and two phenolic compounds. The structures of new compounds were elucidated by the aid of spectroscopic methods. These compounds were assessed for antioxidant activity using three different cell-free bioassay systems and for HIV-1 integrase inhibitory activity. Five new quinic acid derivatives showed potent DPPH radical scavenging, superoxide anion scavenging, and lipid peroxidation inhibition activities. These new quinic acid derivatives also exhibited HIV-1 integrase inhibitory activity.
|
Inhibition of soybean 15-lipoxygenase
|
Glycine max
|
36.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Inhibition of 15-lipoxygenase-catalysed oxygenation of arachidonic acid by substituted benzoic acids.
Year : 2008
Volume : 16
Issue : 8
First Page : 4589
Last Page : 4593
Authors : Russell WR, Scobbie L, Duthie GG, Chesson A.
Abstract : Elevated levels of phospholipases, prostaglandin synthases and lipoxygenases in colonic cells at various stages of malignancy indicate a strong link between dietary lipids and colon cancer. Lipoxygenase-catalysed arachidonic acid metabolism plays a key role in colorectal carcinogenesis and has the potential to be modulated by phenolic compounds. Plant-based foods are rich sources of phenolic compounds and in the human colon they are predominantly available as simple phenolics such as the benzoic acids. Benzoic acids were determined in faecal waters from four volunteers consuming a western-style diet. Structure-activity relationships were established for the lipoxygenase-catalysed oxygenation of arachidonic acid using an oxygen electrode. All compounds studied inhibited this reaction (21-73%; p<0.001) and many of the structural features could be rationalised by computational modelling. No correlation was observed with the ability to act as reductants, supporting the hypothesis that their mode of inhibition may not be by a direct redox effect on the non-haem iron.
|
Antioxidant activity assessed as superoxide radical scavenging activity at 100 uM by nitroblue tetrazolium method
|
None
|
71.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of hydroxycoumarins and hydroxybenzo[f]- or [h]coumarins as lipid peroxidation inhibitors.
Year : 2009
Volume : 19
Issue : 4
First Page : 1139
Last Page : 1142
Authors : Symeonidis T, Chamilos M, Hadjipavlou-Litina DJ, Kallitsakis M, Litinas KE.
Abstract : Substituted hydroxycoumarins and 7- or 8-hydroxybenzo[f]coumarins were prepared by the treatment of phenols and naphthalenediols, respectively, with malic acid and H(2)SO(4) under microwave irradiation. 7- or 8-Hydroxybenzo[f]coumarins and 6-hydroxybenzo[h]coumarin were synthesized by the reaction of naphthalenediols with ethylpropiolate in the presence of ZnCl(2) in refluxing dioxane. The compounds were tested in vitro for their ability: (i) to interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, (ii) to inhibit lipid peroxidation, (iii) to scavenge the superoxide anion, (iv) to inhibit the activity of soybean lipoxygenase and (v) to inhibit in vivo the carrageenin-induced rat paw edema. Most of them are potent superoxide anion scavengers and inhibit in vitro lipid peroxidation. The majority of the compounds did not show high lipoxygenase inhibitory activity. No differences were observed between biological responses of hydroxycoumarins and hydroxybenzocoumarins. Compound 3i was found to present a promising antioxidant profile.
|
Antioxidant activity assessed as DPPH radical scavenging activity after 20 mins by UV-visible spectrophotometry
|
None
|
3.0
ug
|
|
Journal : J. Nat. Prod.
Title : An extract of Tagetes lucida and its phenolic constituents as antioxidants.
Year : 2002
Volume : 65
Issue : 12
First Page : 1773
Last Page : 1776
Authors : Aquino R, Cáceres A, Morelli S, Rastrelli L.
Abstract : Analysis of a methanolic extract of Tagetes lucida leaves has resulted in the isolation of a new flavonol glycoside, quercetagenin 3,4'-dimethyl ether 7-O-beta-D-glucopyranoside (1), two new phenolic acids, 3-(2-O-beta-D-glucopyranosyl-4-methoxyphenyl)propanoic acid (2) and its methylester (3), and known flavonols, aromatic acids, and 7-methoxycoumarin. Using the DPPH degrees test, the extract and some of its constituents showed a significant free-radical-scavenging effect in comparison to alpha-tocopherol and standard flavonols.
|
Antioxidant activity assessed as DPPH free radical scavenging activity
|
None
|
12.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Antioxidant flavonoid glycosides from Daphniphyllum calycinum.
Year : 1998
Volume : 61
Issue : 5
First Page : 706
Last Page : 708
Authors : Gamez EJ, Luyengi L, Lee SK, Zhu LF, Zhou BN, Fong HH, Pezzuto JM, Kinghorn AD.
Abstract : A novel flavonoid diglycoside, 5,6,7,4'-tetrahydroxyflavonol 3-O-rutinoside (1), and a previously known compound, kaempferol 3-O-neohesperidoside (2), were isolated from an ethyl acetate extract of Daphniphyllum calycinum leaves that showed significant activity in a 1,1-diphenyl-2-picrylhydrazyl (DPPH) free-radical assay. The structure of 1 was elucidated by a combination of spectroscopic methods, and compounds 1 and 2 were found to be moderately active as antioxidants in the DPPH assay.
|
Antioxidant activity assessed as inhibition of AAPH-induced lipid peroxidation at 100 uM
|
None
|
17.5
%
|
|
Journal : Eur. J. Med. Chem.
Title : Syntheses and evaluation of the antioxidant activity of acitretin analogs with amide bond(s) in the polyene spacer.
Year : 2010
Volume : 45
Issue : 1
First Page : 298
Last Page : 310
Authors : Hadjipavlou-Litina D, Magoulas GE, Krokidis M, Papaioannou D.
Abstract : Ester analogs of the antipsoriatic drug acitretin were synthesized by coupling either anilines with N-protected indole-3-carboxylic acid, followed by deprotection and coupling with O-monoprotected dicarboxylic acids or Wittig reaction of indole-3-carboxaldehyde, 3-acetyl-1-tosylpyrrole and 4-amino-9-fluorenone with Ph3P=CHCO2tBu, followed by N-deprotection, where necessary, and finally coupling with cinnamoyl fluorides. Corresponding free acids were obtained through TFA-mediated carboxyl group deprotection. Although these analogs and acitretin showed very low reducing abilities, analogs 5, 6, 8 and 12 strongly inhibited LOX with IC50 values ranging from 35-65 microM. Acitretin and its analogs 5-7, 10, 11 and 15 inhibited lipid peroxidation more strongly than trolox whereas acitretin and analog 4 were in vivo more potent anti-inflammatory agents on rat paw oedema induced by Carrageenan than indomethacin.
|
Antinociceptive activity in Swiss mouse by inhibition of acetic acid-induced abdominal constriction at 10 mg/kg, ip after 20 mins
|
Mus musculus
|
34.6
%
|
|
Journal : Eur. J. Med. Chem.
Title : Antinociceptive properties of caffeic acid derivatives in mice.
Year : 2009
Volume : 44
Issue : 11
First Page : 4596
Last Page : 4602
Authors : de Campos Buzzi F, Franzoi CL, Antonini G, Fracasso M, Cechinel Filho V, Yunes RA, Niero R.
Abstract : Ten ester derivatives from caffeic acid were synthesized, and their antinociceptive properties are evaluated in mice. The most active compound, dodecyl ester derivative, exhibited potent and dose-related activity against the writhing test, with a calculated ID(50) value of 15.1 (11.9-19.1)micromol/kg and MI of 78.8% being several times more active than reference drugs. It was also effective in other experimental models, such as formalin, capsaicin and glutamate-induced pain tests, but was inactive in the hot-plate test. Although the mechanism of action has still not been elucidated, these results appear to support its therapeutic potential against painful diseases.
|
Antiallergic activity in Ca(2+)-stimulated differentiated human HeLa cells assessed as inhibition of cys-leukotriene release after 6 days by ELISA
|
Homo sapiens
|
44.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Inhibitory activity of Brazilian green propolis components and their derivatives on the release of cys-leukotrienes.
Year : 2010
Volume : 18
Issue : 1
First Page : 151
Last Page : 157
Authors : Tani H, Hasumi K, Tatefuji T, Hashimoto K, Koshino H, Takahashi S.
Abstract : The effects of Brazilian green propolis ethanol extract on Cry j1-induced cys-leukotrienes and histamine release from peripheral leukocytes of patients with allergic rhinitis were investigated. One of the key mechanisms for the anti-allergic properties of the extract was revealed to be the suppression of cys-LTs release. Furthermore, a series of propolis components and their phenethyl esters were synthesized and evaluated as inhibitors of cys-LTs release. Artepillin C, baccharin, and kaempferide were the major active components of the ethanol extract. The inhibitory activity of artepillin C phenethyl ester was comparable to that of existing LT synthesis inhibitors.
|
Antiinflammatory activity against carrageenan-induced paw edema in rat at 30 mg/kg, po
|
Rattus norvegicus
|
8.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenylacetic acid regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore: evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity.
Year : 2010
Volume : 20
Issue : 3
First Page : 896
Last Page : 902
Authors : Yu G, Chowdhury MA, Abdellatif KR, Dong Y, Praveen Rao PN, Das D, Velázquez CA, Suresh MR, Knaus EE.
Abstract : A novel class of phenylacetic acid regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore attached to its C-2, C-3 or C-4 position was designed for evaluation as anti-inflammatory (AI) agents. A number of compounds exhibited a combination of potent in vitro cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitory activities. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-4-yl)phenylacetic acid (9a) exerted the most potent AI activity among this group of compounds. Molecular modeling studies showed that the N-difluoromethyl-1,2-dihydropyridin-2-one moiety present in 9a inserts into the secondary pocket present in COX-2 to confer COX-2 selectivity, and that the N-difluoromethyl-1,2-dihydropyrid-2-one group (9a) binds close to the region of the 15-LOX enzyme containing catalytic iron (His361, His366). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties that make it an attractive pharmacophore suitable for the design of dual COX-2/5-LOX inhibitory AI drugs.
|
Inhibition of soybean LOX at 100 uM
|
Glycine max
|
600.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological screening of some novel amidocarbamate derivatives of ketoprofen.
Year : 2010
Volume : 45
Issue : 7
First Page : 3162
Last Page : 3168
Authors : Sahoo PK, Behera P.
Abstract : A series of novel ketoprofen derivatives 4a-j bearing both amide and carbamate functionalities were prepared using benzotriazole. Selective reduction of ketoprofen produced hydroxy derivative 2, which reacts with one or 2 mol of 1-benzotriazole carboxylic acid chloride (1) gave benzotriazole derivatives 3a and 3b respectively. Antioxidative screenings revealed that the prepared compounds 3b and 4a-j possess excellent lipid peroxidation inhibition at 0.1 mM concentration. Two of the compounds 3b and 4 g also showed high soybean lipoxygenase inhibition activity, where as the amidocarbamate derivatives of ketoprofen showed only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses.
|
Antioxidant activity against AAPH-induced lipid peroxidation assessed as inhibition of conjugated diene hydroperoxide production at 0.1 mM by UV spectrophotometry
|
None
|
17.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Does conjugation of antioxidants improve their antioxidative/anti-inflammatory potential?
Year : 2010
Volume : 18
Issue : 23
First Page : 8204
Last Page : 8217
Authors : Hadjipavlou-Litina D, Magoulas GE, Bariamis SE, Drainas D, Avgoustakis K, Papaioannou D.
