|
In vitro inhibition of collagen-induced platelet aggregation in guinea pig platelet rich plasma
|
Cavia porcellus
|
0.32
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and platelet aggregation inhibitory activity of 4,5-bis(aryl)-2-substituted-thiazoles.
Year : 1981
Volume : 24
Issue : 12
First Page : 1507
Last Page : 1510
Authors : Rynbrandt RH, Nishizawa EE, Balogoyen DP, Mendoza AR, Annis KA.
Abstract : In our continuing effort to discover compound which inhibit collagen-induced platelet aggregation, we have screened compounds in a mouse pulmonary thromboembolism screen. Methyl 4,5-bis(4-methoxyphenyl)-2-thiazoleacetate (3) was very active in the above screen. However, 3 was active for less than 5 min when given orally to guinea pigs. As a result, our synthetic goal was to prepare 2-substituted thiazoles with a much longer duration of activity. This paper describes the preparation of a number 4,5-bis(aryl)-2-substituted-thiazoles and their in vitro and ex vivo activity against collagen-induced platelet aggregation. It was determined that 4,5-bis(4-methoxyphenyl)-2-(trifluoromethyl)thiazole (16) is the most promising compound.
|
In vitro inhibition of collagen-induced platelet aggregation in human platelet rich plasma
|
Homo sapiens
|
0.32
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and platelet aggregation inhibitory activity of 4,5-bis(aryl)-2-substituted-thiazoles.
Year : 1981
Volume : 24
Issue : 12
First Page : 1507
Last Page : 1510
Authors : Rynbrandt RH, Nishizawa EE, Balogoyen DP, Mendoza AR, Annis KA.
Abstract : In our continuing effort to discover compound which inhibit collagen-induced platelet aggregation, we have screened compounds in a mouse pulmonary thromboembolism screen. Methyl 4,5-bis(4-methoxyphenyl)-2-thiazoleacetate (3) was very active in the above screen. However, 3 was active for less than 5 min when given orally to guinea pigs. As a result, our synthetic goal was to prepare 2-substituted thiazoles with a much longer duration of activity. This paper describes the preparation of a number 4,5-bis(aryl)-2-substituted-thiazoles and their in vitro and ex vivo activity against collagen-induced platelet aggregation. It was determined that 4,5-bis(4-methoxyphenyl)-2-(trifluoromethyl)thiazole (16) is the most promising compound.
|
Percent inhibition of collagen-induced platelet aggregation at a concentration of 100 uM
|
Homo sapiens
|
89.0
%
|
|
Journal : J. Med. Chem.
Title : Replacement of aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents with the ferrocene group.
Year : 1983
Volume : 26
Issue : 2
First Page : 226
Last Page : 229
Authors : Maryanoff BE, Keeley SL, Persico FJ.
Abstract : Ferrocene analogues of the antiinflammatory agents tolmetin (1), fenbufen (2), flurbiprofen (3), and fenclofenac (4) were synthesized and tested for biological activity. The derivatives exhibited little or no antiarthritic or platelet antiaggregatory activity, indicating that the ferrocene moiety is a poor bioisostere for aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents.
|
Percent inhibition of collagen-induced platelet aggregation at a concentration of 20 uM
|
Homo sapiens
|
88.0
%
|
|
Journal : J. Med. Chem.
Title : Replacement of aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents with the ferrocene group.
Year : 1983
Volume : 26
Issue : 2
First Page : 226
Last Page : 229
Authors : Maryanoff BE, Keeley SL, Persico FJ.
Abstract : Ferrocene analogues of the antiinflammatory agents tolmetin (1), fenbufen (2), flurbiprofen (3), and fenclofenac (4) were synthesized and tested for biological activity. The derivatives exhibited little or no antiarthritic or platelet antiaggregatory activity, indicating that the ferrocene moiety is a poor bioisostere for aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents.
|
percent inhibition of serotonin release from platelets at a concentration of 100 uM
|
Homo sapiens
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Replacement of aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents with the ferrocene group.
Year : 1983
Volume : 26
Issue : 2
First Page : 226
Last Page : 229
Authors : Maryanoff BE, Keeley SL, Persico FJ.
Abstract : Ferrocene analogues of the antiinflammatory agents tolmetin (1), fenbufen (2), flurbiprofen (3), and fenclofenac (4) were synthesized and tested for biological activity. The derivatives exhibited little or no antiarthritic or platelet antiaggregatory activity, indicating that the ferrocene moiety is a poor bioisostere for aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents.
|
percent inhibition of serotonin release from platelets at a concentration of 20 uM
|
Homo sapiens
|
86.0
%
|
|
Journal : J. Med. Chem.
Title : Replacement of aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents with the ferrocene group.
Year : 1983
Volume : 26
Issue : 2
First Page : 226
Last Page : 229
Authors : Maryanoff BE, Keeley SL, Persico FJ.
Abstract : Ferrocene analogues of the antiinflammatory agents tolmetin (1), fenbufen (2), flurbiprofen (3), and fenclofenac (4) were synthesized and tested for biological activity. The derivatives exhibited little or no antiarthritic or platelet antiaggregatory activity, indicating that the ferrocene moiety is a poor bioisostere for aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents.
|
In vitro inhibitory activity against Prostaglandin G/H synthase 1 in sheep
|
Ovis aries
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of COX-2 selectivity into flurbiprofen.
Year : 1999
Volume : 9
Issue : 3
First Page : 307
Last Page : 312
Authors : Bayly CI, Black WC, Léger S, Ouimet N, Ouellet M, Percival MD.
Abstract : Comparative computer modeling of the X-ray crystal structures of cyclooxygenase isoforms COX-1 and COX-2 has led to the design of COX-2 selectivity into the nonselective inhibitor flurbiprofen. The COX-2 modeling was based on a postulated binding mode for flurbiprofen and took advantage of a small alcove in the COX-2 active site created by different positions of the Leu384 sidechain between COX-1 and COX-2. The design hypothesis was tested by synthesis and biological assay of a series of flurbiprofen analogs, culminating in the discovery of several inhibitors having up to 78-fold selectivity for COX-2 over COX-1.
|
Reversible competitive inhibition of prostaglandin G/H synthase 1
|
Ovis aries
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Manipulation of kinetic profiles in 2-aryl propionic acid cyclooxygenase inhibitors.
