|
Compound was evaluated for percent inhibition of carrageenan induced rat paw edema at 0.005 mmol/kg
|
Rattus norvegicus
|
30.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage.
Year : 2004
Volume : 14
Issue : 3
First Page : 611
Last Page : 614
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.
|
Compound was evaluated for in vitro inhibition of chymotrypsinogen acting as esterase at 0.1 mM concentration
|
None
|
28.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage.
Year : 2004
Volume : 14
Issue : 3
First Page : 611
Last Page : 614
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.
|
Compound was evaluated for in vitro inhibition of chymotrypsinogen acting as esterase at 1 mM concentration
|
None
|
63.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage.
Year : 2004
Volume : 14
Issue : 3
First Page : 611
Last Page : 614
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.
|
Compound was evaluated for in vitro inhibition of chymotrypsinogen induced proteolysis at 1 mM concentration
|
None
|
89.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage.
Year : 2004
Volume : 14
Issue : 3
First Page : 611
Last Page : 614
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.
|
Compound was evaluated for in vitro inhibition of soybean lipoxygenase at 1 mM concentration
|
None
|
15.1
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage.
Year : 2004
Volume : 14
Issue : 3
First Page : 611
Last Page : 614
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.
|
In vitro inhibition of sirtuin 2 was evaluated using yeast whole cell lysates at 75 uM
|
None
|
0.74
uM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of Sir2: evaluation of splitomicin analogues.
Year : 2004
Volume : 47
Issue : 10
First Page : 2635
Last Page : 2644
Authors : Posakony J, Hirao M, Stevens S, Simon JA, Bedalov A.
Abstract : Splitomicin (1) and 41 analogues were prepared and evaluated in cell-based Sir2 inhibition and toxicity assays and an in vitro Sir2 inhibition assay. Lactone ring or naphthalene (positions 7-9) substituents decrease activity, but other naphthalene substitutions (positions 5 and 6) are well-tolerated. The hydrolytically unstable aromatic lactone is important for activity. Lactone hydrolysis rates were used as a measure of reactivity; hydrolysis rates correlate with inhibitory activity. The most potent Sir2 inhibitors were structurally similar to and had hydrolysis rates similar to 1.
|
Compound was evaluated for in vitro inhibition of trypsin acting as esterase at 0.1 mM concentration
|
None
|
5.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage.
Year : 2004
Volume : 14
Issue : 3
First Page : 611
Last Page : 614
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.
|
Compound was evaluated for in vitro inhibition of trypsin acting as esterase at 1 mM concentration
|
None
|
98.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage.
Year : 2004
Volume : 14
Issue : 3
First Page : 611
Last Page : 614
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.
|
Compound was evaluated for in vitro inhibition of trypsin induced proteolysis at 0.1 mM concentration
|
None
|
12.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage.
Year : 2004
Volume : 14
Issue : 3
First Page : 611
Last Page : 614
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.
|
Compound was evaluated for in vitro inhibition of trypsin induced proteolysis at 1 mM concentration
|
None
|
95.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage.
Year : 2004
Volume : 14
Issue : 3
First Page : 611
Last Page : 614
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.
|
Inhibitory concentration against soybean lipoxygenase upon incubation with sodium linoleate (0.1 mM) at RT
|
Glycine max
|
15.1
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiinflammatory activity of coumarin derivatives.
Year : 2005
Volume : 48
Issue : 20
First Page : 6400
Last Page : 6408
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several coumarin Mannich bases is described. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity was determined experimentally by RPTLC method. All compounds were evaluated for their antiinflammatory and antioxidant activity and for their ability to inhibit in vitro lipoxygenase. The derivatives were found to present antioxidant and antiinflammatory activities. The tested derivatives inhibited carraggeenin-induced hind paw edema. They also significantly suppressed the arthritis induced by Freund's adjuvant. Compound 10, the most active in vivo, was found to possess protective properties against adjuvant-induced arthritis in rats. The biological in vitro activities were concentration dependent. Hydrophilicity, the presence of a free 7-OH, and steric requirements for the substituent at position 8 are the most important factors in terms of SAR. An attempt was made to correlate several physicochemical properties of the molecules with their in vivo/in vitro activity.
|
Percent inhibition of carrageenan 2% (0.1 mL intradermal) induced paw edema at the i.p. dose of 0.01 m mol/kg in fisher 344 rats; n=5
|
Rattus norvegicus
|
30.2
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiinflammatory activity of coumarin derivatives.
