|
Inhibition of beta-lactamase at 100 uM
|
None
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and prediction of promiscuous aggregating inhibitors among known drugs.
Year : 2003
Volume : 46
Issue : 21
First Page : 4477
Last Page : 4486
Authors : Seidler J, McGovern SL, Doman TN, Shoichet BK.
Abstract : Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzymes: beta-lactamase, chymotrypsin, and malate dehydrogenase, none of which are considered targets of these drugs. To be judged promiscuous, the drugs had to inhibit all three enzymes, do so in a time-dependent manner, be sensitive to detergent and to enzyme concentration, and form particles detectable by light scattering. Of the 50 drugs tested, 43 were nonpromiscuous by these criteria. Surprisingly, four of the drugs showed promiscuous, aggregation-based inhibition at concentrations below 100 microM: clotrimazole, benzyl benzoate, nicardipine, and delavirdine. Three other drugs also behaved as aggregation-based inhibitors, but only at high concentrations (about 400 microM). To investigate possible structure-activity relationships among promiscuous drugs, five analogues of the antifungal clotrimazole were studied. Three of these, miconazole, econazole, and sulconazole, were promiscuous but the other two, fluconazole and ketoconazole, were not. Using recursive partitioning, these experimental results were used to develop a model for predicting aggregate-based promiscuity. This model correctly classified 94% of 111 compounds-47 aggregators and 64 nonaggregators-that have been studied for this effect. To evaluate the model, it was used to predict the behavior of 75 drugs not previously investigated for aggregation. Several preliminary points emerge. Most drugs are not promiscuous, even at high concentrations. Nevertheless, at high enough concentrations (20-400 microM), some drugs can aggregate and act promiscuously, suggesting that aggregation may be common among small molecules at micromolar concentrations, at least in biochemical buffers.
|
Inhibition of chymotrypsin at 250 uM
|
unidentified
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and prediction of promiscuous aggregating inhibitors among known drugs.
Year : 2003
Volume : 46
Issue : 21
First Page : 4477
Last Page : 4486
Authors : Seidler J, McGovern SL, Doman TN, Shoichet BK.
Abstract : Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzymes: beta-lactamase, chymotrypsin, and malate dehydrogenase, none of which are considered targets of these drugs. To be judged promiscuous, the drugs had to inhibit all three enzymes, do so in a time-dependent manner, be sensitive to detergent and to enzyme concentration, and form particles detectable by light scattering. Of the 50 drugs tested, 43 were nonpromiscuous by these criteria. Surprisingly, four of the drugs showed promiscuous, aggregation-based inhibition at concentrations below 100 microM: clotrimazole, benzyl benzoate, nicardipine, and delavirdine. Three other drugs also behaved as aggregation-based inhibitors, but only at high concentrations (about 400 microM). To investigate possible structure-activity relationships among promiscuous drugs, five analogues of the antifungal clotrimazole were studied. Three of these, miconazole, econazole, and sulconazole, were promiscuous but the other two, fluconazole and ketoconazole, were not. Using recursive partitioning, these experimental results were used to develop a model for predicting aggregate-based promiscuity. This model correctly classified 94% of 111 compounds-47 aggregators and 64 nonaggregators-that have been studied for this effect. To evaluate the model, it was used to predict the behavior of 75 drugs not previously investigated for aggregation. Several preliminary points emerge. Most drugs are not promiscuous, even at high concentrations. Nevertheless, at high enough concentrations (20-400 microM), some drugs can aggregate and act promiscuously, suggesting that aggregation may be common among small molecules at micromolar concentrations, at least in biochemical buffers.
|
Inhibition of malate dehydrogenase (MDH) at 400 uM
|
None
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and prediction of promiscuous aggregating inhibitors among known drugs.
Year : 2003
Volume : 46
Issue : 21
First Page : 4477
Last Page : 4486
Authors : Seidler J, McGovern SL, Doman TN, Shoichet BK.