Year : 2004
Volume : 14
Issue : 3
First Page : 667
Last Page : 671
Authors : Gupta K, Kaub CJ, Carey KN, Casillas EG, Selinsky BS, Loll PJ.
Abstract : The nonsteroidal anti-inflammatory drugs flurbiprofen and ibuprofen were modified in an attempt to alter the kinetics of inhibitor binding by COX-1. Contrary to prior predictions, a halogen substituent is not sufficient to confer slow tight-binding behavior. Conversion of the carboxylate moiety of flurbiprofen to an ester or amide abolishes slow tight-binding behavior, regardless of halogenation state.
|
In vitro inhibitory activity against Prostaglandin G/H synthase 2 (COX-2) in human
|
None
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of COX-2 selectivity into flurbiprofen.
Year : 1999
Volume : 9
Issue : 3
First Page : 307
Last Page : 312
Authors : Bayly CI, Black WC, Léger S, Ouimet N, Ouellet M, Percival MD.
Abstract : Comparative computer modeling of the X-ray crystal structures of cyclooxygenase isoforms COX-1 and COX-2 has led to the design of COX-2 selectivity into the nonselective inhibitor flurbiprofen. The COX-2 modeling was based on a postulated binding mode for flurbiprofen and took advantage of a small alcove in the COX-2 active site created by different positions of the Leu384 sidechain between COX-1 and COX-2. The design hypothesis was tested by synthesis and biological assay of a series of flurbiprofen analogs, culminating in the discovery of several inhibitors having up to 78-fold selectivity for COX-2 over COX-1.
|
Evaluated for the percentage inhibition by adjuvant arthritis test at a dose of 50 mg/kg administarted perorally
|
Rattus norvegicus
|
55.0
%
|
|
Journal : J. Med. Chem.
Title : Replacement of aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents with the ferrocene group.
Year : 1983
Volume : 26
Issue : 2
First Page : 226
Last Page : 229
Authors : Maryanoff BE, Keeley SL, Persico FJ.
Abstract : Ferrocene analogues of the antiinflammatory agents tolmetin (1), fenbufen (2), flurbiprofen (3), and fenclofenac (4) were synthesized and tested for biological activity. The derivatives exhibited little or no antiarthritic or platelet antiaggregatory activity, indicating that the ferrocene moiety is a poor bioisostere for aromatic or heteroaromatic groups in nonsteroidal antiinflammatory agents.
|
Concentration required to inhibit cyclooxygenase-1 in rat blood
|
Rattus norvegicus
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid(1)(-)(42) secretion.
Year : 2005
Volume : 48
Issue : 18
First Page : 5705
Last Page : 5720
Authors : Peretto I, Radaelli S, Parini C, Zandi M, Raveglia LF, Dondio G, Fontanella L, Misiano P, Bigogno C, Rizzi A, Riccardi B, Biscaioli M, Marchetti S, Puccini P, Catinella S, Rondelli I, Cenacchi V, Bolzoni PT, Caruso P, Villetti G, Facchinetti F, Del Giudice E, Moretto N, Imbimbo BP.
Abstract : Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Abeta42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on Abeta42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Abeta42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.
|
Percent inhibition against beta-amyloid-42 (Abeta42) secretion was evaluated in human neuroglioma cells (H4-APP695NL) at 100 uM
|
Homo sapiens
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid(1)(-)(42) secretion.
Year : 2005
Volume : 48
Issue : 18
First Page : 5705
Last Page : 5720
Authors : Peretto I, Radaelli S, Parini C, Zandi M, Raveglia LF, Dondio G, Fontanella L, Misiano P, Bigogno C, Rizzi A, Riccardi B, Biscaioli M, Marchetti S, Puccini P, Catinella S, Rondelli I, Cenacchi V, Bolzoni PT, Caruso P, Villetti G, Facchinetti F, Del Giudice E, Moretto N, Imbimbo BP.
Abstract : Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Abeta42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on Abeta42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Abeta42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.
|
Inhibition of COX2
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural and functional basis of cyclooxygenase inhibition.
Year : 2007
Volume : 50
Issue : 7
First Page : 1425
Last Page : 1441
Authors : Blobaum AL, Marnett LJ.
|
Inhibition of COX1
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural and functional basis of cyclooxygenase inhibition.
Year : 2007
Volume : 50
Issue : 7
First Page : 1425
Last Page : 1441
Authors : Blobaum AL, Marnett LJ.
|
Antiinflammatory activity in Wistar albino rat assessed as inhibition of carrageenan-induced paw edema at 10 mg/kg, po measured 4 hrs after carrageenan challenge
|
Rattus norvegicus
|
80.29
%
|
|
Journal : Eur. J. Med. Chem.
Title : Condensed bridgehead nitrogen heterocyclic system: synthesis and pharmacological activities of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid.
Year : 2008
Volume : 43
Issue : 10
First Page : 2056
Last Page : 2066
Authors : Amir M, Kumar H, Javed SA.
Abstract : Several 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles were prepared by condensation of 4-amino-5-substituted-3-mercapto-(4H)-1,2,4-triazoles (3a,b) with various substituted aromatic acids and aryl/alkyl isothiocyanates through a one-pot reaction. These compounds were investigated for their anti-inflammatory, analgesic, ulcerogenic, lipid peroxidation, antibacterial and antifungal activities. Some of the synthesized compounds showed potent anti-inflammatory activity along with minimal ulcerogenic effect and lipid peroxidation, compared to those of ibuprofen and flurbiprofen. Some of the tested compounds also showed moderate antimicrobial activity against tested bacterial and fungal strains.
|
Analgesic activity in Swiss albino mouse assessed as effect on reaction time for tail withdrawal administered at 10 mg/kg, po after 4 hrs by tail immersion method
|
Mus musculus
|
69.5
%
|
|
Journal : Eur. J. Med. Chem.
Title : Condensed bridgehead nitrogen heterocyclic system: synthesis and pharmacological activities of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid.
Year : 2008
Volume : 43
Issue : 10
First Page : 2056
Last Page : 2066
Authors : Amir M, Kumar H, Javed SA.