Year : 2005
Volume : 48
Issue : 20
First Page : 6400
Last Page : 6408
Authors : Kontogiorgis CA, Hadjipavlou-Litina DJ.
Abstract : The synthesis of several coumarin Mannich bases is described. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity was determined experimentally by RPTLC method. All compounds were evaluated for their antiinflammatory and antioxidant activity and for their ability to inhibit in vitro lipoxygenase. The derivatives were found to present antioxidant and antiinflammatory activities. The tested derivatives inhibited carraggeenin-induced hind paw edema. They also significantly suppressed the arthritis induced by Freund's adjuvant. Compound 10, the most active in vivo, was found to possess protective properties against adjuvant-induced arthritis in rats. The biological in vitro activities were concentration dependent. Hydrophilicity, the presence of a free 7-OH, and steric requirements for the substituent at position 8 are the most important factors in terms of SAR. An attempt was made to correlate several physicochemical properties of the molecules with their in vivo/in vitro activity.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-aminoanthracene-induced mutation at 600 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
22.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-aminoanthracene-induced mutation at 300 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
0.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-aminoanthracene-induced mutation at 150 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
0.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of acetylaminofluorene-induced mutation at 600 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
36.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of acetylaminofluorene-induced mutation at 300 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
28.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of acetylaminofluorene-induced mutation at 150 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
5.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of benzo[a]pyrene-induced mutation at 600 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
53.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of benzo[a]pyrene-induced mutation at 300 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
16.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of benzo[a]pyrene-induced mutation at 150 ug/plate after 72 hrs in presence of Ames S-9 fraction
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
10.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-nitroflorene-induced mutation at 600 ug/plate after 72 hrs
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
73.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-nitroflorene-induced mutation at 300 ug/plate after 72 hrs
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
17.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Antimutagenic activity in Salmonella Typhimurium T98 assessed as inhibition of 2-nitroflorene-induced mutation at 150 ug/plate after 72 hrs
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
24.0
%
|
|
Journal : J. Nat. Prod.
Title : Plant antimutagenic agents, 3. Coumarins.
Year : 1988
Volume : 51
Issue : 6
First Page : 1148
Last Page : 1152
Authors : Wall ME, Wani MC, Manikumar G, Hughes TJ, Taylor H, McGivney R, Warner J.
Abstract : Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.
|
Inhibition of COX2 at 100 uM by scintillation proximity assay
|
None
|
30.0
%
|
|
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.
|
Pesticidal activity against Dermatophagoides pteronyssinus after 24 hrs
|
Dermatophagoides pteronyssinus
|
0.032
g/m2
|
|
Journal : J. Nat. Prod.
Title : Acaricidal activity of tonka bean extracts. Synthesis and structure-activity relationships of bioactive derivatives.
Year : 2003
Volume : 66
Issue : 5
First Page : 690
Last Page : 692
Authors : Gleye C, Lewin G, Laurens A, Jullian JC, Loiseau P, Bories C, Hocquemiller R.
Abstract : The acaricidal effects of tonka bean, Dipterix odorata, extracts were investigated on Dermatophagoides pteronyssinus, the European house dust mite, and compared with benzyl benzoate as a standard acaricidal compound. A cyclohexane extract was the most effective, with an EC(50) = 0.075 g/m(2) after a 24 h period, as compared with benzyl benzoate (0.025 g/m(2)). Bioassay-guided fractionation of this extract led to the isolation of coumarin (1). Pharmacomodulation of this compound led us to test 20 analogues (2-21), which were either synthesized or purchased.
|
Inhibition of soybean lipoxygenase at 100 uM by UV absorbance based assay
|
Glycine max
|
15.0
%
|
|
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.
|
Antiinflammatory activity in rat assessed as inhibition of carrageenan-induced paw edema at 0.01 mmol/kg, ip after 3.5 hrs
|
Rattus norvegicus
|
30.0
%
|
|
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.
|
Inhibition of human carbonic anhydrase 14 by stopped flow CO2 hydration assay
|
Homo sapiens
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins.