Abstract : Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzymes: beta-lactamase, chymotrypsin, and malate dehydrogenase, none of which are considered targets of these drugs. To be judged promiscuous, the drugs had to inhibit all three enzymes, do so in a time-dependent manner, be sensitive to detergent and to enzyme concentration, and form particles detectable by light scattering. Of the 50 drugs tested, 43 were nonpromiscuous by these criteria. Surprisingly, four of the drugs showed promiscuous, aggregation-based inhibition at concentrations below 100 microM: clotrimazole, benzyl benzoate, nicardipine, and delavirdine. Three other drugs also behaved as aggregation-based inhibitors, but only at high concentrations (about 400 microM). To investigate possible structure-activity relationships among promiscuous drugs, five analogues of the antifungal clotrimazole were studied. Three of these, miconazole, econazole, and sulconazole, were promiscuous but the other two, fluconazole and ketoconazole, were not. Using recursive partitioning, these experimental results were used to develop a model for predicting aggregate-based promiscuity. This model correctly classified 94% of 111 compounds-47 aggregators and 64 nonaggregators-that have been studied for this effect. To evaluate the model, it was used to predict the behavior of 75 drugs not previously investigated for aggregation. Several preliminary points emerge. Most drugs are not promiscuous, even at high concentrations. Nevertheless, at high enough concentrations (20-400 microM), some drugs can aggregate and act promiscuously, suggesting that aggregation may be common among small molecules at micromolar concentrations, at least in biochemical buffers.
|
Inhibitory activity (RA2) against Prostaglandin G/H synthase 2 was calculated relative to aspirin
|
Ovis aries
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Thalidomide and its analogues as cyclooxygenase inhibitors.
Year : 2002
Volume : 12
Issue : 7
First Page : 1043
Last Page : 1046
Authors : Noguchi T, Shimazawa R, Nagasawa K, Hashimoto Y.
Abstract : Thalidomide showed cyclooxygenase (COX)-1/2 inhibitory activity with a potency comparable to that of aspirin. Structural development studies of thalidomide resulted in potent COX-1/2 inhibitors, and COX-1-selective and COX-2-selective inhibitors.
|
Inhibitory activity (RA1) against Prostaglandin G/H synthase 1 was calculated relative to aspirin
|
Ovis aries
|
370.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Thalidomide and its analogues as cyclooxygenase inhibitors.
Year : 2002
Volume : 12
Issue : 7
First Page : 1043
Last Page : 1046
Authors : Noguchi T, Shimazawa R, Nagasawa K, Hashimoto Y.
Abstract : Thalidomide showed cyclooxygenase (COX)-1/2 inhibitory activity with a potency comparable to that of aspirin. Structural development studies of thalidomide resulted in potent COX-1/2 inhibitors, and COX-1-selective and COX-2-selective inhibitors.
|
Inhibition of LPS-induced Tumor necrosis factor-alpha production (TNF-alpha) in THP-1 cells
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Enhanced potency of perfluorinated thalidomide derivatives for inhibition of LPS-induced tumor necrosis factor-alpha production is associated with a change of mechanism of action.
Year : 1998
Volume : 8
Issue : 9
First Page : 1071
Last Page : 1076
Authors : Niwayama S, Loh C, Turk BE, Liu JO, Miyachi H, Hashimoto Y.
Abstract : Perfluorination of phthalimides leads to dramatically increased potency as inhibitors of TNF-alpha production. We examined the enantiodependence for several tetrafluorophthalimides and alpha-methylthalidomide, 3. Only 3 exhibited strikingly enantiodependent activity. The key structural determinant for the enhanced activity is the tetrafluorophthaloyl group, which confers enhanced potency and a change in the mechanism of inhibition.
|
Inhibition of TNF-alpha production from human monocytes upon stimulation with bacterial lipopolysaccharide (LPS) at a concentration of 1 uM
|
None
|
95.0
%
|
|
Journal : J. Med. Chem.
Title : Potent inhibition of tumor necrosis factor-alpha production by tetrafluorothalidomide and tetrafluorophthalimides.