Abstract : Several 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles were prepared by condensation of 4-amino-5-substituted-3-mercapto-(4H)-1,2,4-triazoles (3a,b) with various substituted aromatic acids and aryl/alkyl isothiocyanates through a one-pot reaction. These compounds were investigated for their anti-inflammatory, analgesic, ulcerogenic, lipid peroxidation, antibacterial and antifungal activities. Some of the synthesized compounds showed potent anti-inflammatory activity along with minimal ulcerogenic effect and lipid peroxidation, compared to those of ibuprofen and flurbiprofen. Some of the tested compounds also showed moderate antimicrobial activity against tested bacterial and fungal strains.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema administered orally at equimolar oral dose relative to 10 mg/kg flurbiprofen measured after 3 hrs of carrageenan challenge
|
Rattus norvegicus
|
75.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : 1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid: synthesis and preliminary evaluation of biological properties.
Year : 2008
Volume : 43
Issue : 12
First Page : 2688
Last Page : 2698
Authors : Kumar H, Javed SA, Khan SA, Amir M.
Abstract : A series of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid were synthesized in order to obtain new compounds with potential anti-inflammatory activity, analgesic activity and lower ulcerogenic potential. All compounds were evaluated for their anti-inflammatory activity by the carrageenan induced rat paw edema test method. The compounds possessing potent anti-inflammatory activity were further tested for their analgesic, ulcerogenic and antioxidant activities. Out of all tested compounds, the compounds 3, 7, 17 and 20, showed significant reduction in rat paw edema induced by carrageenan treatment. These compounds showed significant analgesic effect and at an equimolar oral doses relative to flurbiprofen were also found to be non-gastrotoxic in rats. Compound 17 was evaluated as the lead compound having more anti-inflammatory activity (81.81%) than the reference drug (79.54%), low ulcerogenic potential and protective effect on lipid peroxidation.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema administered orally at equimolar oral dose relative to 10 mg/kg flurbiprofen measured after 4 hrs of carrageenan challenge
|
Rattus norvegicus
|
79.54
%
|
|
Journal : Eur. J. Med. Chem.
Title : 1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid: synthesis and preliminary evaluation of biological properties.
Year : 2008
Volume : 43
Issue : 12
First Page : 2688
Last Page : 2698
Authors : Kumar H, Javed SA, Khan SA, Amir M.
Abstract : A series of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid were synthesized in order to obtain new compounds with potential anti-inflammatory activity, analgesic activity and lower ulcerogenic potential. All compounds were evaluated for their anti-inflammatory activity by the carrageenan induced rat paw edema test method. The compounds possessing potent anti-inflammatory activity were further tested for their analgesic, ulcerogenic and antioxidant activities. Out of all tested compounds, the compounds 3, 7, 17 and 20, showed significant reduction in rat paw edema induced by carrageenan treatment. These compounds showed significant analgesic effect and at an equimolar oral doses relative to flurbiprofen were also found to be non-gastrotoxic in rats. Compound 17 was evaluated as the lead compound having more anti-inflammatory activity (81.81%) than the reference drug (79.54%), low ulcerogenic potential and protective effect on lipid peroxidation.
|
Analgesic activity in Swiss albino mouse assessed as inhibition of tail withdrawal administered orally at equimolar oral dose relative to 10 mg/kg flurbiprofen after 4 hrs
|
Mus musculus
|
69.5
%
|
|
Journal : Eur. J. Med. Chem.
Title : 1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid: synthesis and preliminary evaluation of biological properties.
Year : 2008
Volume : 43
Issue : 12
First Page : 2688
Last Page : 2698
Authors : Kumar H, Javed SA, Khan SA, Amir M.
Abstract : A series of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid were synthesized in order to obtain new compounds with potential anti-inflammatory activity, analgesic activity and lower ulcerogenic potential. All compounds were evaluated for their anti-inflammatory activity by the carrageenan induced rat paw edema test method. The compounds possessing potent anti-inflammatory activity were further tested for their analgesic, ulcerogenic and antioxidant activities. Out of all tested compounds, the compounds 3, 7, 17 and 20, showed significant reduction in rat paw edema induced by carrageenan treatment. These compounds showed significant analgesic effect and at an equimolar oral doses relative to flurbiprofen were also found to be non-gastrotoxic in rats. Compound 17 was evaluated as the lead compound having more anti-inflammatory activity (81.81%) than the reference drug (79.54%), low ulcerogenic potential and protective effect on lipid peroxidation.
|
Inhibition of ovine COX1
|
Ovis aries
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : In silico search for multi-target anti-inflammatories in Chinese herbs and formulas.
Year : 2010
Volume : 18
Issue : 6
First Page : 2204
Last Page : 2218
Authors : Ehrman TM, Barlow DJ, Hylands PJ.
Abstract : Chinese herbs were screened for compounds which may be active against four targets involved in inflammation, using pharmacophore-assisted docking. Multiple LigandScout (LS) pharmacophores built from ligand-receptor complexes in the protein databank (PDB) were first employed to select compounds. These compounds were then docked using LS-derived templates and ranked according to docking score. The targets comprised cyclo-oxygenases 1 & 2 (COX), p38 MAP kinase (p38), c-Jun terminal-NH(2) kinase (JNK) and type 4 cAMP-specific phosphodiesterase (PDE4). The results revealed that multi-target inhibitors are likely to be relatively common in Chinese herbs. Details of their distribution are given, in addition to experimental evidence supporting these results. Examples of compounds predicted to be active against at least three targets are presented, and their features outlined. The distribution of herbs containing predicted inhibitors was also analysed in relation to 192 Chinese formulas from over 50 herbal categories. Among those found to contain a high proportion of these herbs were formulas traditionally used to treat fever, headache, rheumatoid arthritis, inflammatory bowel disorders, skin disease, cancer, and traumatic injury. Relationships between multi-target drug discovery and Chinese medicine are discussed.
|
Inhibition of mouse COX2
|
Mus musculus
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : In silico search for multi-target anti-inflammatories in Chinese herbs and formulas.
Year : 2010
Volume : 18
Issue : 6
First Page : 2204
Last Page : 2218
Authors : Ehrman TM, Barlow DJ, Hylands PJ.