Year : 2010
Volume : 53
Issue : 1
First Page : 335
Last Page : 344
Authors : Maresca A, Temperini C, Pochet L, Masereel B, Scozzafava A, Supuran CT.
Abstract : Coumarin derivatives were recently shown to constitute a totally new class of inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), being hydrolyzed within the CA active site to 2-hydroxycinnamic acids. We explore here a new series of variously substituted coumarins and a thiocoumarin for their interaction with 13 mammalian CA isoforms, detecting low nanomolar and isoform selective inhibitors. The mechanism of action of this class of inhibitors is delineated in detail by resolving the X-ray crystal structure of CA II in complex with trans-2-hydroxy-cinnamic acid, the in situ hydrolysis product of simple coumarin. Thiocoumarins also act as efficient CAIs, similarly to coumarins. The versatility of the (thio)coumarin chemistry, the cis-trans isomerization evidenced here, and easy derivatization of the (thio)coumarin rings, coupled with the nanomolar inhibition range of several isozymes, afford isoform-selective CAIs with various biomedical applications, which render these classes of compounds superior to the clinically used sulfonamides.
|
Inhibition of human recombinant CA9 catalytic domain by stopped-flow CO2 hydration method
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 7,8-disubstituted- but not 6,7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II in the low nanomolar/subnanomolar range.
Year : 2010
Volume : 20
Issue : 24
First Page : 7255
Last Page : 7258
Authors : Maresca A, Scozzafava A, Supuran CT.
Abstract : Two series of disubstituted coumarins incorporating ether and acetyl/propionyl moieties in positions 6,7- and 7,8- of the heterocyclic ring were synthesized investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). All these coumarins were very weak or ineffective as inhibitors of the housekeeping, offtarget isoforms CA I and II. The 6,7-disubstituted series showed ineffective inhibition also for the transmembrane tumor-associated isoforms CA IX and XII, whereas the corresponding isomeric 7,8-disubstituted coumarins showed nanomolar/subnanomolar inhibition of CA IX/XII. The nature and position of the groups substituting the coumarin ring in the 7,8-positions greatly influenced CA inhibitory properties, with C1-C4 alkyl ethers being the most effective inhibitors.
|
Inhibition of human recombinant CA12 catalytic domain by stopped-flow CO2 hydration method
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 7,8-disubstituted- but not 6,7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II in the low nanomolar/subnanomolar range.
Year : 2010
Volume : 20
Issue : 24
First Page : 7255
Last Page : 7258
Authors : Maresca A, Scozzafava A, Supuran CT.
Abstract : Two series of disubstituted coumarins incorporating ether and acetyl/propionyl moieties in positions 6,7- and 7,8- of the heterocyclic ring were synthesized investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). All these coumarins were very weak or ineffective as inhibitors of the housekeeping, offtarget isoforms CA I and II. The 6,7-disubstituted series showed ineffective inhibition also for the transmembrane tumor-associated isoforms CA IX and XII, whereas the corresponding isomeric 7,8-disubstituted coumarins showed nanomolar/subnanomolar inhibition of CA IX/XII. The nature and position of the groups substituting the coumarin ring in the 7,8-positions greatly influenced CA inhibitory properties, with C1-C4 alkyl ethers being the most effective inhibitors.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/cytochalasin B-induced superoxide anion production at 10 ug/mL after 5 mins by spectrophotometer analysis
|
Homo sapiens
|
8.5
%
|
|
Journal : J. Nat. Prod.
Title : Thymol, benzofuranoid, and phenylpropanoid derivatives: anti-inflammatory constituents from Eupatorium cannabinum.