Year : 1996
Volume : 39
Issue : 16
First Page : 3044
Last Page : 3045
Authors : Niwayama S, Turk BE, Liu JO.
|
Inhibition of TNF-alpha production from human monocytes upon stimulation with bacterial lipopolysaccharide (LPS) at a concentration of 10 uM
|
None
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Potent inhibition of tumor necrosis factor-alpha production by tetrafluorothalidomide and tetrafluorophthalimides.
Year : 1996
Volume : 39
Issue : 16
First Page : 3044
Last Page : 3045
Authors : Niwayama S, Turk BE, Liu JO.
|
Inhibition of TNF-alpha production from human monocytes upon stimulation with bacterial lipopolysaccharide (LPS) at a concentration of 100 uM
|
None
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : Potent inhibition of tumor necrosis factor-alpha production by tetrafluorothalidomide and tetrafluorophthalimides.
Year : 1996
Volume : 39
Issue : 16
First Page : 3044
Last Page : 3045
Authors : Niwayama S, Turk BE, Liu JO.
|
Inhibition of TNF-alpha production from human monocytes upon stimulation with bacterial lipopolysaccharide (LPS) at a concentration of 200 uM
|
None
|
64.0
%
|
|
Journal : J. Med. Chem.
Title : Potent inhibition of tumor necrosis factor-alpha production by tetrafluorothalidomide and tetrafluorophthalimides.
Year : 1996
Volume : 39
Issue : 16
First Page : 3044
Last Page : 3045
Authors : Niwayama S, Turk BE, Liu JO.
|
The cytotoxicity assessed using human embryonic lung fibroblast WI-38 cells.
|
Homo sapiens
|
100.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Novel biological response modifiers: phthalimides with tumor necrosis factor-alpha production-regulating activity.
Year : 1997
Volume : 40
Issue : 18
First Page : 2858
Last Page : 2865
Authors : Miyachi H, Azuma A, Ogasawara A, Uchimura E, Watanabe N, Kobayashi Y, Kato F, Kato M, Hashimoto Y.
Abstract : Novel N-substituted phthalimides (2-substituted 1H-isoindole-1,3-diones) were prepared, and their effects on tumor necrosis factor-alpha (TNF-alpha) production by human leukemia cell line HL-60 stimulated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or okadaic acid (OA) were examined. A structure-activity relationship study of the N-phenylphthalimides and N-benzylphthalimides revealed that their enhancing effect on TPA-induced TNF-alpha production by HL-60 cells and their inhibiting effect on OA-induced TNF-alpha production by HL-60 cells are only partially correlated.
|
Inhibitory activity against tubulin polymerization at 20 uM
|
Sus scrofa
|
10.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tubulin-polymerization inhibitors derived from thalidomide.
Year : 2005
Volume : 15
Issue : 2
First Page : 321
Last Page : 325
Authors : Inatsuki S, Noguchi T, Miyachi H, Oda S, Iguchi T, Kizaki M, Hashimoto Y, Kobayashi H.
Abstract : 2-(2,6-Diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33), which was obtained during our previous structural development studies on thalidomide, was revealed to possess potent tubulin-polymerization-inhibiting activity, comparable to that of the known tubulin-polymerization inhibitors, rhizoxin and colchicine. A major metabolite of thalidomide, 5-hydroxythalidomide, which possesses a hydroxyl group at the position corresponding to that of 5HPP-33, also showed moderate inhibitory activity.
|
Inhibitory activity in HUVEC tube formation assay at 100 uM
|
Homo sapiens
|
26.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Angiogenesis inhibitors derived from thalidomide.
Year : 2005
Volume : 15
Issue : 24
First Page : 5509
Last Page : 5513
Authors : Noguchi T, Fujimoto H, Sano H, Miyajima A, Miyachi H, Hashimoto Y.
Abstract : 5-Hydroxy-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33: 10), which was obtained during our previous structural development studies on thalidomide, was revealed to possess potent anti-angiogenic activity in a human umbilical vein endothelial cell (HUVEC) assay. Thalidomide (1) and its metabolite, 5-hydroxythalidomide (5-HT: 2), which possesses a hydroxyl group at the position corresponding to that of 5HPP-33, as well as IMiDs (immunomodulatory derivatives of thalidomide: 3 and 5), also showed weak or moderate activity in the same assay.
|
Inhibition of TNF gene expression in FRT Jurkat TNF reporter cells at 100 uM
|
Homo sapiens
|
38.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling.