Abstract : Chinese herbs were screened for compounds which may be active against four targets involved in inflammation, using pharmacophore-assisted docking. Multiple LigandScout (LS) pharmacophores built from ligand-receptor complexes in the protein databank (PDB) were first employed to select compounds. These compounds were then docked using LS-derived templates and ranked according to docking score. The targets comprised cyclo-oxygenases 1 & 2 (COX), p38 MAP kinase (p38), c-Jun terminal-NH(2) kinase (JNK) and type 4 cAMP-specific phosphodiesterase (PDE4). The results revealed that multi-target inhibitors are likely to be relatively common in Chinese herbs. Details of their distribution are given, in addition to experimental evidence supporting these results. Examples of compounds predicted to be active against at least three targets are presented, and their features outlined. The distribution of herbs containing predicted inhibitors was also analysed in relation to 192 Chinese formulas from over 50 herbal categories. Among those found to contain a high proportion of these herbs were formulas traditionally used to treat fever, headache, rheumatoid arthritis, inflammatory bowel disorders, skin disease, cancer, and traumatic injury. Relationships between multi-target drug discovery and Chinese medicine are discussed.
|
Antiinflammatory activity against mouse RAW264.7 cells assessed as inhibition of LPS-induced nitrate production at 10 uM treated 30 mins before LPS challenge measured after 24 hrs by Griess reagent method relative to control
|
Mus musculus
|
80.7
%
|
|
Journal : J. Med. Chem.
Title : Inhibition of amyloidogenesis by nonsteroidal anti-inflammatory drugs and their hybrid nitrates.
Year : 2011
Volume : 54
Issue : 7
First Page : 2293
Last Page : 2306
Authors : Schiefer IT, Abdul-Hay S, Wang H, Vanni M, Qin Z, Thatcher GR.
Abstract : Poor blood-brain barrier penetration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer's disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogues were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogues were obtained with enhanced anti-inflammatory and antiamyloidogenic properties compared to 1, however, esterification led to elevated Aβ(1-42) levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate CHF5074. Although hybrid nitrates elevated Aβ(1-42) at higher concentration, SALA activity was observed at low concentrations (≤1 μM): both Aβ(1-42) and the ratio of Aβ(1-42)/Aβ(1-40) were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds, the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach toward a clinically useful SALA.
|
Antiinflammatory activity against mouse RAW264.7 cells assessed as inhibition of LPS-induced nitrate production at 100 uM treated 30 mins before LPS challenge measured after 24 hrs by Griess reagent method relative to control
|
Mus musculus
|
69.1
%
|
|
Journal : J. Med. Chem.
Title : Inhibition of amyloidogenesis by nonsteroidal anti-inflammatory drugs and their hybrid nitrates.
Year : 2011
Volume : 54
Issue : 7
First Page : 2293
Last Page : 2306
Authors : Schiefer IT, Abdul-Hay S, Wang H, Vanni M, Qin Z, Thatcher GR.
Abstract : Poor blood-brain barrier penetration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer's disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogues were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogues were obtained with enhanced anti-inflammatory and antiamyloidogenic properties compared to 1, however, esterification led to elevated Aβ(1-42) levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate CHF5074. Although hybrid nitrates elevated Aβ(1-42) at higher concentration, SALA activity was observed at low concentrations (≤1 μM): both Aβ(1-42) and the ratio of Aβ(1-42)/Aβ(1-40) were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds, the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach toward a clinically useful SALA.
|
Antiamyloidogenic activity in mouse N2A cells transfected with human APP Swedish mutant assessed as reduction of amyloid beta (1 to 42) level at 1 uM after 24 hrs by ELISA relative to control
|
Mus musculus
|
86.6
%
|
|
Journal : J. Med. Chem.
Title : Inhibition of amyloidogenesis by nonsteroidal anti-inflammatory drugs and their hybrid nitrates.
Year : 2011
Volume : 54
Issue : 7
First Page : 2293
Last Page : 2306
Authors : Schiefer IT, Abdul-Hay S, Wang H, Vanni M, Qin Z, Thatcher GR.
Abstract : Poor blood-brain barrier penetration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer's disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogues were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogues were obtained with enhanced anti-inflammatory and antiamyloidogenic properties compared to 1, however, esterification led to elevated Aβ(1-42) levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate CHF5074. Although hybrid nitrates elevated Aβ(1-42) at higher concentration, SALA activity was observed at low concentrations (≤1 μM): both Aβ(1-42) and the ratio of Aβ(1-42)/Aβ(1-40) were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds, the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach toward a clinically useful SALA.
|
DRUGMATRIX: Cyclooxygenase COX-1 enzyme inhibition (substrate: Arachidonic acid)
|
Homo sapiens
|
21.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Cyclooxygenase COX-2 enzyme inhibition (substrate: Arachidonic acid)
|
None
|
359.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Antineuroinflammatory activity in LPS-stimulated rat microglia cells assessed as inhibition of PMA-stimulated TXB2 release preincubated for 15 mins measured 70 mins after PMA challenge
|
Rattus norvegicus
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Marine sponge Hymeniacidon sp. amphilectane metabolites potently inhibit rat brain microglia thromboxane B2 generation.
Year : 2012
Volume : 20
Issue : 1
First Page : 279
Last Page : 282
Authors : Mayer AM, Avilés E, Rodríguez AD.
Abstract : The effects of five Hymeniacidon sp. amphilectane metabolites (1-5) and two semi-synthetic analogs (6 and 7) on thromboxane B(2) (TXB(2)) and superoxide anion (O(2)(-)) generation from Escherichia coli LPS-activated rat brain microglia were investigated. All Hymeniacidon sp. metabolites and analogs potently inhibited TXB(2) (IC(50)=0.20-4.69μM) with low lactate dehydrogenase release and minimal mitochondrial dehydrogenase inhibition. While a lack of O(2)(-) inhibition would suggest that Hymeniacidon sp. metabolites and derivatives inhibit TXB(2) synthesis by a cyclooxygenase-dependent mechanism, their pharmacologic potency and limited in vitro cytotoxicity warrants further investigation to develop them as lead compounds to modulate enhanced TBX(2) release by activated microglia in neuroinflammatory disorders.
|
TP_TRANSPORTER: inhibition of PAH uptake (PAH: 2 uM, Flurbiprofen: 1000 uM) in Xenopus laevis oocytes
|
Xenopus laevis
|
100.0
%
|
|
Journal : Mol. Pharmacol.
Title : Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes.
Year : 1999
Volume : 55
Issue : 1
First Page : 847
Last Page : 854
Authors : Apiwattanakul N, Sekine T, Chairoungdua A, Kanai Y, Nakajima N, Sophasan S, Endou H.