Abstract : A series of symmetric and asymmetric spermine (SPM) conjugates with all-trans-retinoic acid (ATRA), acitretin (ACI), (E)-3-(trioxsalen-4'-yl)acrylic acid (TRAA) and L-DOPA, amides of ACI, l-DOPA and TRAA with 1-aminobutane, benzylamine, dopamine and 1,12-diaminobutane as well as hybrid conjugates of O,O'-dimethylcaffeic acid (DMCA) with TRAA or N-fumaroyl-indole-3-carboxanilide (FICA) and 2-(2-aminoethoxy)ethanol were synthesized and their antioxidant properties were studied. The reducing activity (RA)% of the compounds were evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging assay and found to be in the range 0-92(20 min)%/96(60 min)% at 100μM, the most powerful being the conjugates L-DOPA-SPM-L-DOPA (8, RA=89%/96%) and L-DOPA-dopamine (13, RA=92%/92%). Conjugate DMCA-NH(CH₂CH₂O)₂-FICA (14) was the most powerful LOX inhibitor with IC₅₀ 33.5μM, followed by the conjugates ACI-NHCH₂Ph (10, IC₅₀ 40.5μM), ACI-SPM-TRAA (7, IC₅₀ 41.5μM), DMCA-NH(CH₂CH₂O)₂-TRAA (15, IC₅₀ 65μM), 13 (IC₅₀ 81.5μM) and ACI-dopamine (11, IC₅₀ 87μM). The most potent inhibitors of lipid peroxidation at 100μM were the conjugates 15 (98%) and ACI-SPM-ACI (4, 97%) whereas all other compounds showed activities comparable or lower than trolox. The most interesting compounds, namely ATRA-SPM-ATRA (3), 4, 10, 11 and 15, as well as unconjugated compounds such as ATRA and dopamine, were studied for their anti-inflammatory activity in vivo on rat paw oedema induced by Carrageenan and found to exhibit, for doses of 0.01 mmol/mL of conjugates per Kg of rat body weight, weaker anti-inflammatory activities (3.6-40%) than indomethacin (47%) with conjugate 3 being the most potent (40%) in this series of compounds. The cytocompatibility of selected compounds was evaluated by the viability of RAMEC cells in the presence of different concentrations (0.5-50μM) of the compounds. Conjugates 3 (IC₅₀ 2.6μM) and 4 (IC₅₀ 4.7μM) were more cytotoxic than the corresponding unconjugated retinoids ATRA (IC₅₀ 18.3μM) and ACI (IC₅₀ 14.6μM), whereas conjugate 15 (IC₅₀ 12.9μM) was less cytotoxic than either DCSP (IC₅₀ 11.3μM) or the tert-butyl ester of TRAA (IC₅₀ 2.9μM).
|
Antihemorrhagic activity in ddY mouse assessed as inhibition of Protobothrops flavoviridis venom-induced hemorrhage incubated with compound for 10 mins measured after 24 hrs
|
Mus musculus
|
190.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Contribution of cinnamic acid analogues in rosmarinic acid to inhibition of snake venom induced hemorrhage.
Year : 2011
Volume : 19
Issue : 7
First Page : 2392
Last Page : 2396
Authors : Aung HT, Furukawa T, Nikai T, Niwa M, Takaya Y.
Abstract : In our previous paper, we reported that rosmarinic acid (1) of Argusia argentea could neutralize snake venom induced hemorrhagic action. Rosmarinic acid (1) consists of two phenylpropanoids: caffeic acid (2) and 3-(3,4-dihydroxyphenyl)lactic acid (3). In this study, we investigated the structural requirements necessary for inhibition of snake venom activity through the use of compounds, which are structurally related to rosmarinic acid (1). By examining anti-hemorrhagic activity of cinnamic acid analogs against Protobothrops flavoviridis (Habu) venom, it was revealed that the presence of the E-enoic acid moiety (-CH=CH-COOH) was critical. Furthermore, among the compound tested, it was concluded that rosmarinic acid (1) (IC(50) 0.15 μM) was the most potent inhibitor against the venom.
|
Antioxidant activity against AAPH-induced lipid peroxidation assessed as linoleic acid oxidation to diene hydroperoxide at 0.1 mM by UV-visible spectrophotometry
|
None
|
17.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, in silico docking experiments of new 2-pyrrolidinone derivatives and study of their anti-inflammatory activity.
Year : 2011
Volume : 19
Issue : 9
First Page : 2888
Last Page : 2902
Authors : Moutevelis-Minakakis P, Papavassilopoulou E, Michas G, Georgikopoulou K, Ragoussi ME, Neophytou N, Zoumpoulakis P, Mavromoustakos T, Hadjipavlou-Litina D.
Abstract : A new class of 2-pyrrolidinone derivatives was designed, synthesized, and tested for their antioxidant and anti-inflammatory activities. The compounds were evaluated for their inhibitory activity against LOX. The most potent among them, 14d [IC(50) 0.08 (±0.005)mM], and 14e [IC(50) 0.0705 (±0.003)mM], were also tested in vivo. The compound 14d induced equipotent inhibition against rat paw edema, which is very close to the effect produced by the commonly used standard, namely indomethacin (47%). The LOX inhibitory activity of the compound 14e proceeds in parallel to the % inhibitory value of lipid peroxidation meaning that this LOX inhibitory activity is supported by the lipid peroxidation inhibition. The molecular features that govern their bioactivity were explored through in silico docking experiments. The results showed that acidic moieties must be placed in certain distance and orientation in the active site of LOX enzyme in order to productively exhibit inhibitory activity. In addition, the 2-pyrrolidinone template significantly contributes in the inhibitory properties of the new compounds.
|
Antihemorrhagic activity in ddY mouse assessed as inhibition of Protobothrops flavoviridis venom-induced hemorrhagic lesion formation compound incubated with venom for 10 mins and administered subcutaneously measured after 24 hrs
|
Mus musculus
|
190.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzenepolycarboxylic acids with potential anti-hemorrhagic properties and structure-activity relationships.
Year : 2011
Volume : 19
Issue : 23
First Page : 7000
Last Page : 7002
Authors : Aung HT, Nikai T, Niwa M, Takaya Y.
Abstract : Previously, we reported the structural requirements of the cinnamic acid relatives for inhibition of snake venom hemorrhagic action. In the present study, we examined the effect of benzenepolycarboxylic acids and substituted benzoic acids against Protobothropsflavoviridis venom-induced hemorrhage. Pyromellitic acid (1,2,4,5-benzenetetracarboxylic acid) was found to be a potent inhibitor of hemorrhage, with an IC(50) value of 0.035 μM. In addition, most of the antihemorrhagic activity of compounds tested in this experiment showed good correlation to acidity.
|
Inhibition of human recombinant GST-tagged AKR1C1 expressed in Escherichia coli using S-tetralol as substrate at 100 uM by fluorometry
|
Homo sapiens
|
6.0
%
|
|
Journal : J. Nat. Prod.
Title : Selective inhibition of human type-5 17β-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis.
Year : 2012
Volume : 75
Issue : 4
First Page : 716
Last Page : 721
Authors : Endo S, Matsunaga T, Kanamori A, Otsuji Y, Nagai H, Sundaram K, El-Kabbani O, Toyooka N, Ohta S, Hara A.
Abstract : The human aldo-keto reductase (AKR) 1C3, also known as type-5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examined by Brazilian propolis-derived cinnamic acid derivatives that show potential antitumor activity, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Molecular docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser118, Met120, and Phe311 in AKR1C3 are important for determining the inhibitory potency and selectivity of 1. The AKR1C3-mediated metabolism of 17-ketosteroid and farnesal in cancer cells was inhibited by 1, which was effective from 0.2 μM with an IC(50) value of about 30 μM. Additionally, 1 suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3.
|
Inhibition of human recombinant AKR1C2 expressed in Escherichia coli using S-tetralol as substrate at 100 uM by fluorometry
|
Homo sapiens
|
19.0
%
|
|
Journal : J. Nat. Prod.
Title : Selective inhibition of human type-5 17β-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis.
Year : 2012
Volume : 75
Issue : 4
First Page : 716
Last Page : 721
Authors : Endo S, Matsunaga T, Kanamori A, Otsuji Y, Nagai H, Sundaram K, El-Kabbani O, Toyooka N, Ohta S, Hara A.
Abstract : The human aldo-keto reductase (AKR) 1C3, also known as type-5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examined by Brazilian propolis-derived cinnamic acid derivatives that show potential antitumor activity, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Molecular docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser118, Met120, and Phe311 in AKR1C3 are important for determining the inhibitory potency and selectivity of 1. The AKR1C3-mediated metabolism of 17-ketosteroid and farnesal in cancer cells was inhibited by 1, which was effective from 0.2 μM with an IC(50) value of about 30 μM. Additionally, 1 suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3.
|
Inhibition of human recombinant AKR1C3 expressed in Escherichia coli JM109 cells using S-tetralol as substrate at 100 uM by fluorometry
|
Homo sapiens
|
36.0
%
|
|
Journal : J. Nat. Prod.
Title : Selective inhibition of human type-5 17β-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis.
Year : 2012
Volume : 75
Issue : 4
First Page : 716
Last Page : 721
Authors : Endo S, Matsunaga T, Kanamori A, Otsuji Y, Nagai H, Sundaram K, El-Kabbani O, Toyooka N, Ohta S, Hara A.
Abstract : The human aldo-keto reductase (AKR) 1C3, also known as type-5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examined by Brazilian propolis-derived cinnamic acid derivatives that show potential antitumor activity, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Molecular docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser118, Met120, and Phe311 in AKR1C3 are important for determining the inhibitory potency and selectivity of 1. The AKR1C3-mediated metabolism of 17-ketosteroid and farnesal in cancer cells was inhibited by 1, which was effective from 0.2 μM with an IC(50) value of about 30 μM. Additionally, 1 suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3.
|
Inhibition of human recombinant GST-tagged AKR1C4 expressed in Escherichia coli using S-tetralol as substrate at 100 uM by fluorometry
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Nat. Prod.
Title : Selective inhibition of human type-5 17β-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis.
Year : 2012
Volume : 75
Issue : 4
First Page : 716
Last Page : 721
Authors : Endo S, Matsunaga T, Kanamori A, Otsuji Y, Nagai H, Sundaram K, El-Kabbani O, Toyooka N, Ohta S, Hara A.
Abstract : The human aldo-keto reductase (AKR) 1C3, also known as type-5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examined by Brazilian propolis-derived cinnamic acid derivatives that show potential antitumor activity, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Molecular docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser118, Met120, and Phe311 in AKR1C3 are important for determining the inhibitory potency and selectivity of 1. The AKR1C3-mediated metabolism of 17-ketosteroid and farnesal in cancer cells was inhibited by 1, which was effective from 0.2 μM with an IC(50) value of about 30 μM. Additionally, 1 suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3.
|
Inhibition of nitrite level in LPS-induced mouse RAW264.7 cells at 5 uM by Griess assay relative to LPS treated control
|
Mus musculus
|
23.2
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and effects of some novel tetrahydronaphthalene derivatives on proliferation and nitric oxide production in lipopolysaccharide activated Raw 264.7 macrophages.
Year : 2011
Volume : 46
Issue : 2
First Page : 468
Last Page : 479
Authors : Gurkan AS, Karabay AZ, Buyukbingol Z, Buyukbingol E.