Year : 2011
Volume : 74
Issue : 5
First Page : 1021
Last Page : 1027
Authors : Chen JJ, Tsai YC, Hwang TL, Wang TC.
Abstract : Five new compounds, 9-O-angeloyl-8,10-dehydrothymol (1), 9-(3-methylbutanoyl)-8,10-dehydrothymol (2), eupatobenzofuran (3), 2-hydroxy-2,6-dimethylbenzofuran-3(2H)-one (4), and 1-(2-hydroxy-4-methylphenyl)propan-1,2-dione (5), have been isolated from the aerial part of Eupatorium cannabinum subsp. asiaticum, together with 16 known compounds (6-21). Compounds 6-8, 11, 13, and 15 exhibited inhibition (IC50 values≤18.4 μM) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 2, 3, 10, 13, and 15 inhibited fMLP/CB-induced elastase release with IC50 values≤18.3 μM.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/cytochalasin B-induced elastase release using MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide as elastase substrate at 10 ug/mL after 5 mins
|
Homo sapiens
|
23.8
%
|
|
Journal : J. Nat. Prod.
Title : Thymol, benzofuranoid, and phenylpropanoid derivatives: anti-inflammatory constituents from Eupatorium cannabinum.
Year : 2011
Volume : 74
Issue : 5
First Page : 1021
Last Page : 1027
Authors : Chen JJ, Tsai YC, Hwang TL, Wang TC.
Abstract : Five new compounds, 9-O-angeloyl-8,10-dehydrothymol (1), 9-(3-methylbutanoyl)-8,10-dehydrothymol (2), eupatobenzofuran (3), 2-hydroxy-2,6-dimethylbenzofuran-3(2H)-one (4), and 1-(2-hydroxy-4-methylphenyl)propan-1,2-dione (5), have been isolated from the aerial part of Eupatorium cannabinum subsp. asiaticum, together with 16 known compounds (6-21). Compounds 6-8, 11, 13, and 15 exhibited inhibition (IC50 values≤18.4 μM) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 2, 3, 10, 13, and 15 inhibited fMLP/CB-induced elastase release with IC50 values≤18.3 μM.
|
Antioxidant activity assessed as hydroxyl radical scavenging activity at 100 uM after 30 mins
|
None
|
78.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of (2,5-dihydro-1H-pyrrol-1-yl)-2H-chromen-2-ones as free radical scavengers.
Year : 2011
Volume : 46
Issue : 12
First Page : 5894
Last Page : 5901
Authors : Balabani A, Hadjipavlou-Litina DJ, Litinas KE, Mainou M, Tsironi CC, Vronteli A.
Abstract : The allylation of aminocoumarins in the presence of excess of anhydrous K(2)CO(3) and allyl bromide to diallylaminocoumarins is described. The Ring Closing Metathesis reaction of the later with the Grubbs' 1rst generation catalyst under reflux or MW irradiation has resulted mainly to (2,5-dihydro-1H-pyrrol-1-yl)coumarins and (1H-pyrrol-1-yl)coumarins. The new 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 LO and (v) to scavenge hydroxyl radicals. Most of them were found to be potent lipid peroxidation inhibitors in vitro. The majority of the compounds showed significant hydroxyl radical scavenging activity. Compounds 11a and 12c presenting higher LO inhibitory activity as well as compound 17 were found to present a promising antioxidant and LO inhibitory profile.
|
Inhibition of soybean lipoxygenase assessed as conversion of sodium linoleate to 13-hydroperoxylinoleic acid at 100 uM
|
Glycine max
|
15.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of (2,5-dihydro-1H-pyrrol-1-yl)-2H-chromen-2-ones as free radical scavengers.
Year : 2011
Volume : 46
Issue : 12
First Page : 5894
Last Page : 5901
Authors : Balabani A, Hadjipavlou-Litina DJ, Litinas KE, Mainou M, Tsironi CC, Vronteli A.