Abstract : Organic anion transporter 1 (OAT1) is the para-aminohippurate (PAH) transporter in the basolateral membrane of the proximal tubule. The present study investigated whether or not nonsteroidal anti-inflammatory drugs (NSAIDs) are transported by OAT1. All of the NSAIDs tested inhibited [14C]PAH uptake via OAT1 expressed in Xenopus laevis oocytes. Ibuprofen, indomethacin, salicylurate, and naproxen showed the strongest potency to inhibit [14C]PAH uptake (Ki approximately 2-10 microM); acetylsalicylate, salicylate, and phenacetin exhibited moderate potency (Ki approximately 300-400 microM), and acetaminophen (paracetamol) exhibited the weakest inhibitory potency (Ki approximately 2 mM). Radiolabeled acetylsalicylate, salicylate, and indomethacin were taken up by OAT1 and the uptake rate of these three NSAIDs was enhanced by the outwardly directed dicarboxylate gradient. The efflux of the preloaded [14C]PAH from the oocytes via OAT1 was trans-stimulated by PAH and glutarate added to the media. The addition of salicylate, acetylsalicylate, or salicylurate into the media also trans-stimulated the efflux of PAH, whereas indomethacin did not. The present study indicates that OAT1 is responsible for the renal uptake and secretion of NSAIDs.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
227.02
%
|
|
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
|
98.28
%
|
|
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 human recombinant TTR Y78F mutant-mediated fibrillogenesis at 40 uM after 30 mins by turbidimetric assay relative to control
|
Homo sapiens
|
35.0
%
|
|
Journal : J. Med. Chem.
Title : Modulation of the fibrillogenesis inhibition properties of two transthyretin ligands by halogenation.
Year : 2013
Volume : 56
Issue : 22
First Page : 9110
Last Page : 9121
Authors : Cotrina EY, Pinto M, Bosch L, Vilà M, Blasi D, Quintana J, Centeno NB, Arsequell G, Planas A, Valencia G.
Abstract : The amyloidogenic protein transthyretin (TTR) is thought to aggregate into amyloid fibrils by tetramer dissociation which can be inhibited by a number of small molecule compounds. Our analysis of a series of crystallographic protein-inhibitor complexes has shown no clear correlation between the observed molecular interactions and the in vitro activity of the inhibitors. From this analysis, it emerged that halogen bonding (XB) could be mediating some key interactions. Analysis of the halogenated derivatives of two well-known TTR inhibitors has shown that while flufenamic acid affinity for TTR was unchanged by halogenation, diflunisal gradually improves binding up to 1 order of magnitude after iodination through interactions that can be interpreted as a suboptimal XB (carbonyl Thr106: I...O distance 3.96-4.05 Å; C-I...O angle 152-156°) or as rather optimized van der Waals contacts or as a mixture of both. These results illustrate the potential of halogenation strategies in designing and optimizing TTR fibrillogenesis inhibitors.
|
Antineuroinflammatory activity in rat brain neonatal microglia
|
Rattus norvegicus
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dactyloditerpenol acetate, a new prenylbisabolane-type diterpene from Aplysia dactylomela with significant in vitro anti-neuroinflammatory activity.
Year : 2014
Volume : 24
Issue : 1
First Page : 344
Last Page : 348
Authors : Jiménez-Romero C, Mayer AM, Rodríguez AD.
Abstract : A new regular diterpene possessing an unusual 1,6-anti-3-methylcyclohex-2-en-1-ol ring system, dactyloditerpenol acetate (1), has been extracted from the tropical sea hare Aplysia dactylomela and its stereostructure elucidated by spectroscopic methods. The absolute configuration of 1 was determined as 1S, 6S, 7R, 10S, and 11R by application of Kishi's method for the assignment of absolute configuration of alcohols. The new diterpene potently inhibited in vitro thromboxane B2 (TXB2) (IC50 0.4μM) and superoxide anion (O2(-)) (IC50 1μM) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low short-term toxicity.
|
Inhibition of COX in human Mahlavu cells after 48 hrs by fluorometric assay
|
Homo sapiens
|
70.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel triazolothiadiazines act as potent anticancer agents in liver cancer cells through Akt and ASK-1 proteins.
Year : 2016
Volume : 24
Issue : 4
First Page : 858
Last Page : 872
Authors : Aytaç PS, Durmaz I, Houston DR, Çetin-Atalay R, Tozkoparan B.
Abstract : Newly designed triazolothiadiazines incorporating with structural motifs of nonsteroidal analgesic anti-inflammatory drugs were synthesized and screened for their bioactivity against epithelial cancer cells. Compounds with bioactivities less then ∼5μM (IC50) were further analyzed and showed to induce apoptotic cell death and SubG1 cell cycle arrest in liver cancer cells. Among this group, two compounds (1g and 1h) were then studied to identify the mechanism of action. These molecules triggered oxidative stress induced apoptosis through ASK-1 protein activation and Akt protein inhibition as demonstrated by downstream targets such as GSK3β, β-catenin and cyclin D1. QSAR and molecular docking models provide insight into the mechanism of inhibition and indicate the optimal direction of future synthetic efforts. Furthermore, molecular docking results were confirmed with in vitro COX bioactivity studies. This study demonstrates that the novel triazolothiadiazine derivatives are promising drug candidates for epithelial cancers, especially liver cancer.
|
Inhibition of COX in human HuH7 cells after 48 hrs by fluorometric assay
|
Homo sapiens
|
70.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel triazolothiadiazines act as potent anticancer agents in liver cancer cells through Akt and ASK-1 proteins.
Year : 2016
Volume : 24
Issue : 4
First Page : 858
Last Page : 872
Authors : Aytaç PS, Durmaz I, Houston DR, Çetin-Atalay R, Tozkoparan B.
Abstract : Newly designed triazolothiadiazines incorporating with structural motifs of nonsteroidal analgesic anti-inflammatory drugs were synthesized and screened for their bioactivity against epithelial cancer cells. Compounds with bioactivities less then ∼5μM (IC50) were further analyzed and showed to induce apoptotic cell death and SubG1 cell cycle arrest in liver cancer cells. Among this group, two compounds (1g and 1h) were then studied to identify the mechanism of action. These molecules triggered oxidative stress induced apoptosis through ASK-1 protein activation and Akt protein inhibition as demonstrated by downstream targets such as GSK3β, β-catenin and cyclin D1. QSAR and molecular docking models provide insight into the mechanism of inhibition and indicate the optimal direction of future synthetic efforts. Furthermore, molecular docking results were confirmed with in vitro COX bioactivity studies. This study demonstrates that the novel triazolothiadiazine derivatives are promising drug candidates for epithelial cancers, especially liver cancer.
|
Inhibition of ovine COX1 assessed as production of PGF2-alpha preincubated with compound followed by the addition of 5 uM arachidonic acid as substrate by enzyme immunoassay
|
Ovis aries
|
150.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies.