Abstract : In this study, novel N-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-carboxamide (6-15) and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide (16-32) derivatives were synthesized and their in vitro effects at 5 μM and 50 μM concentrations on proliferation and nitric oxide (NO*) production in lipopolysaccharide (LPS) activated RAW 264.7 macrophage cells were determined. Compounds 12, 17, 24 and 26 were found to decrease nitrite levels in a dose-dependent manner in LPS-activated cells. At the tested concentrations, these compounds did not exhibit cytotoxic effects. Interestingly, compound 27 which contains nitroxide free radical was the most active compound in this series showing 59.2% nitrite inhibition in LPS-activated macrophage cells.
|
Inhibition of nitrite level in LPS-induced mouse RAW264.7 cells at 50 uM by Griess assay relative to LPS treated control
|
Mus musculus
|
44.2
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and effects of some novel tetrahydronaphthalene derivatives on proliferation and nitric oxide production in lipopolysaccharide activated Raw 264.7 macrophages.
Year : 2011
Volume : 46
Issue : 2
First Page : 468
Last Page : 479
Authors : Gurkan AS, Karabay AZ, Buyukbingol Z, Buyukbingol E.
Abstract : In this study, novel N-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-carboxamide (6-15) and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide (16-32) derivatives were synthesized and their in vitro effects at 5 μM and 50 μM concentrations on proliferation and nitric oxide (NO*) production in lipopolysaccharide (LPS) activated RAW 264.7 macrophage cells were determined. Compounds 12, 17, 24 and 26 were found to decrease nitrite levels in a dose-dependent manner in LPS-activated cells. At the tested concentrations, these compounds did not exhibit cytotoxic effects. Interestingly, compound 27 which contains nitroxide free radical was the most active compound in this series showing 59.2% nitrite inhibition in LPS-activated macrophage cells.
|
Inhibition of HFIP pretreated self-mediated amyloid beta (1 to 40) aggregation at 20 uM after 24 hrs by thioflavin-T based fluorimetric assay
|
None
|
32.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and pharmacological evaluation of novel tacrine-caffeic acid hybrids as multi-targeted compounds against Alzheimer's disease.
Year : 2012
Volume : 22
Issue : 20
First Page : 6498
Last Page : 6502
Authors : Chao X, He X, Yang Y, Zhou X, Jin M, Liu S, Cheng Z, Liu P, Wang Y, Yu J, Tan Y, Huang Y, Qin J, Rapposelli S, Pi R.
Abstract : A novel series of tacrine-caffeic acid hybrids (5a-f) were designed and synthesized by combining caffeic acid (CA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to CA. Among these compounds, 5e showed the highest selectivity in inhibiting acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). Enzyme kinetic study had suggested that 5e binds to both catalytic (CAS) and peripheral anionic sites (PAS) of AChE. Moreover, compound 5e also inhibited self- or AChE-induced β-amyloid(1-40) aggregation, as well as had potent neuroprotective effects against H(2)O(2)- and glutamate- induced cell death with low toxicity in HT22 cells.
|
Inhibition of HFIP pretreated AChE-induced amyloid beta (1 to 40) aggregation at 100 uM after 24 hrs by thioflavin-T based fluorimetric assay
|
None
|
31.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and pharmacological evaluation of novel tacrine-caffeic acid hybrids as multi-targeted compounds against Alzheimer's disease.
Year : 2012
Volume : 22
Issue : 20
First Page : 6498
Last Page : 6502
Authors : Chao X, He X, Yang Y, Zhou X, Jin M, Liu S, Cheng Z, Liu P, Wang Y, Yu J, Tan Y, Huang Y, Qin J, Rapposelli S, Pi R.
Abstract : A novel series of tacrine-caffeic acid hybrids (5a-f) were designed and synthesized by combining caffeic acid (CA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to CA. Among these compounds, 5e showed the highest selectivity in inhibiting acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). Enzyme kinetic study had suggested that 5e binds to both catalytic (CAS) and peripheral anionic sites (PAS) of AChE. Moreover, compound 5e also inhibited self- or AChE-induced β-amyloid(1-40) aggregation, as well as had potent neuroprotective effects against H(2)O(2)- and glutamate- induced cell death with low toxicity in HT22 cells.
|
Inhibition of porcine pancreatic lipase using micellar solution of triolein as substrate at 1 mM preincubated for 5 mins before substrate addition measured after 30 mins
|
Sus scrofa
|
13.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Substrate-like water soluble lipase inhibitors from Filipendula kamtschatica.
Year : 2012
Volume : 22
Issue : 20
First Page : 6410
Last Page : 6412
Authors : Kato E, Yama M, Nakagomi R, Shibata T, Hosokawa K, Kawabata J.
Abstract : Filipendula kamtschatica is a plant utilized as a traditional medicine by Ainu people in Japan, but its chemical constituents are not much studied. Pancreatic lipase inhibitors are a promising tool for the treatment of obesity. We searched for natural lipase inhibitors from F. kamtschatica and two new compounds were isolated along with the known flavonoid glycoside. The structure elucidation of new compounds revealed these two to be 2-O-caffeoyl-4-O-galloyl-L-threonic acid and 3-O-caffeoyl-4-O-galloyl-L-threonic acid, which can be recognized as a pancreatic lipase's substrate-like structure. The isolated compounds all showed an inhibitory activity against porcine pancreatic lipase and one of the isomer, 3-O-caffeoyl-4-O-galloyl-L-threonic acid, possessed the most potent activity with IC(50) value showing an order lower value compared to others. The substrate-like structure of the new compounds seemed to be important for their activity.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
2.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of horse BChE at 2 mg/ml by Ellman's method
|
Equus caballus
|
0.67
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of Glycine max (soybean) lipoxygenase using sodium linoleate as substrate at 1 X 10'-4
|
Glycine max
|
600.0
%
|
|
Journal : Med Chem Res
Title : The novel amidocarbamate derivatives of ketoprofen: synthesis and biological activity.
Year : 2011
Volume : 20
Issue : 2
First Page : 210
Last Page : 219
Authors : Rajić Z, Hadjipavlou-Litina D, Pontiki E, Balzarini J, Zorc B.
Abstract : A series of novel ketoprofen derivatives <b>4a</b>-<b>j</b> bearing both amide and carbamate functionalities were prepared using the benzotriazole method of carboxylic and hydroxy group activation. Selective reduction of ketoprofen produced hydroxy derivative <b>2</b>, which in the reaction with one or two moles of 1-benzotriazole carboxylic acid chloride (<b>1</b>) gave benzotriazole derivatives <b>3a</b> and <b>3b</b>, respectively. Compounds <b>3a</b> and <b>3b</b> with various amines afforded amidocarbamates <b>4a</b>-<b>j</b>. Antioxidative screenings revealed that the prepared compounds <b>3b</b> and <b>4a</b>-<b>j</b> possess excellent lipid peroxidation inhibition at 0.1 mM concentration, higher than 95% for the derivatives bearing aromatic, cycloalkyl or heterocyclic substituents. Two of the compounds, <b>3b</b> and <b>4g</b>, also show high soybean lipoxygenase inhibition activity (95 and 83.5%, respectively). On the other hand, the amidocarbamate derivatives of ketoprofen show only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses. Most compounds were endowed with a moderate (IC<sub>50</sub>: 10-25 μM) cytostatic activity.
|
Inhibition of yeast alpha-glucosidase using p-nitrophenyl-alpha-D-glucopyranoside as substrate preincubated at 300 uM for 10 min before substrate addition and measured after 10 min by spectrophotometry
|
Saccharomyces cerevisiae
|
10.2
%
|
|
Journal : Med Chem Res
Title : Synthesis and structureactivity relationships of serotonin derivatives effect on -glucosidase inhibition
Year : 2012
Volume : 21
Issue : 8
First Page : 1762
Last Page : 1770
Authors : Takahashi T, Miyazawa M
|
Antioxidant activity assessed as inhibition of DPPH radical production after 30 min by spectrophotometric analysis
|
None
|
1.8
ug.mL-1
|
|
Journal : Med Chem Res
Title : Antioxidant phenolic compounds and flavonoids of Mitragyna rotundifolia (Roxb.) Kuntze in vitro
Year : 2010
Volume : 19
Issue : 9
First Page : 1222
Last Page : 1232
Authors : Kang W, Li C, Liu Y
|
Antioxidant activity assessed as inhibition of ABTS radical production after 10 min by spectrophotometric analysis
|
None
|
1.54
ug.mL-1
|
|
Journal : Med Chem Res
Title : Antioxidant phenolic compounds and flavonoids of Mitragyna rotundifolia (Roxb.) Kuntze in vitro
Year : 2010
Volume : 19
Issue : 9
First Page : 1222
Last Page : 1232
Authors : Kang W, Li C, Liu Y
|
Antiproliferative activity against human T47D cells after 5 days by MTT assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antiproliferative and apoptotic effects of the oxidative dimerization product of methyl caffeate on human breast cancer cells.
Year : 2013
Volume : 23
Issue : 2
First Page : 574
Last Page : 578
Authors : Bailly F, Toillon RA, Tomavo O, Jouy N, Hondermarck H, Cotelle P.
Abstract : Caffeic acid derivatives are increasingly regarded as potential oncoprotective that could inhibit both the initiation and progression of cancer. Here we have synthesized seven 1-arylnaphthalene lignans and related compounds and tested their impact on breast cancer cell growth in tissue culture. The product of the oxidative dimerization of methyl caffeate, 1-phenylnaphthalene lignan, was found to induce a strong decrease in breast cancer cell number (IC(50) ~1 μM) and was selected for further investigation. Flow cytometry analysis revealed a decrease in cell proliferation and an increase in apoptosis in both MCF-7 and MDA-MB-231 breast cancer cell lines that are representative of the two main categories of breast tumors. The 3,4-dihydroxyphenyl group probably induced the biological activity, as the control compounds lacking it had no effect on breast cancer cells. Together, our data indicate that the oxidative dimerization product of methyl caffeate can inhibit breast cancer cell growth at a concentration adequate for pharmacological use.
|
Inhibition of MMP9 in human Hep3B cells using gelatin as substrate
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationship analysis of caffeic acid amides as selective matrix metalloproteinase inhibitors.
Year : 2013
Volume : 23
Issue : 5
First Page : 1206
Last Page : 1211
Authors : Shi ZH, Li NG, Shi QP, Tang H, Tang YP, Li W, Yin L, Yang JP, Duan JA.
Abstract : Four series of acid amides were synthesized, and through measurement using a fluorogenic substrate assay with human recombinant MMP-1, MMP-2 and MMP-9, compound 3f showed considerable inhibitory activities against MMP-2, MMP-9 and the best selectivity over MMP-1. Preliminary structure-activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities.
|
Inhibition of human recombinant MMP9 using succinylated gelatin as substrate incubated for 30 mins prior to substrate addition measured after 60 mins
|
Homo sapiens
|
21.22
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationship analysis of caffeic acid amides as selective matrix metalloproteinase inhibitors.
Year : 2013
Volume : 23
Issue : 5
First Page : 1206
Last Page : 1211
Authors : Shi ZH, Li NG, Shi QP, Tang H, Tang YP, Li W, Yin L, Yang JP, Duan JA.