Abstract : The allylation of aminocoumarins in the presence of excess of anhydrous K(2)CO(3) and allyl bromide to diallylaminocoumarins is described. The Ring Closing Metathesis reaction of the later with the Grubbs' 1rst generation catalyst under reflux or MW irradiation has resulted mainly to (2,5-dihydro-1H-pyrrol-1-yl)coumarins and (1H-pyrrol-1-yl)coumarins. The new 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 LO and (v) to scavenge hydroxyl radicals. Most of them were found to be potent lipid peroxidation inhibitors in vitro. The majority of the compounds showed significant hydroxyl radical scavenging activity. Compounds 11a and 12c presenting higher LO inhibitory activity as well as compound 17 were found to present a promising antioxidant and LO inhibitory profile.
|
Inhibition of recombinant human BACE1 using Rh-EVNLDAEFK as substrate at 500 uM after 60 mins by fluorescence quenching assay
|
Homo sapiens
|
8.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor.
Year : 2012
Volume : 20
Issue : 2
First Page : 784
Last Page : 788
Authors : Marumoto S, Miyazawa M.
Abstract : The present study was demonstrated to evaluate the effects of naturally occurring coumarins (NOCs) including simple coumarins, furanocoumarins, and pyranocoumarins on the inhibition of β-secretase (BACE1) activity. Of 41 NOCs examined, some furanocoumarins inhibited BACE1 activity, but simple coumarins and pyranocoumarins did not affect. The most potent inhibitor was 5-geranyloxy-8-methoxypsoralen (31), which has an IC(50) value of 9.9 μM. Other furanocoumarin derivatives, for example, 8-geranyloxy-5-methoxypsoralen (35), 8-geranyloxypsoralen (24), and bergamottin (18) inhibited BACE1 activity, with the IC(50) values <25.0 μM. Analyses of the inhibition mechanism by Dixon plots and Cornish-Bowden plots showed that compounds 18, 31 and 35 were mixed-type inhibitor. The kinetics of inhibition of BACE1 by coumarins 24 was non-competitive inhibitors.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
7.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
38.2
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
9.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
116.63
%
|
|
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
|
99.05
%
|
|
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.
|
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
|
2.66
%
|
|
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.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
23.55
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
24.36
%
|
|
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
|
-0.02
%
|
|
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
|
-0.02
%
|
|
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
|
-0.02
%
|
|
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.
|
Inhibition of human CYP2A6 at 10 uM
|
Homo sapiens
|
98.19
%
|
|
Journal : J Med Chem
Title : Novel Pyrrolopyridone Bromodomain and Extra-Terminal Motif (BET) Inhibitors Effective in Endocrine-Resistant ER+ Breast Cancer with Acquired Resistance to Fulvestrant and Palbociclib.
Year : 2020
Volume : 63
Issue : 13
First Page : 7186
Last Page : 7210
Authors : Li Y, Zhao J, Gutgesell LM, Shen Z, Ratia K, Dye K, Dubrovskyi O, Zhao H, Huang F, Tonetti DA, Thatcher GRJ, Xiong R.
Abstract : Acquired resistance to fulvestrant and palbociclib is a new challenge to treatment of estrogen receptor positive (ER+) breast cancer. ER is expressed in most resistance settings; thus, bromodomain and extra-terminal protein inhibitors (BETi) that target BET-amplified ER-mediated transcription have therapeutic potential. Novel pyrrolopyridone BETi leveraged novel interactions with L92/L94 confirmed by a cocrystal structure of 27 with BRD4. Optimization of BETi using growth inhibition in fulvestrant-resistant (MCF-7:CFR) cells was confirmed in endocrine-resistant, palbociclib-resistant, and ESR1 mutant cell lines. 27 was more potent in MCF-7:CFR cells than six BET inhibitors in clinical trials. Transcriptomic analysis differentiated 27 from the benchmark BETi, JQ-1, showing downregulation of oncogenes and upregulation of tumor suppressors and apoptosis. The therapeutic approach was validated by oral administration of 27 in orthotopic xenografts of endocrine-resistant breast cancer in monotherapy and in combination with fulvestrant. Importantly, at an equivalent dose in rats, thrombocytopenia was mitigated.