Year : 2016
Volume : 109
First Page : 216
Last Page : 237
Authors : Migliore M, Habrant D, Sasso O, Albani C, Bertozzi SM, Armirotti A, Piomelli D, Scarpelli R.
Abstract : Non-steroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological effects by inhibiting cyclooxygenase (COX)-1 and COX-2. Though widely prescribed for pain and inflammation, these agents have limited utility in chronic diseases due to serious mechanism-based adverse events such as gastrointestinal damage. Concomitant blockade of fatty acid amide hydrolase (FAAH) enhances the therapeutic effects of the NSAIDs while attenuating their propensity to cause gastrointestinal injury. This favorable interaction is attributed to the accumulation of protective FAAH substrates, such as the endocannabinoid anandamide, and suggests that agents simultaneously targeting COX and FAAH might provide an innovative strategy to combat pain and inflammation with reduced side effects. Here, we describe the rational design and structure-active relationship (SAR) properties of the first class of potent multitarget FAAH-COX inhibitors. A focused SAR exploration around the prototype 10r (ARN2508) led to the identification of achiral (18b) as well as racemic (29a-c and 29e) analogs. Absolute configurational assignment and pharmacological evaluation of single enantiomers of 10r are also presented. (S)-(+)-10r is the first highly potent and selective chiral inhibitor of FAAH-COX with marked in vivo activity, and represents a promising lead to discover novel analgesics and anti-inflammatory drugs.
|
Inhibition of self-induced aggregation of amyloid beta (1 to 42) (unknown origin) at 25 uM after 24 hrs by thioflavin T fluorescence method relative to control
|
Homo sapiens
|
12.3
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment.
Year : 2018
Volume : 26
Issue : 5
First Page : 1102
Last Page : 1115
Authors : Cao Z, Yang J, Xu R, Song Q, Zhang X, Liu H, Qiang X, Li Y, Tan Z, Deng Y.
Abstract : A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ1-42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.
|
Inhibition of cupric ion-mediated amyloid beta (1 to 42) aggregation at 25 uM after 24 hrs by thioflavin T fluorescence assay relative to control
|
None
|
6.2
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment.
Year : 2018
Volume : 26
Issue : 5
First Page : 1102
Last Page : 1115
Authors : Cao Z, Yang J, Xu R, Song Q, Zhang X, Liu H, Qiang X, Li Y, Tan Z, Deng Y.
Abstract : A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ1-42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.
|
Antiinflammatory activity in mouse BV2 cells assessed as inhibition of LPS-induced nitric oxide production at 2.5 uM pretreated for 30 mins followed by LPS-stimulation measured after 24 hrs by Griess assay relative to control
|
Mus musculus
|
11.8
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment.
Year : 2018
Volume : 26
Issue : 5
First Page : 1102
Last Page : 1115
Authors : Cao Z, Yang J, Xu R, Song Q, Zhang X, Liu H, Qiang X, Li Y, Tan Z, Deng Y.
Abstract : A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ1-42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.
|
Antiinflammatory activity in mouse BV2 cells assessed as inhibition of LPS-induced nitric oxide production at 10 uM pretreated for 30 mins followed by LPS-stimulation measured after 24 hrs by Griess assay relative to control
|
Mus musculus
|
23.0
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment.
Year : 2018
Volume : 26
Issue : 5
First Page : 1102
Last Page : 1115
Authors : Cao Z, Yang J, Xu R, Song Q, Zhang X, Liu H, Qiang X, Li Y, Tan Z, Deng Y.
Abstract : A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ1-42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.
|
Antiinflammatory activity in mouse BV2 cells assessed as inhibition of LPS-induced TNFalpha production at 2.5 uM pretreated for 30 mins followed by LPS-stimulation measured after 24 hrs by ELISA relative to control
|
Mus musculus
|
9.6
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment.
Year : 2018
Volume : 26
Issue : 5
First Page : 1102
Last Page : 1115
Authors : Cao Z, Yang J, Xu R, Song Q, Zhang X, Liu H, Qiang X, Li Y, Tan Z, Deng Y.
Abstract : A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ1-42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.
|
Antiinflammatory activity in mouse BV2 cells assessed as inhibition of LPS-induced TNFalpha production at 10 uM pretreated for 30 mins followed by LPS-stimulation measured after 24 hrs by ELISA relative to control
|
Mus musculus
|
30.3
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment.
Year : 2018
Volume : 26
Issue : 5
First Page : 1102
Last Page : 1115
Authors : Cao Z, Yang J, Xu R, Song Q, Zhang X, Liu H, Qiang X, Li Y, Tan Z, Deng Y.
Abstract : A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ1-42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
10.54
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-5.67
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
4.59
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
44.27
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
19.06
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
8.89
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-3.5
%
|
|
|
Anti-inflammatory activity in human BV2 cells assessed as inhibition of LPS-stimulated NO release at 2.5 uM preincubated for 30 mins followed by LPS stimulation and measured after 24 hrs by Griess reagent based assay relative to control
|
Homo sapiens
|
11.8
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2018
Volume : 26
Issue : 23-24
First Page : 6115
Last Page : 6127
Authors : Song Q, Li Y, Cao Z, Liu H, Tian C, Yang Z, Qiang X, Tan Z, Deng Y.
Abstract : A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC<sub>50</sub> = 0.56 μM and 5.12 μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (IC<sub>50</sub> = 3.05 μM) and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation (71.7% at 25.0 μM), and displayed significant disaggregation ability to self- and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation fibrils (75.2% and 77.2% at 25.0 μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.
|
Anti-inflammatory activity in human BV2 cells assessed as inhibition of LPS-stimulated NO release at 10 uM preincubated for 30 mins followed by LPS stimulation and measured after 24 hrs by Griess reagent based assay relative to control
|
Homo sapiens
|
23.0
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2018
Volume : 26
Issue : 23-24
First Page : 6115
Last Page : 6127
Authors : Song Q, Li Y, Cao Z, Liu H, Tian C, Yang Z, Qiang X, Tan Z, Deng Y.