Abstract : Four series of acid amides were synthesized, and through measurement using a fluorogenic substrate assay with human recombinant MMP-1, MMP-2 and MMP-9, compound 3f showed considerable inhibitory activities against MMP-2, MMP-9 and the best selectivity over MMP-1. Preliminary structure-activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities.
|
Inhibition of human recombinant MMP2 using succinylated gelatin as substrate incubated for 30 mins prior to substrate addition measured after 60 mins
|
Homo sapiens
|
24.26
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationship analysis of caffeic acid amides as selective matrix metalloproteinase inhibitors.
Year : 2013
Volume : 23
Issue : 5
First Page : 1206
Last Page : 1211
Authors : Shi ZH, Li NG, Shi QP, Tang H, Tang YP, Li W, Yin L, Yang JP, Duan JA.
Abstract : Four series of acid amides were synthesized, and through measurement using a fluorogenic substrate assay with human recombinant MMP-1, MMP-2 and MMP-9, compound 3f showed considerable inhibitory activities against MMP-2, MMP-9 and the best selectivity over MMP-1. Preliminary structure-activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities.
|
Inhibition of human recombinant MMP1 using succinylated gelatin as substrate incubated for 30 mins prior to substrate addition measured after 60 mins
|
Homo sapiens
|
238.91
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationship analysis of caffeic acid amides as selective matrix metalloproteinase inhibitors.
Year : 2013
Volume : 23
Issue : 5
First Page : 1206
Last Page : 1211
Authors : Shi ZH, Li NG, Shi QP, Tang H, Tang YP, Li W, Yin L, Yang JP, Duan JA.
Abstract : Four series of acid amides were synthesized, and through measurement using a fluorogenic substrate assay with human recombinant MMP-1, MMP-2 and MMP-9, compound 3f showed considerable inhibitory activities against MMP-2, MMP-9 and the best selectivity over MMP-1. Preliminary structure-activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities.
|
Inhibition of Gloeobacter violaceus ligand-gated ion channel E177A mutant at 100 uM
|
Gloeobacter violaceus
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of cinnamic acid derivatives as novel antagonists of the prokaryotic proton-gated ion channel GLIC.
Year : 2013
Volume : 56
Issue : 11
First Page : 4619
Last Page : 4630
Authors : Prevost MS, Delarue-Cochin S, Marteaux J, Colas C, Van Renterghem C, Blondel A, Malliavin T, Corringer PJ, Joseph D.
Abstract : Pentameric ligand gated ion channels (pLGICs) mediate signal transduction. The binding of an extracellular ligand is coupled to the transmembrane channel opening. So far, all known agonists bind at the interface between subunits in a topologically conserved "orthosteric site" whose amino acid composition defines the pharmacological specificity of pLGIC subtypes. A striking exception is the bacterial proton-activated GLIC protein, exhibiting an uncommon orthosteric binding site in terms of sequence and local architecture. Among a library of Gloeobacter violaceus metabolites, we identified a series of cinnamic acid derivatives, which antagonize the GLIC proton-elicited response. Structure-activity analysis shows a key contribution of the carboxylate moiety to GLIC inhibition. Molecular docking coupled to site-directed mutagenesis support that the binding pocket is located below the classical orthosteric site. These antagonists provide new tools to modulate conformation of GLIC, currently used as a prototypic pLGIC, and opens new avenues to study the signal transduction mechanism.
|
Inhibition of Gloeobacter violaceus ligand-gated ion channel R105A mutant at 100 uM
|
Gloeobacter violaceus
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of cinnamic acid derivatives as novel antagonists of the prokaryotic proton-gated ion channel GLIC.
Year : 2013
Volume : 56
Issue : 11
First Page : 4619
Last Page : 4630
Authors : Prevost MS, Delarue-Cochin S, Marteaux J, Colas C, Van Renterghem C, Blondel A, Malliavin T, Corringer PJ, Joseph D.
Abstract : Pentameric ligand gated ion channels (pLGICs) mediate signal transduction. The binding of an extracellular ligand is coupled to the transmembrane channel opening. So far, all known agonists bind at the interface between subunits in a topologically conserved "orthosteric site" whose amino acid composition defines the pharmacological specificity of pLGIC subtypes. A striking exception is the bacterial proton-activated GLIC protein, exhibiting an uncommon orthosteric binding site in terms of sequence and local architecture. Among a library of Gloeobacter violaceus metabolites, we identified a series of cinnamic acid derivatives, which antagonize the GLIC proton-elicited response. Structure-activity analysis shows a key contribution of the carboxylate moiety to GLIC inhibition. Molecular docking coupled to site-directed mutagenesis support that the binding pocket is located below the classical orthosteric site. These antagonists provide new tools to modulate conformation of GLIC, currently used as a prototypic pLGIC, and opens new avenues to study the signal transduction mechanism.
|
Inhibition of Gloeobacter violaceus ligand-gated ion channel R77A mutant at 100 uM
|
Gloeobacter violaceus
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of cinnamic acid derivatives as novel antagonists of the prokaryotic proton-gated ion channel GLIC.
Year : 2013
Volume : 56
Issue : 11
First Page : 4619
Last Page : 4630
Authors : Prevost MS, Delarue-Cochin S, Marteaux J, Colas C, Van Renterghem C, Blondel A, Malliavin T, Corringer PJ, Joseph D.
Abstract : Pentameric ligand gated ion channels (pLGICs) mediate signal transduction. The binding of an extracellular ligand is coupled to the transmembrane channel opening. So far, all known agonists bind at the interface between subunits in a topologically conserved "orthosteric site" whose amino acid composition defines the pharmacological specificity of pLGIC subtypes. A striking exception is the bacterial proton-activated GLIC protein, exhibiting an uncommon orthosteric binding site in terms of sequence and local architecture. Among a library of Gloeobacter violaceus metabolites, we identified a series of cinnamic acid derivatives, which antagonize the GLIC proton-elicited response. Structure-activity analysis shows a key contribution of the carboxylate moiety to GLIC inhibition. Molecular docking coupled to site-directed mutagenesis support that the binding pocket is located below the classical orthosteric site. These antagonists provide new tools to modulate conformation of GLIC, currently used as a prototypic pLGIC, and opens new avenues to study the signal transduction mechanism.
|
Inhibition of Gloeobacter violaceus ligand-gated ion channel E181A mutant at 100 uM
|
Gloeobacter violaceus
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of cinnamic acid derivatives as novel antagonists of the prokaryotic proton-gated ion channel GLIC.
Year : 2013
Volume : 56
Issue : 11
First Page : 4619
Last Page : 4630
Authors : Prevost MS, Delarue-Cochin S, Marteaux J, Colas C, Van Renterghem C, Blondel A, Malliavin T, Corringer PJ, Joseph D.
Abstract : Pentameric ligand gated ion channels (pLGICs) mediate signal transduction. The binding of an extracellular ligand is coupled to the transmembrane channel opening. So far, all known agonists bind at the interface between subunits in a topologically conserved "orthosteric site" whose amino acid composition defines the pharmacological specificity of pLGIC subtypes. A striking exception is the bacterial proton-activated GLIC protein, exhibiting an uncommon orthosteric binding site in terms of sequence and local architecture. Among a library of Gloeobacter violaceus metabolites, we identified a series of cinnamic acid derivatives, which antagonize the GLIC proton-elicited response. Structure-activity analysis shows a key contribution of the carboxylate moiety to GLIC inhibition. Molecular docking coupled to site-directed mutagenesis support that the binding pocket is located below the classical orthosteric site. These antagonists provide new tools to modulate conformation of GLIC, currently used as a prototypic pLGIC, and opens new avenues to study the signal transduction mechanism.
|
Inhibition of Gloeobacter violaceus ligand-gated ion channel expressed in Xenopus laevis oocytes assessed as inhibition of MES buffer pH 5.5 -induced currents at 1 mM after 30 secs by voltage clamp technique
|
Gloeobacter violaceus
|
93.76
%
|
|
Journal : J. Med. Chem.
Title : Identification of cinnamic acid derivatives as novel antagonists of the prokaryotic proton-gated ion channel GLIC.
Year : 2013
Volume : 56
Issue : 11
First Page : 4619
Last Page : 4630
Authors : Prevost MS, Delarue-Cochin S, Marteaux J, Colas C, Van Renterghem C, Blondel A, Malliavin T, Corringer PJ, Joseph D.
Abstract : Pentameric ligand gated ion channels (pLGICs) mediate signal transduction. The binding of an extracellular ligand is coupled to the transmembrane channel opening. So far, all known agonists bind at the interface between subunits in a topologically conserved "orthosteric site" whose amino acid composition defines the pharmacological specificity of pLGIC subtypes. A striking exception is the bacterial proton-activated GLIC protein, exhibiting an uncommon orthosteric binding site in terms of sequence and local architecture. Among a library of Gloeobacter violaceus metabolites, we identified a series of cinnamic acid derivatives, which antagonize the GLIC proton-elicited response. Structure-activity analysis shows a key contribution of the carboxylate moiety to GLIC inhibition. Molecular docking coupled to site-directed mutagenesis support that the binding pocket is located below the classical orthosteric site. These antagonists provide new tools to modulate conformation of GLIC, currently used as a prototypic pLGIC, and opens new avenues to study the signal transduction mechanism.
|
Antioxidant activity assessed as hydroxyl radical scavenging activity after 20 mins by spectrophotometric analysis
|
None
|
0.37
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New bioactive dihydrofuranocoumarins from the roots of the Tunisian Ferula lutea (Poir.) Maire.
Year : 2013
Volume : 23
Issue : 14
First Page : 4248
Last Page : 4252
Authors : Ben Salem S, Jabrane A, Harzallah-Skhiri F, Ben Jannet H.
Abstract : A phytochemical investigation of the roots of Ferula lutea (Poir.) Maire led to the isolation of new dihydrofuranocoumarins as two inseparable isomers, (-)-5-hydroxyprantschimgin 1 and (-)-5-hydroxydeltoin 2, together with eight known compounds, (-)-prantschimgin 3, (-)-deltoin 4, psoralen 5, xanthotoxin 6, umbelliferone 7, caffeic acid 8, β-sitosterol 9 and stigmasterol 10. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR experiments and mass spectroscopy analysis, as well as by comparison with literature data. The anti-acetylcholinesterase and cytotoxic effects of the isolates and antioxidant activities of the mixture (1+2) were also evaluated in this work. Results showed that the mixture (1+2) has the most cytotoxic activity with IC50 values 0.29±0.05 and 1.61±0.57μM against the cell lines HT-29 and HCT 116, respectively. The greatest acetylcholinesterase inhibitory activity (IC50=0.76±0.03) was exhibited by the xanthotoxin 6. In addition, the mixture (1+2) was investigated for its antioxidant activity and showed IC50 values 18.56, 13.06, 7.59, and 4.81μM towards DPPH free radical scavenging, ABTS radical monocation, singlet oxygen and hydrogen peroxide, respectively.
|
Antioxidant activity assessed as superoxide radical scavenging activity measured every 30 seconds for 5 mins by spectrophotometric analysis
|
None
|
0.38
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New bioactive dihydrofuranocoumarins from the roots of the Tunisian Ferula lutea (Poir.) Maire.
Year : 2013
Volume : 23
Issue : 14
First Page : 4248
Last Page : 4252
Authors : Ben Salem S, Jabrane A, Harzallah-Skhiri F, Ben Jannet H.
Abstract : A phytochemical investigation of the roots of Ferula lutea (Poir.) Maire led to the isolation of new dihydrofuranocoumarins as two inseparable isomers, (-)-5-hydroxyprantschimgin 1 and (-)-5-hydroxydeltoin 2, together with eight known compounds, (-)-prantschimgin 3, (-)-deltoin 4, psoralen 5, xanthotoxin 6, umbelliferone 7, caffeic acid 8, β-sitosterol 9 and stigmasterol 10. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR experiments and mass spectroscopy analysis, as well as by comparison with literature data. The anti-acetylcholinesterase and cytotoxic effects of the isolates and antioxidant activities of the mixture (1+2) were also evaluated in this work. Results showed that the mixture (1+2) has the most cytotoxic activity with IC50 values 0.29±0.05 and 1.61±0.57μM against the cell lines HT-29 and HCT 116, respectively. The greatest acetylcholinesterase inhibitory activity (IC50=0.76±0.03) was exhibited by the xanthotoxin 6. In addition, the mixture (1+2) was investigated for its antioxidant activity and showed IC50 values 18.56, 13.06, 7.59, and 4.81μM towards DPPH free radical scavenging, ABTS radical monocation, singlet oxygen and hydrogen peroxide, respectively.
|
Antioxidant activity assessed as ABTS radical scavenging activity after 6 mins by spectrophotometric analysis
|
None
|
0.57
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New bioactive dihydrofuranocoumarins from the roots of the Tunisian Ferula lutea (Poir.) Maire.
Year : 2013
Volume : 23
Issue : 14
First Page : 4248
Last Page : 4252
Authors : Ben Salem S, Jabrane A, Harzallah-Skhiri F, Ben Jannet H.
Abstract : A phytochemical investigation of the roots of Ferula lutea (Poir.) Maire led to the isolation of new dihydrofuranocoumarins as two inseparable isomers, (-)-5-hydroxyprantschimgin 1 and (-)-5-hydroxydeltoin 2, together with eight known compounds, (-)-prantschimgin 3, (-)-deltoin 4, psoralen 5, xanthotoxin 6, umbelliferone 7, caffeic acid 8, β-sitosterol 9 and stigmasterol 10. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR experiments and mass spectroscopy analysis, as well as by comparison with literature data. The anti-acetylcholinesterase and cytotoxic effects of the isolates and antioxidant activities of the mixture (1+2) were also evaluated in this work. Results showed that the mixture (1+2) has the most cytotoxic activity with IC50 values 0.29±0.05 and 1.61±0.57μM against the cell lines HT-29 and HCT 116, respectively. The greatest acetylcholinesterase inhibitory activity (IC50=0.76±0.03) was exhibited by the xanthotoxin 6. In addition, the mixture (1+2) was investigated for its antioxidant activity and showed IC50 values 18.56, 13.06, 7.59, and 4.81μM towards DPPH free radical scavenging, ABTS radical monocation, singlet oxygen and hydrogen peroxide, respectively.
|
Antioxidant activity assessed as DPPH free radical scavenging activity after 30 mins by spectrophotometric analysis
|
None
|
0.39
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New bioactive dihydrofuranocoumarins from the roots of the Tunisian Ferula lutea (Poir.) Maire.
Year : 2013
Volume : 23
Issue : 14
First Page : 4248
Last Page : 4252
Authors : Ben Salem S, Jabrane A, Harzallah-Skhiri F, Ben Jannet H.
Abstract : A phytochemical investigation of the roots of Ferula lutea (Poir.) Maire led to the isolation of new dihydrofuranocoumarins as two inseparable isomers, (-)-5-hydroxyprantschimgin 1 and (-)-5-hydroxydeltoin 2, together with eight known compounds, (-)-prantschimgin 3, (-)-deltoin 4, psoralen 5, xanthotoxin 6, umbelliferone 7, caffeic acid 8, β-sitosterol 9 and stigmasterol 10. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR experiments and mass spectroscopy analysis, as well as by comparison with literature data. The anti-acetylcholinesterase and cytotoxic effects of the isolates and antioxidant activities of the mixture (1+2) were also evaluated in this work. Results showed that the mixture (1+2) has the most cytotoxic activity with IC50 values 0.29±0.05 and 1.61±0.57μM against the cell lines HT-29 and HCT 116, respectively. The greatest acetylcholinesterase inhibitory activity (IC50=0.76±0.03) was exhibited by the xanthotoxin 6. In addition, the mixture (1+2) was investigated for its antioxidant activity and showed IC50 values 18.56, 13.06, 7.59, and 4.81μM towards DPPH free radical scavenging, ABTS radical monocation, singlet oxygen and hydrogen peroxide, respectively.
|
Antibacterial activity against Fusarium graminearum ATCC 24373 at 50 ug/ml after 24 hrs by agar well diffusion method relative to control
|
Gibberella zeae
|
63.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : A novel one-pot synthesis and preliminary biological activity evaluation of cis-restricted polyhydroxy stilbenes incorporating protocatechuic acid and cinnamic acid fragments.
Year : 2013
Volume : 66
First Page : 185
Last Page : 192
Authors : Miliovsky M, Svinyarov I, Mitrev Y, Evstatieva Y, Nikolova D, Chochkova M, Bogdanov MG.
Abstract : A series of new stilbenes 4a-e, 5 were synthesized through a novel one-pot Perkin-like reaction between 6,7-dimethoxyhomophthalic anhydride and aromatic aldehydes, followed by treatment with BBr3. This synthesis is straightforward and allows polyhydroxylated cis-stilbenes gathering two well-known pharmacophoric fragments to be obtained in good yields and for short reaction times. The structure of the newly synthesized compounds was established by spectroscopic methods ((1)H NMR, (13)C NMR, IR and HRMS) and the double bond configuration was unequivocally elucidated by means of gated decoupling (13)C NMR spectra and 2D NOESY experiments. Preliminary differentiating screening of their radical scavenging, antibacterial, anti-fungal and tyrosinase inhibitory activity was further performed. The results obtained suggest that the tested compounds possess a triple biological action as potent radical scavengers, antifungal agents and tyrosinase inhibitors in micromolar concentration. The most promising bioactive compound amongst the others was 4a, acting as excellent radical scavenger against DPPH(•) radical (IC₅₀ ≤ 10 μM), antifungal agent suppressing the growth of Fusarium graminearum (89% inhibition at 0.17 μmol/mL), and tyrosinase inhibitor showing higher activity than hydroquinone at 23 μM.
|
Antibacterial activity against Aspergillus flavus IMI 052104 at 50 ug/ml after 24 hrs by agar well diffusion method relative to control
|
Aspergillus flavus
|
16.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : A novel one-pot synthesis and preliminary biological activity evaluation of cis-restricted polyhydroxy stilbenes incorporating protocatechuic acid and cinnamic acid fragments.
Year : 2013
Volume : 66
First Page : 185
Last Page : 192
Authors : Miliovsky M, Svinyarov I, Mitrev Y, Evstatieva Y, Nikolova D, Chochkova M, Bogdanov MG.
Abstract : A series of new stilbenes 4a-e, 5 were synthesized through a novel one-pot Perkin-like reaction between 6,7-dimethoxyhomophthalic anhydride and aromatic aldehydes, followed by treatment with BBr3. This synthesis is straightforward and allows polyhydroxylated cis-stilbenes gathering two well-known pharmacophoric fragments to be obtained in good yields and for short reaction times. The structure of the newly synthesized compounds was established by spectroscopic methods ((1)H NMR, (13)C NMR, IR and HRMS) and the double bond configuration was unequivocally elucidated by means of gated decoupling (13)C NMR spectra and 2D NOESY experiments. Preliminary differentiating screening of their radical scavenging, antibacterial, anti-fungal and tyrosinase inhibitory activity was further performed. The results obtained suggest that the tested compounds possess a triple biological action as potent radical scavengers, antifungal agents and tyrosinase inhibitors in micromolar concentration. The most promising bioactive compound amongst the others was 4a, acting as excellent radical scavenger against DPPH(•) radical (IC₅₀ ≤ 10 μM), antifungal agent suppressing the growth of Fusarium graminearum (89% inhibition at 0.17 μmol/mL), and tyrosinase inhibitor showing higher activity than hydroquinone at 23 μM.
|
Antibacterial activity against Aspergillus niger A3 at 50 ug/ml after 24 hrs by agar well diffusion method relative to control
|
Aspergillus niger
|
35.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : A novel one-pot synthesis and preliminary biological activity evaluation of cis-restricted polyhydroxy stilbenes incorporating protocatechuic acid and cinnamic acid fragments.
Year : 2013
Volume : 66
First Page : 185
Last Page : 192
Authors : Miliovsky M, Svinyarov I, Mitrev Y, Evstatieva Y, Nikolova D, Chochkova M, Bogdanov MG.
Abstract : A series of new stilbenes 4a-e, 5 were synthesized through a novel one-pot Perkin-like reaction between 6,7-dimethoxyhomophthalic anhydride and aromatic aldehydes, followed by treatment with BBr3. This synthesis is straightforward and allows polyhydroxylated cis-stilbenes gathering two well-known pharmacophoric fragments to be obtained in good yields and for short reaction times. The structure of the newly synthesized compounds was established by spectroscopic methods ((1)H NMR, (13)C NMR, IR and HRMS) and the double bond configuration was unequivocally elucidated by means of gated decoupling (13)C NMR spectra and 2D NOESY experiments. Preliminary differentiating screening of their radical scavenging, antibacterial, anti-fungal and tyrosinase inhibitory activity was further performed. The results obtained suggest that the tested compounds possess a triple biological action as potent radical scavengers, antifungal agents and tyrosinase inhibitors in micromolar concentration. The most promising bioactive compound amongst the others was 4a, acting as excellent radical scavenger against DPPH(•) radical (IC₅₀ ≤ 10 μM), antifungal agent suppressing the growth of Fusarium graminearum (89% inhibition at 0.17 μmol/mL), and tyrosinase inhibitor showing higher activity than hydroquinone at 23 μM.
|
Antioxidant activity assessed as inhibition of ABTS free radical generation at 17 uM after 20 mins by UV spectrophotometric analysis relative to control
|
None
|
71.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Indole derivatives as dual-effective agents for the treatment of neurodegenerative diseases: synthesis, biological evaluation, and molecular modeling studies.
Year : 2013
Volume : 21
Issue : 15
First Page : 4575
Last Page : 4580
Authors : Buemi MR, De Luca L, Chimirri A, Ferro S, Gitto R, Alvarez-Builla J, Alajarin R.
Abstract : Several indole derivatives, that were highly potent ligands of GluN2B-subunit-containing N-methyl-D-aspartate (NMDA) receptor, also demonstrated antioxidant properties in ABTS method. In particular, the 2-(4-benzylpiperidin-1-yl)-1-(5-hydroxy-1H-indol-3-yl)ethanone (1) proved to be a dual-effective neuroprotective agent. With the aim to increase the antioxidant properties we added a catechol moiety onto piperidine moiety. The designed hybrid derivative 3,4-dihydroxy-N-[1-[2-(5-hydroxy-1H-indol-3-yl)-2-oxoethyl]piperidin-4-yl]benzamide (10) was the most effective antioxidant agent (>94.1 ± 0.1% of inhibition at 17 μM) and showed GluN2B/NMDA receptor affinity at low micromolar concentration (IC₅₀ 0.66 μM). By means of computational studies we explored the effect of the presence of this antioxidant fragment during the recognition process to binding pocket.
|
Antioxidant activity assessed as DPPH radical scavenging activity after 15 mins by spectrophotometry
|
None
|
150.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Quercitylcinnamates, a new series of antidiabetic bioconjugates possessing α-glucosidase inhibition and antioxidant.