Abstract : A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC<sub>50</sub> = 0.56 μM and 5.12 μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (IC<sub>50</sub> = 3.05 μM) and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation (71.7% at 25.0 μM), and displayed significant disaggregation ability to self- and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation fibrils (75.2% and 77.2% at 25.0 μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.
|
Anti-inflammatory activity in human BV2 cells assessed as inhibition of LPS-stimulated TNFalpha release at 2.5 uM preincubated for 30 mins followed by LPS stimulation and measured after 24 hrs by ELISA relative to control
|
Homo sapiens
|
9.6
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2018
Volume : 26
Issue : 23-24
First Page : 6115
Last Page : 6127
Authors : Song Q, Li Y, Cao Z, Liu H, Tian C, Yang Z, Qiang X, Tan Z, Deng Y.
Abstract : A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC<sub>50</sub> = 0.56 μM and 5.12 μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (IC<sub>50</sub> = 3.05 μM) and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation (71.7% at 25.0 μM), and displayed significant disaggregation ability to self- and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation fibrils (75.2% and 77.2% at 25.0 μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.
|
Anti-inflammatory activity in human BV2 cells assessed as inhibition of LPS-stimulated TNFalpha release at 10 uM preincubated for 30 mins followed by LPS stimulation and measured after 24 hrs by ELISA relative to control
|
Homo sapiens
|
30.3
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2018
Volume : 26
Issue : 23-24
First Page : 6115
Last Page : 6127
Authors : Song Q, Li Y, Cao Z, Liu H, Tian C, Yang Z, Qiang X, Tan Z, Deng Y.
Abstract : A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC<sub>50</sub> = 0.56 μM and 5.12 μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (IC<sub>50</sub> = 3.05 μM) and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation (71.7% at 25.0 μM), and displayed significant disaggregation ability to self- and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation fibrils (75.2% and 77.2% at 25.0 μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.
|
Inhibition of HFIP-pretreated human amyloid beta (1 to 42) self-induced aggregation at 25 uM measured after 24 hrs by thioflavin-T fluorescence assay relative to control
|
Homo sapiens
|
12.84
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of 4'-OH-flurbiprofen Mannich base derivatives as potential Alzheimer's disease treatment with multiple inhibitory activities.
Year : 2019
Volume : 27
Issue : 6
First Page : 991
Last Page : 1001
Authors : Liu H, Qiang X, Song Q, Li W, He Y, Ye C, Tan Z, Deng Y.
Abstract : A series of 4'-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (65.03% at 25.0 μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD.
|
Inhibition of Cu2+-induced human amyloid beta (1 to 42) aggregation at 25 uM after 24 hrs by thioflavin T-based fluorometric assay relative to control
|
None
|
7.56
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of 4'-OH-flurbiprofen Mannich base derivatives as potential Alzheimer's disease treatment with multiple inhibitory activities.
Year : 2019
Volume : 27
Issue : 6
First Page : 991
Last Page : 1001
Authors : Liu H, Qiang X, Song Q, Li W, He Y, Ye C, Tan Z, Deng Y.
Abstract : A series of 4'-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (65.03% at 25.0 μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD.
|
Inhibition of Electrophorus electricus AChE at 50 uM using acetylthiocholine iodide as substrate measured after 15 mins by Ellman's method relative to control
|
Electrophorus electricus
|
15.6
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of 4'-OH-flurbiprofen Mannich base derivatives as potential Alzheimer's disease treatment with multiple inhibitory activities.
Year : 2019
Volume : 27
Issue : 6
First Page : 991
Last Page : 1001
Authors : Liu H, Qiang X, Song Q, Li W, He Y, Ye C, Tan Z, Deng Y.
Abstract : A series of 4'-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (65.03% at 25.0 μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD.
|
Inhibition of LPS-induced nitric oxide production in mouse BV2 cells at 2.5 uM pretreated for 30 mins followed by LPS-stimulation and measured after 24 hrs by Griess assay relative to control
|
Mus musculus
|
11.8
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of 4'-OH-flurbiprofen Mannich base derivatives as potential Alzheimer's disease treatment with multiple inhibitory activities.
Year : 2019
Volume : 27
Issue : 6
First Page : 991
Last Page : 1001
Authors : Liu H, Qiang X, Song Q, Li W, He Y, Ye C, Tan Z, Deng Y.
Abstract : A series of 4'-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (65.03% at 25.0 μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD.
|
Inhibition of LPS-induced nitric oxide production in mouse BV2 cells at 10 uM pretreated for 30 mins followed by LPS-stimulation and measured after 24 hrs by Griess assay relative to control
|
Mus musculus
|
23.0
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of 4'-OH-flurbiprofen Mannich base derivatives as potential Alzheimer's disease treatment with multiple inhibitory activities.
Year : 2019
Volume : 27
Issue : 6
First Page : 991
Last Page : 1001
Authors : Liu H, Qiang X, Song Q, Li W, He Y, Ye C, Tan Z, Deng Y.
Abstract : A series of 4'-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (65.03% at 25.0 μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD.
|
Inhibition of LPS-induced TNFalpha production in mouse BV2 cells at 2.5 uM pretreated for 30 mins followed by LPS-stimulation and measured after 24 hrs by ELISA relative to control
|
Mus musculus
|
9.6
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of 4'-OH-flurbiprofen Mannich base derivatives as potential Alzheimer's disease treatment with multiple inhibitory activities.
Year : 2019
Volume : 27
Issue : 6
First Page : 991
Last Page : 1001
Authors : Liu H, Qiang X, Song Q, Li W, He Y, Ye C, Tan Z, Deng Y.
Abstract : A series of 4'-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (65.03% at 25.0 μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD.
|
Inhibition of LPS-induced TNFalpha production in mouse BV2 cells at 10 uM pretreated for 30 mins followed by LPS-stimulation and measured after 24 hrs by ELISA relative to control
|
Mus musculus
|
30.3
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of 4'-OH-flurbiprofen Mannich base derivatives as potential Alzheimer's disease treatment with multiple inhibitory activities.