Year : 2013
Volume : 66
First Page : 296
Last Page : 304
Authors : Rattanangkool E, Kittikhunnatham P, Damsud T, Wacharasindhu S, Phuwapraisirisan P.
Abstract : Antidiabetic agents possessing dual functions, α-glucosidase inhibition and antioxidant, have been accepted to be more useful than currently used antidiabetic drugs because they not only suppress hyperglycemia but also prevent risk of complications. Herein, we design antidiabetic bioconjugates comprising of (+)-proto-quercitol as a glucomimic and cinnamic analogs as antioxidant moieties. Fifteen quercitylcinnamates were synthesized by direct coupling through ester bond in the presence of DCC and DMAP. Particular quercityl esters 6a, 7a and 8a selectively inhibited rat intestinal maltase and sucrose 4-6 times more potently than their parents 6, 7 and 8. Of synthesized bioconjugates, 6a was the most potent inhibitor against maltase and sucrose with IC₅₀ values of 5.31 and 43.65 μM, respectively. Of interest, its inhibitory potency toward maltase was 6 times greater than its parent, caffeic acid (6), while its radical scavenging (SC₅₀ 0.11 mM) was comparable to that of commercial antioxidant BHA. Subsequent investigation on mechanism underlying inhibitory effect of 6a indicated that it blocked maltase and sucrose functions by mixed inhibition through competitive and noncompetitive manners.
|
Inhibition of yeast type 1 alpha-glucosidase using PNPG as substrate at 10 mg/ml incubated for 10 mins prior to substrate addition measured after 20 mins by spectrophotometry
|
Saccharomyces cerevisiae
|
30.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Quercitylcinnamates, a new series of antidiabetic bioconjugates possessing α-glucosidase inhibition and antioxidant.
Year : 2013
Volume : 66
First Page : 296
Last Page : 304
Authors : Rattanangkool E, Kittikhunnatham P, Damsud T, Wacharasindhu S, Phuwapraisirisan P.
Abstract : Antidiabetic agents possessing dual functions, α-glucosidase inhibition and antioxidant, have been accepted to be more useful than currently used antidiabetic drugs because they not only suppress hyperglycemia but also prevent risk of complications. Herein, we design antidiabetic bioconjugates comprising of (+)-proto-quercitol as a glucomimic and cinnamic analogs as antioxidant moieties. Fifteen quercitylcinnamates were synthesized by direct coupling through ester bond in the presence of DCC and DMAP. Particular quercityl esters 6a, 7a and 8a selectively inhibited rat intestinal maltase and sucrose 4-6 times more potently than their parents 6, 7 and 8. Of synthesized bioconjugates, 6a was the most potent inhibitor against maltase and sucrose with IC₅₀ values of 5.31 and 43.65 μM, respectively. Of interest, its inhibitory potency toward maltase was 6 times greater than its parent, caffeic acid (6), while its radical scavenging (SC₅₀ 0.11 mM) was comparable to that of commercial antioxidant BHA. Subsequent investigation on mechanism underlying inhibitory effect of 6a indicated that it blocked maltase and sucrose functions by mixed inhibition through competitive and noncompetitive manners.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
69.6
%
|
|
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
|
94.0
%
|
|
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.
|
Antiinflammatory activity in rat polymorphonuclear leukocytes assessed as inhibition of PAF-induced release of glucuronidase at 10 uM
|
Rattus norvegicus
|
40.3
%
|
|
Journal : J. Nat. Prod.
Title : Homosecoiridoid alkaloids with amino acid units from the flower buds of Lonicera japonica.
Year : 2013
Volume : 76
Issue : 12
First Page : 2226
Last Page : 2233
Authors : Yu Y, Zhu C, Wang S, Song W, Yang Y, Shi J.
Abstract : Nine new homosecoiridoid alkaloids, named lonijaposides O-W (1-9), along with 19 known compounds, were isolated from an aqueous extract of the flower buds of Lonicera japonica. Their structures and absolute configurations were determined by spectroscopic data analysis and chemical methods. Lonijaposides O-W have structural features that involve amino acid units sharing the N atom with a pyridinium (1-5) or nicotinic acid (6-9) moiety. The absolute configurations of the amino acid units were determined by oxidation of each pyridinium ring moiety with potassium ferricyanide, hydrolysis of the oxidation product, and Marfey's analysis of the hydrolysate. This procedure was validated by oxidizing and hydrolyzing synthetic model compounds. The phenylalanine units in compounds 4, 5, and 9 have the d-configuration, and the other amino acid units in 1-3 and 6-8 possess the l-configuration. Compounds 1, 4, 6, and 9 and the known compounds 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, and 5'-O-methyladenosine exhibited antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2) with IC50 values of 3.4-11.6 μM, and 4 inhibited Coxsackie virus B3 replication with an IC50 value of 12.3 μM.
|
Antioxidant activity of the compound assessed as inhibition of ABTS radicals at 17 uM after 20 mins by spectrophotometric analysis
|
None
|
71.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, modelling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors.
Year : 2014
Volume : 22
Issue : 3
First Page : 1040
Last Page : 1048
Authors : Gitto R, De Luca L, Ferro S, Russo E, De Sarro G, Chisari M, Ciranna L, Alvarez-Builla J, Alajarin R, Buemi MR, Chimirri A.
Abstract : A three-step synthetic pathway has been employed to synthesize a small library of 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethanone and 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethane-1,2-dione derivatives that have been screened in [(3)H]ifenprodil competition binding assay. Some compounds exhibited significant binding affinity at nanomolar concentration, the most active being ligand 35 (IC50=5.5nM). Docking experiments suggested the main interactions between 35 and GluN2B-containing NMDA receptors. Notably, the compound 35 reduced NMDA-mediated excitatory post-synaptic currents recorded in mouse hippocampal slices indicating antagonistic effects (50nM). Moreover, the compound 35 has shown antioxidant effects in a preliminary screening, thus suggesting that it might be considered prototype for future drug development of novel 'dual target' neuroprotective agents.
|
Antioxidant activity of the compound assessed as inhibition of ABTS radicals at 33 uM after 20 mins by spectrophotometric analysis
|
None
|
93.4
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, modelling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors.
Year : 2014
Volume : 22
Issue : 3
First Page : 1040
Last Page : 1048
Authors : Gitto R, De Luca L, Ferro S, Russo E, De Sarro G, Chisari M, Ciranna L, Alvarez-Builla J, Alajarin R, Buemi MR, Chimirri A.
Abstract : A three-step synthetic pathway has been employed to synthesize a small library of 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethanone and 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethane-1,2-dione derivatives that have been screened in [(3)H]ifenprodil competition binding assay. Some compounds exhibited significant binding affinity at nanomolar concentration, the most active being ligand 35 (IC50=5.5nM). Docking experiments suggested the main interactions between 35 and GluN2B-containing NMDA receptors. Notably, the compound 35 reduced NMDA-mediated excitatory post-synaptic currents recorded in mouse hippocampal slices indicating antagonistic effects (50nM). Moreover, the compound 35 has shown antioxidant effects in a preliminary screening, thus suggesting that it might be considered prototype for future drug development of novel 'dual target' neuroprotective agents.
|
Antioxidant activity assessed as DPPH radical scavenging activity at 10 uM after 60 mins by spectrophotometry
|
None
|
44.1
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD.
Year : 2015
Volume : 25
Issue : 4
First Page : 807
Last Page : 810
Authors : Digiacomo M, Chen Z, Wang S, Lapucci A, Macchia M, Yang X, Chu J, Han Y, Pi R, Rapposelli S.
Abstract : A novel series of tacrine derivatives were designed and synthesized by combining caffeic acid (CA), ferulic acid (FA) and lipoic acid (LA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to CA. Among these compounds, 1b possessed a good ability to inhibit the β-amyloid protein (Aβ) self-aggregation, sub-micromole acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitory, modest BACE1 inhibitory. Moreover, compound 1b also was a DPPH radical scavenger and copper chelatory as well as had potent neuroprotective effects against glutamate-induced cell death with low toxicity in HT22 cells. Our findings suggest that the compound 1b might be a promising lead multi-targeted ligand and worthy of further developing for the therapy of Alzheimer's disease.
|
Antioxidant activity assessed as DPPH radical scavenging activity at 30 uM after 60 mins by spectrophotometry
|
None
|
90.27
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD.
Year : 2015
Volume : 25
Issue : 4
First Page : 807
Last Page : 810
Authors : Digiacomo M, Chen Z, Wang S, Lapucci A, Macchia M, Yang X, Chu J, Han Y, Pi R, Rapposelli S.
Abstract : A novel series of tacrine derivatives were designed and synthesized by combining caffeic acid (CA), ferulic acid (FA) and lipoic acid (LA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to CA. Among these compounds, 1b possessed a good ability to inhibit the β-amyloid protein (Aβ) self-aggregation, sub-micromole acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitory, modest BACE1 inhibitory. Moreover, compound 1b also was a DPPH radical scavenger and copper chelatory as well as had potent neuroprotective effects against glutamate-induced cell death with low toxicity in HT22 cells. Our findings suggest that the compound 1b might be a promising lead multi-targeted ligand and worthy of further developing for the therapy of Alzheimer's disease.
|
Inhibition of Pseudomonas aeruginosa recombinant PqsD expressed in Escherichia coli BL21 (lambdaDE3) using ACoA/beta-ketodecanoic acid as substrate at 50 uM after 10 mins
|
Pseudomonas aeruginosa
|
26.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD.
Year : 2015
Volume : 90
First Page : 351
Last Page : 359
Authors : Allegretta G, Weidel E, Empting M, Hartmann RW.
Abstract : A new strategy for treating Pseudomonas aeruginosa infections could be disrupting the Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system. The goal is to impair communication among the cells and, hence, reduce the expression of virulence factors and the formation of biofilms. PqsD is an essential enzyme for the synthesis of PQS and shares some features with chalcone synthase (CHS2), an enzyme expressed in Medicago sativa. Both proteins are quite similar concerning the size of the active site, the catalytic residues and the electrostatic surface potential at the entrance of the substrate tunnel. Hence, we evaluated selected substrates of the vegetable enzyme as potential inhibitors of the bacterial protein. This similarity-guided approach led to the identification of a new class of PqsD inhibitors having a catechol structure as an essential feature for activity, a saturated linker with two or more carbons and an ester moiety bearing bulky substituents. The developed compounds showed PqsD inhibition with IC50 values in the single-digit micromolar range. The binding mode of these compounds was investigated by Surface Plasmon Resonance (SPR) experiments revealing that their interaction with the protein is not influenced by the presence of the anthranilic acid bound to active site cysteine. Importantly, some compounds reduced the signal molecule production in cellulo.
|
Inhibition of Pseudomonas aeruginosa PA14 PqsH transposon mutant assessed as extracellular level of HHQ at 500 uM after 16 hrs
|
Pseudomonas aeruginosa PA14
|
10.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD.
Year : 2015
Volume : 90
First Page : 351
Last Page : 359
Authors : Allegretta G, Weidel E, Empting M, Hartmann RW.
Abstract : A new strategy for treating Pseudomonas aeruginosa infections could be disrupting the Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system. The goal is to impair communication among the cells and, hence, reduce the expression of virulence factors and the formation of biofilms. PqsD is an essential enzyme for the synthesis of PQS and shares some features with chalcone synthase (CHS2), an enzyme expressed in Medicago sativa. Both proteins are quite similar concerning the size of the active site, the catalytic residues and the electrostatic surface potential at the entrance of the substrate tunnel. Hence, we evaluated selected substrates of the vegetable enzyme as potential inhibitors of the bacterial protein. This similarity-guided approach led to the identification of a new class of PqsD inhibitors having a catechol structure as an essential feature for activity, a saturated linker with two or more carbons and an ester moiety bearing bulky substituents. The developed compounds showed PqsD inhibition with IC50 values in the single-digit micromolar range. The binding mode of these compounds was investigated by Surface Plasmon Resonance (SPR) experiments revealing that their interaction with the protein is not influenced by the presence of the anthranilic acid bound to active site cysteine. Importantly, some compounds reduced the signal molecule production in cellulo.
|
Inhibition of human purified MPG pre-incubated with compound for 10 mins followed by addition of 1,N6 ethenoadenine containing 32P-labeled duplex oligonucleotide substrates at 20 uM by gel-based excision activity assay
|
Homo sapiens
|
0.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Naturally occurring polyphenol, morin hydrate, inhibits enzymatic activity of N-methylpurine DNA glycosylase, a DNA repair enzyme with various roles in human disease.
Year : 2015
Volume : 23
Issue : 5
First Page : 1102
Last Page : 1111
Authors : Dixon M, Woodrick J, Gupta S, Karmahapatra SK, Devito S, Vasudevan S, Dakshanamurthy S, Adhikari S, Yenugonda VM, Roy R.
Abstract : Interest in the mechanisms of DNA repair pathways, including the base excision repair (BER) pathway specifically, has heightened since these pathways have been shown to modulate important aspects of human disease. Modulation of the expression or activity of a particular BER enzyme, N-methylpurine DNA glycosylase (MPG), has been demonstrated to play a role in carcinogenesis and resistance to chemotherapy as well as neurodegenerative diseases, which has intensified the focus on studying MPG-related mechanisms of repair. A specific small molecule inhibitor for MPG activity would be a valuable biochemical tool for understanding these repair mechanisms. By screening several small molecule chemical libraries, we identified a natural polyphenolic compound, morin hydrate, which inhibits MPG activity specifically (IC50=2.6μM). Detailed mechanism analysis showed that morin hydrate inhibited substrate DNA binding of MPG, and eventually the enzymatic activity of MPG. Computational docking studies with an x-ray derived MPG structure as well as comparison studies with other structurally-related flavonoids offer a rationale for the inhibitory activity of morin hydrate observed. The results of this study suggest that the morin hydrate could be an effective tool for studying MPG function and it is possible that morin hydrate and its derivatives could be utilized in future studies focused on the role of MPG in human disease.
|
Antioxidant activity assessed as inhibition of AAPH-induced lipid peroxidation at 200 ug/ml after 3 hrs by TBA-MDA test
|
None
|
99.98
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, electronic properties, antioxidant and antibacterial activity of some new benzimidazoles.
Year : 2015
Volume : 23
Issue : 19
First Page : 6317
Last Page : 6326
Authors : Mavrova ATs, Yancheva D, Anastassova N, Anichina K, Zvezdanovic J, Djordjevic A, Markovic D, Smelcerovic A.
Abstract : Two groups of benzimidazole derivatives were synthesized using as precursors 5(6)-substituted 2-mercapto-benzimidazol-thiols and their antioxidant activity was investigated using TBA-MDA test. In the group of 1,3-disubstituted-benzimidazol-2-imines the highest lipid peroxidation inhibition effect 74.04% (IC₅₀=141.89 μg/mL) revealed ethyl [3-(2-ethoxy-2-oxoethyl)-2-imino-5-benzoyl-2,3-dihydro-1H-benzimdazol-1-yl]acetate 12 while in the group of 2-substituted-1,3-thiazolo[3,2-a]benzimidazolones the highest inhibition effect showed 2-(4-fluorobenzylidene)-7-(phenylcarbonyl)[1,3]thiazolo[3,2-a]benzimidazol-3(2H)-one 17 90.76% (IC₅₀=53.70 μg/mL). In order to estimate the capability of the studied benzimidazoles to act as radical scavengers the structure of the most active derivative within the both subseries was optimized at B3LYP/6-311++G(∗∗) level and the respective bond dissociation enthalpies were calculated. The appropriate models for the HAT and SET-mechanism of the antioxidant activity were proposed. The antibacterial activity of the compounds was evaluated against two Gram-positive bacteria (Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538) and three Gram-negative bacteria (Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027 and Salmonella abony NCTC 6017). 1,3-Diphenylpropyl-5-methyl-1,3-dihydro-2H-benzimidazol-2-imine 14 exhibited significant activity against B. subtilis, S. aureus, S. abony and E. coli (with MIC values of 0.125, 0.016, 0.50 and 0.50mg/mL, respectively). The group of thiazolobenzimidazolones did not reveal antibacterial activity against the tested strains.
|
Antioxidant activity assessed as inhibition of AAPH-induced lipid peroxidation after 3 hrs by TBA-MDA test
|
None
|
3.79
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, electronic properties, antioxidant and antibacterial activity of some new benzimidazoles.
Year : 2015
Volume : 23
Issue : 19
First Page : 6317
Last Page : 6326
Authors : Mavrova ATs, Yancheva D, Anastassova N, Anichina K, Zvezdanovic J, Djordjevic A, Markovic D, Smelcerovic A.
Abstract : Two groups of benzimidazole derivatives were synthesized using as precursors 5(6)-substituted 2-mercapto-benzimidazol-thiols and their antioxidant activity was investigated using TBA-MDA test. In the group of 1,3-disubstituted-benzimidazol-2-imines the highest lipid peroxidation inhibition effect 74.04% (IC₅₀=141.89 μg/mL) revealed ethyl [3-(2-ethoxy-2-oxoethyl)-2-imino-5-benzoyl-2,3-dihydro-1H-benzimdazol-1-yl]acetate 12 while in the group of 2-substituted-1,3-thiazolo[3,2-a]benzimidazolones the highest inhibition effect showed 2-(4-fluorobenzylidene)-7-(phenylcarbonyl)[1,3]thiazolo[3,2-a]benzimidazol-3(2H)-one 17 90.76% (IC₅₀=53.70 μg/mL). In order to estimate the capability of the studied benzimidazoles to act as radical scavengers the structure of the most active derivative within the both subseries was optimized at B3LYP/6-311++G(∗∗) level and the respective bond dissociation enthalpies were calculated. The appropriate models for the HAT and SET-mechanism of the antioxidant activity were proposed. The antibacterial activity of the compounds was evaluated against two Gram-positive bacteria (Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538) and three Gram-negative bacteria (Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027 and Salmonella abony NCTC 6017). 1,3-Diphenylpropyl-5-methyl-1,3-dihydro-2H-benzimidazol-2-imine 14 exhibited significant activity against B. subtilis, S. aureus, S. abony and E. coli (with MIC values of 0.125, 0.016, 0.50 and 0.50mg/mL, respectively). The group of thiazolobenzimidazolones did not reveal antibacterial activity against the tested strains.
|
Inhibition of phorbol myristate acetate-induced human neutrophils oxidative burst assessed as reduction in luminol oxidation up to 200 uM preincubated for 5 mins followed by PMA addition measured after 15 mins by chemiluminescence assay
|
Homo sapiens
|
44.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Combined dual effect of modulation of human neutrophils' oxidative burst and inhibition of colon cancer cells proliferation by hydroxycinnamic acid derivatives.
Year : 2016
Volume : 24
Issue : 16
First Page : 3556
Last Page : 3564
Authors : Tavares-da-Silva EJ, Varela CL, Pires AS, Encarnação JC, Abrantes AM, Botelho MF, Carvalho RA, Proença C, Freitas M, Fernandes E, Roleira FM.
Abstract : Colon cancer is one of the most incident cancers in the Western World. While both genetic and epigenetic factors may contribute to the development of colon cancer, it is known that chronic inflammation associated to excessive production of reactive oxygen and nitrogen species by phagocytes may ultimately initiate the multistep process of colon cancer development. Phenolic compounds, which reveal antioxidant and antiproliferative activities in colon cancer cells, can be a good approach to surpass this problem. In this work, hydroxycinnamic amides and the respective acid precursors were tested in vitro for their capacity to modulate human neutrophils' oxidative burst and simultaneously to inhibit growth of colon cancer cells. A phenolic amide derivative, caffeic acid hexylamide (CAHA) (4) was found to be the most active compound in both assays, inhibiting human neutrophils' oxidative burst, restraining the inflammatory process, inhibiting growth of colon cancer cells and triggering mitochondrial dysfunction that leads cancer cells to apoptosis. Altogether, these achievements can contribute to the understanding of the relationship between antioxidant and anticancer activities and based on the structure-activity relationships (SAR) established can be the starting point to find more effective phenolic compounds as anticancer agents.
|
Inhibition of phorbol myristate acetate-induced superoxide radical generation in human neutrophils at 100 uM preincubated for 5 mins followed by PMA addition by lucigenin chemiluminescence assay
|
Homo sapiens
|
84.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Combined dual effect of modulation of human neutrophils' oxidative burst and inhibition of colon cancer cells proliferation by hydroxycinnamic acid derivatives.
Year : 2016
Volume : 24
Issue : 16
First Page : 3556
Last Page : 3564
Authors : Tavares-da-Silva EJ, Varela CL, Pires AS, Encarnação JC, Abrantes AM, Botelho MF, Carvalho RA, Proença C, Freitas M, Fernandes E, Roleira FM.
Abstract : Colon cancer is one of the most incident cancers in the Western World. While both genetic and epigenetic factors may contribute to the development of colon cancer, it is known that chronic inflammation associated to excessive production of reactive oxygen and nitrogen species by phagocytes may ultimately initiate the multistep process of colon cancer development. Phenolic compounds, which reveal antioxidant and antiproliferative activities in colon cancer cells, can be a good approach to surpass this problem. In this work, hydroxycinnamic amides and the respective acid precursors were tested in vitro for their capacity to modulate human neutrophils' oxidative burst and simultaneously to inhibit growth of colon cancer cells. A phenolic amide derivative, caffeic acid hexylamide (CAHA) (4) was found to be the most active compound in both assays, inhibiting human neutrophils' oxidative burst, restraining the inflammatory process, inhibiting growth of colon cancer cells and triggering mitochondrial dysfunction that leads cancer cells to apoptosis. Altogether, these achievements can contribute to the understanding of the relationship between antioxidant and anticancer activities and based on the structure-activity relationships (SAR) established can be the starting point to find more effective phenolic compounds as anticancer agents.
|
Antioxidant activity assessed as inhibition of allopurinol-xanthine oxidase system-mediated superoxide formation measured over 7 mins by lucigenin-based chemiluminescence analysis
|
None
|
100.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : On the vasoprotective mechanisms underlying novel β-phosphorylated nitrones: Focus on free radical characterization, scavenging and NO-donation in a biological model of oxidative stress.
Year : 2016
Volume : 119
First Page : 197
Last Page : 217
Authors : Cassien M, Petrocchi C, Thétiot-Laurent S, Robin M, Ricquebourg E, Kandouli C, Asteian A, Rockenbauer A, Mercier A, Culcasi M, Pietri S.