Year : 2019
Volume : 27
Issue : 6
First Page : 991
Last Page : 1001
Authors : Liu H, Qiang X, Song Q, Li W, He Y, Ye C, Tan Z, Deng Y.
Abstract : A series of 4'-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ<sub>1-42</sub> aggregation (65.03% at 25.0 μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.74
%
|
|
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
|
0.34
%
|
|
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
|
0.34
%
|
|
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.
|
Antiinflammatory activity against LPS-induced rat Primary neonatal microglia assessed as inhibition in TXB2 generation preincubated for 20 mins followed by PMA-stimulation and measured after 70 mins by immunoassay
|
Rattus norvegicus
|
100.0
nM
|
|
Journal : J Nat Prod
Title : 6-Deoxy- and 11-Hydroxytolypodiols: Meroterpenoids from the Cyanobacterium HT-58-2.
Year : 2020
Volume : 83
Issue : 5
First Page : 1691
Last Page : 1695
Authors : Gurr JR, O'Donnell TJ, Luo Y, Yoshida WY, Hall ML, Mayer AMS, Sun R, Williams PG.
Abstract : Chemical investigation of cyanobacterial strain HT-58-2, which most closely aligns with the genus <i>Brasilomena</i>, has led to the isolation of two compounds related to tolypodiol. The structures and absolute configuration of 6-deoxytolypodiol (<b>1</b>) and 11-hydroxytolypodiol (<b>2</b>) were elucidated by spectroscopic and spectrometric analysis. While tolypodiol previously showed anti-inflammatory activity in a mouse ear edema assay, only <b>2</b> reduced <i>in vitro</i> thromboxane B<sub>2</sub> and superoxide anion (O<sub>2</sub><sup>-</sup>) generation from <i>Escherichia coli</i> lipopolysaccharide-activated rat neonatal microglia to any appreciable degree.
|
Inhibition of HFIP-pretreated amyloid beta (1 to 42) (unknown origin) self-aggregation at 25 uM after 24 hrs by thioflavin-T fluorescence assay relative to control
|
Homo sapiens
|
12.57
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer's disease.
Year : 2020
Volume : 28
Issue : 7
First Page : 115374
Last Page : 115374
Authors : Yang Z, Song Q, Cao Z, Yu G, Liu Z, Tan Z, Deng Y.
Abstract : A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu<sup>2+</sup>-induced β-amyloid aggregation. Furthermore, some target compounds, especially 7i and 7r, also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activity and appropriate BBB permeability. These biological activities indicated that the representative compound 7i and 7r might be promising multifunctional agents for AD treatment.
|
Inhibition of Cu2+-induced HFIP-pretreated amyloid beta (1 to 42) (unknown origin) aggregation at 25 uM measured after 24 hrs by thioflavin-T fluorescence assay relative to control
|
None
|
7.29
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer's disease.
Year : 2020
Volume : 28
Issue : 7
First Page : 115374
Last Page : 115374
Authors : Yang Z, Song Q, Cao Z, Yu G, Liu Z, Tan Z, Deng Y.
Abstract : A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu<sup>2+</sup>-induced β-amyloid aggregation. Furthermore, some target compounds, especially 7i and 7r, also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activity and appropriate BBB permeability. These biological activities indicated that the representative compound 7i and 7r might be promising multifunctional agents for AD treatment.
|
Anti-neuroinflammatory activity in mouse BV2 cells assessed as inhibition of LPS-induced NO production at 2.5 uM preincubated for 30 mins followed by LPS stimulation measured after 24 hrs by Griess reagent based assay relative to control
|
Mus musculus
|
12.5
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer's disease.
Year : 2020
Volume : 28
Issue : 7
First Page : 115374
Last Page : 115374
Authors : Yang Z, Song Q, Cao Z, Yu G, Liu Z, Tan Z, Deng Y.
Abstract : A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu<sup>2+</sup>-induced β-amyloid aggregation. Furthermore, some target compounds, especially 7i and 7r, also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activity and appropriate BBB permeability. These biological activities indicated that the representative compound 7i and 7r might be promising multifunctional agents for AD treatment.
|
Anti-neuroinflammatory activity in mouse BV2 cells assessed as inhibition of LPS-induced NO production at 10 uM preincubated for 30 mins followed by LPS stimulation measured after 24 hrs by Griess reagent based assay relative to control
|
Mus musculus
|
26.2
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer's disease.
Year : 2020
Volume : 28
Issue : 7
First Page : 115374
Last Page : 115374
Authors : Yang Z, Song Q, Cao Z, Yu G, Liu Z, Tan Z, Deng Y.
Abstract : A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu<sup>2+</sup>-induced β-amyloid aggregation. Furthermore, some target compounds, especially 7i and 7r, also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activity and appropriate BBB permeability. These biological activities indicated that the representative compound 7i and 7r might be promising multifunctional agents for AD treatment.
|
Anti-neuroinflammatory activity in mouse BV2 cells assessed as inhibition of LPS-induced TNFalpha production at 2.5 uM preincubated for 30 mins followed by LPS stimulation measured after 24 hrs by ELISA relative to control
|
Mus musculus
|
10.2
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer's disease.
Year : 2020
Volume : 28
Issue : 7
First Page : 115374
Last Page : 115374
Authors : Yang Z, Song Q, Cao Z, Yu G, Liu Z, Tan Z, Deng Y.
Abstract : A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu<sup>2+</sup>-induced β-amyloid aggregation. Furthermore, some target compounds, especially 7i and 7r, also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activity and appropriate BBB permeability. These biological activities indicated that the representative compound 7i and 7r might be promising multifunctional agents for AD treatment.
|
Anti-neuroinflammatory activity in mouse BV2 cells assessed as inhibition of LPS-induced TNFalpha production at 10 uM preincubated for 30 mins followed by LPS stimulation measured after 24 hrs by ELISA relative to control
|
Mus musculus
|
31.2
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer's disease.
Year : 2020
Volume : 28
Issue : 7
First Page : 115374
Last Page : 115374
Authors : Yang Z, Song Q, Cao Z, Yu G, Liu Z, Tan Z, Deng Y.
Abstract : A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu<sup>2+</sup>-induced β-amyloid aggregation. Furthermore, some target compounds, especially 7i and 7r, also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activity and appropriate BBB permeability. These biological activities indicated that the representative compound 7i and 7r might be promising multifunctional agents for AD treatment.