Abstract : A series of new hybrid 2-(diethoxyphosphoryl)-N-(benzylidene)propan-2-amine oxide derivatives with different aromatic substitution (PPNs) were synthesized. These molecules were evaluated for their EPR spin trapping potential on eleven different radicals and NO-donation properties in vitro, cytotoxicity and vasoprotective effect on precontracted rat aortic rings. A subfamily of the new PPNs featured an antioxidant moiety occurring in natural phenolic acids. From the experimental screening of these hydroxyphenyl- and methoxyphenyl-substituted PPNs, biocompatible nitrones 4d, and 4g-4i deriving from caffeic, gallic, ferulic and sinapic acids, which combined improved EPR probing of ROS formation, vasorelaxant action and antioxidant potency, might be potential drug candidate alternatives to PBN and its analogues.
|
Inhibition of Malassezia globosa recombinant beta-carbonic anhydrase preincubated for 15 mins prior to testing measured for 10 to 100 secs by phenol red-based stopped-flow CO2 hydration assay
|
Malassezia globosa
|
600.0
nM
|
|
Journal : Bioorg Med Chem
Title : Inhibition of Malassezia globosa carbonic anhydrase with phenols.
Year : 2017
Volume : 25
Issue : 9
First Page : 2577
Last Page : 2582
Authors : Entezari Heravi Y, Bua S, Nocentini A, Del Prete S, Saboury AA, Sereshti H, Capasso C, Gratteri P, Supuran CT.
Abstract : A panel of 22 phenols was investigated as inhibitors of the β-class carbonic anhydrase (CAs, EC 4.2.1.1) from the fungal parasite Malassezia globosa (MgCA), a validated anti-dandruff drug target. The displayed inhibitory activities were compared to the ones previously reported against the off-target widely distributed human (h) isoforms hCA I and II. All tested phenols possessed a better efficacy in inhibiting MgCA than the clinically used sulfonamide acetazolamide, with KIs in the range of 2.5 and 65.0μM. A homology-built model of MgCA was also used for understanding the binding mode of phenols to the fungal enzyme. Indeed, a wide network of hydrogen bonds and hydrophobic interactions between the phenol and active site residues were evidenced. The OH moiety of the inhibitor was observed anchored to the zinc-coordinated water, also making hydrogen bonds with Ser48 and Asp49. The diverse substituents at the phenolic scaffold were observed to interact with different portions of the hydrophobic pocket according to their nature and position. Considering the effective MgCA inhibitory properties of phenols, beside to the rather low inhibition against the off-target hCA I and II, this class of compounds might be of considerable interest in the cosmetics field as potential anti-dandruff drugs.
|
Inhibition of butter milk XOD (unknown origin) at 10 uM using xanthine as substrate after 8 mins relative to control
|
Not specified
|
10.0
%
|
|
Journal : Eur J Med Chem
Title : Structure-activity relations of rosmarinic acid derivatives for the amyloid β aggregation inhibition and antioxidant properties.
Year : 2017
Volume : 138
First Page : 1066
Last Page : 1075
Authors : Taguchi R, Hatayama K, Takahashi T, Hayashi T, Sato Y, Sato D, Ohta K, Nakano H, Seki C, Endo Y, Tokuraku K, Uwai K.
Abstract : Amyloid-β aggregation inhibitors are expected to be therapeutic or prophylactic agents for Alzheimer's disease. Rosmarinic acid, which is one of the main aggregation inhibitors derived from Lamiaceae, was employed as a lead compound and its 25 derivatives were synthesized. In this study, the structure-activity relations of rosmarinic acid derivatives for the amyloid-β aggregation inhibitory effect (MSHTS assay), antioxidant properties, and xanthine oxidase inhibition were evaluated. Among the tested compounds, compounds 16d and 19 were found to the most potent amyloid aggregation inhibitors. The SAR revealed that the necessity of the presence of the phenolic hydroxyl on one side of the molecule as well as the lipophilicity of the entire molecule. The importance of these structural properties was also supported by docking simulations.
|
Inhibition of butter milk XOD (unknown origin) at 100 uM using xanthine as substrate after 8 mins relative to control
|
Not specified
|
10.0
%
|
|
Journal : Eur J Med Chem
Title : Structure-activity relations of rosmarinic acid derivatives for the amyloid β aggregation inhibition and antioxidant properties.
Year : 2017
Volume : 138
First Page : 1066
Last Page : 1075
Authors : Taguchi R, Hatayama K, Takahashi T, Hayashi T, Sato Y, Sato D, Ohta K, Nakano H, Seki C, Endo Y, Tokuraku K, Uwai K.
Abstract : Amyloid-β aggregation inhibitors are expected to be therapeutic or prophylactic agents for Alzheimer's disease. Rosmarinic acid, which is one of the main aggregation inhibitors derived from Lamiaceae, was employed as a lead compound and its 25 derivatives were synthesized. In this study, the structure-activity relations of rosmarinic acid derivatives for the amyloid-β aggregation inhibitory effect (MSHTS assay), antioxidant properties, and xanthine oxidase inhibition were evaluated. Among the tested compounds, compounds 16d and 19 were found to the most potent amyloid aggregation inhibitors. The SAR revealed that the necessity of the presence of the phenolic hydroxyl on one side of the molecule as well as the lipophilicity of the entire molecule. The importance of these structural properties was also supported by docking simulations.
|
Antioxidant activity assessed as inhibition of DPPH radical at 100 uM incubated for 20 mins measured for 60 mins relative to control
|
None
|
49.0
%
|
|
Journal : Eur J Med Chem
Title : Structure-activity relations of rosmarinic acid derivatives for the amyloid β aggregation inhibition and antioxidant properties.
Year : 2017
Volume : 138
First Page : 1066
Last Page : 1075
Authors : Taguchi R, Hatayama K, Takahashi T, Hayashi T, Sato Y, Sato D, Ohta K, Nakano H, Seki C, Endo Y, Tokuraku K, Uwai K.
Abstract : Amyloid-β aggregation inhibitors are expected to be therapeutic or prophylactic agents for Alzheimer's disease. Rosmarinic acid, which is one of the main aggregation inhibitors derived from Lamiaceae, was employed as a lead compound and its 25 derivatives were synthesized. In this study, the structure-activity relations of rosmarinic acid derivatives for the amyloid-β aggregation inhibitory effect (MSHTS assay), antioxidant properties, and xanthine oxidase inhibition were evaluated. Among the tested compounds, compounds 16d and 19 were found to the most potent amyloid aggregation inhibitors. The SAR revealed that the necessity of the presence of the phenolic hydroxyl on one side of the molecule as well as the lipophilicity of the entire molecule. The importance of these structural properties was also supported by docking simulations.
|
Antioxidant activity assessed as inhibition of DPPH radical at 500 uM incubated for 20 mins measured for 60 mins relative to control
|
None
|
63.0
%
|
|
Journal : Eur J Med Chem
Title : Structure-activity relations of rosmarinic acid derivatives for the amyloid β aggregation inhibition and antioxidant properties.
Year : 2017
Volume : 138
First Page : 1066
Last Page : 1075
Authors : Taguchi R, Hatayama K, Takahashi T, Hayashi T, Sato Y, Sato D, Ohta K, Nakano H, Seki C, Endo Y, Tokuraku K, Uwai K.
Abstract : Amyloid-β aggregation inhibitors are expected to be therapeutic or prophylactic agents for Alzheimer's disease. Rosmarinic acid, which is one of the main aggregation inhibitors derived from Lamiaceae, was employed as a lead compound and its 25 derivatives were synthesized. In this study, the structure-activity relations of rosmarinic acid derivatives for the amyloid-β aggregation inhibitory effect (MSHTS assay), antioxidant properties, and xanthine oxidase inhibition were evaluated. Among the tested compounds, compounds 16d and 19 were found to the most potent amyloid aggregation inhibitors. The SAR revealed that the necessity of the presence of the phenolic hydroxyl on one side of the molecule as well as the lipophilicity of the entire molecule. The importance of these structural properties was also supported by docking simulations.
|
Antioxidant activity assessed as DPPH free radical scavenging activity
|
None
|
47.8
nM
|
|
Journal : Eur J Med Chem
Title : Free radicals and polyphenols: The redox chemistry of neurodegenerative diseases.
Year : 2017
Volume : 133
First Page : 379
Last Page : 402
Authors : Losada-Barreiro S, Bravo-Díaz C.
Abstract : The oxidation of bioorganic materials by air and, particularly, the oxidative stress involved in the cell loss and other pathologies associated with neurodegenerative diseases (NDs) are of enormous social and economic importance. NDs generally involve free radical reactions, beginning with the formation of an initiating radical by some redox, thermal or photochemical process, causing nucleic acid, protein and lipid oxidations and the production of harmful oxidative products. Physically, persons afflicted by NDs suffer progressive loss of memory and thinking ability, mood swings, personality changes, and loss of independence. Therefore, the development of antioxidant strategies to retard or minimize the oxidative degradation of bioorganic materials has been, and still is, of paramount importance. While we are aware of the importance of investigating the biological and medical aspects of the diseases, elucidation of the associated chemistry is crucial to understanding their progression, heading to intelligent chemical intervention to find more efficient therapies to prevent or delay the onset of the diseases. Accordingly, this review aims to provide the reader with a chemical base to understand the behavior and properties of the reactive oxygen species involved and of typical radical scavengers such as polyphenolic antioxidants. Some discussion on the structures of the various species, their formation, chemical reactivities and lifetimes is included. The ultimate goal is to understand how, when and where they form, how far they travel prior to react, which molecules are their targets, and how we can, eventually, control their activity to minimize their impact by means of chemical methods. Recent strategies explore chemical modifications of the hydrophobicity of potent, natural antioxidants to improve their efficiency by fine-tuning their concentrations at the reaction site.
|
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
|
4.45
%
|
|
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.
|
Inhibition of human TAS2R39 expressed in HEK293 cells coexpressing G-protein at 10 mM assessed as reduction in epicatechin gallate-induced intracellular calcium release by Fluo-4-AM dye based fluorescence assay relative to control
|
Homo sapiens
|
30.0
%
|
|
Title : Flavan-3-ol containing foodstuffs
|
Inhibition of MB-COMT in Wistar rat brain assessed as metanephrine formation preincubated for 20 mins followed by addition of adrenaline as substrate and SAM measured after 15 mins by chromatographic analysis
|
Rattus norvegicus
|
92.82
nM
|
|
Journal : J Med Chem
Title : Development of Blood-Brain Barrier Permeable Nitrocatechol-Based Catechol O-Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity.
Year : 2016
Volume : 59
Issue : 16
First Page : 7584
Last Page : 7597
Authors : Silva T, Mohamed T, Shakeri A, Rao PP, Martínez-González L, Pérez DI, Martínez A, Valente MJ, Garrido J, Uriarte E, Serrão P, Soares-da-Silva P, Remião F, Borges F.
Abstract : Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood-brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 μM with rat primary hepatocytes. Moreover, their unique acidity and electrochemical properties decreased the chances of formation of reactive quinone-imines and, as such, the potential for hepatotoxicity. The binding mode of 16 confirmed that the major interactions with COMT were established via the nitrocatechol ring, allowing derivatization of the side chain for future lead optimization efforts.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.6
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-26.34
%
|
|
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
|
0.02
%
|
|
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
|
-0.12
%
|
|
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
|
-0.12
%
|
|
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
|
0.02
%
|
|
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.
|
Displacement of [125-I]-[Sar1, AngII from AT1R (unknown origin) expressed in Escherichia coli BL 21 (DE3) incubated for 2 hrs by radioimmunoassay
|
Homo sapiens
|
124.6
nM
|
|