Year : 2007
Volume : 17
Issue : 21
First Page : 5819
Last Page : 5824
Authors : Stewart SG, Spagnolo D, Polomska ME, Sin M, Karimi M, Abraham LJ.
Abstract : A library of new thalidomide analogues containing an olefin functionality were synthesised using a Heck cross coupling reaction from their aryl halogenated precursor. All analogues were tested for their ability to inhibit the synthesis of the proinflammatory cytokine Tumour Necrosis Factor (TNF). Compounds 22, 29, 33 and 37 were the most effective in this assay inhibiting TNF expression 50%, 69%, 52% and 50%, respectively.
|
Inhibition of TNF gene expression in FRT Jurkat TNF reporter cells at 10 uM
|
Homo sapiens
|
35.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling.
Year : 2007
Volume : 17
Issue : 21
First Page : 5819
Last Page : 5824
Authors : Stewart SG, Spagnolo D, Polomska ME, Sin M, Karimi M, Abraham LJ.
Abstract : A library of new thalidomide analogues containing an olefin functionality were synthesised using a Heck cross coupling reaction from their aryl halogenated precursor. All analogues were tested for their ability to inhibit the synthesis of the proinflammatory cytokine Tumour Necrosis Factor (TNF). Compounds 22, 29, 33 and 37 were the most effective in this assay inhibiting TNF expression 50%, 69%, 52% and 50%, respectively.
|
Inhibition of TNF gene expression in FRT-Jurkat TNF reporter cells at 1 uM
|
Homo sapiens
|
31.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling.
Year : 2007
Volume : 17
Issue : 21
First Page : 5819
Last Page : 5824
Authors : Stewart SG, Spagnolo D, Polomska ME, Sin M, Karimi M, Abraham LJ.
Abstract : A library of new thalidomide analogues containing an olefin functionality were synthesised using a Heck cross coupling reaction from their aryl halogenated precursor. All analogues were tested for their ability to inhibit the synthesis of the proinflammatory cytokine Tumour Necrosis Factor (TNF). Compounds 22, 29, 33 and 37 were the most effective in this assay inhibiting TNF expression 50%, 69%, 52% and 50%, respectively.
|
Antitumor activity against mouse Ehrlich ascites carcinoma cells implanted in Swiss albino mouse treated after 7 days post-tumor implantation at 1.25 mM/kg, sc for 5 days relative to control
|
Mus musculus
|
80.6
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and antitumor evaluation of novel thalidomide dithiocarbamate and dithioate analogs against Ehrlich ascites carcinoma-induced solid tumor in Swiss albino mice.
Year : 2008
Volume : 16
Issue : 22
First Page : 9708
Last Page : 9718
Authors : Zahran MA, Salem TA, Samaka RM, Agwa HS, Awad AR.
Abstract : A series of 16 novel thalidomide sulfur analogs containing one and two sulfur atoms 2 and 4-18, respectively, were designed and synthesized. These compounds were screened for in vitro antitumor activity against Ehrlich ascites carcinoma (EAC) cell line and exhibited potent cytotoxic activity. On the bases of the obtained results for in vitro cytotoxic activity, thalidomide sulfur analogs containing two sulfur atoms 8, 9, 13 and 14 were selected and tested in vivo against EAC-induced solid tumor in female mice compared to thalidomide 1 as well as its analog 2 and exhibited a highly significant reduction in tumor volume (TV). Results illustrated the antioxidative activity of these compounds as the level of hepatic lipid peroxidation decreased and levels of antioxidant enzymes like superoxide dismutase (SOD) and catalase were elevated. The histopathological investigations revealed that thalidomide sulfur analogs 2, 8, 9, 13 and 14 have antimitotic, apoptotic and necrotic activities against solid tumor. These compounds lead to increase of Fas-L expression. The immunohistochemical studies showed a decrease in Ki67 and vascular endothelial growth factor (VEGF) staining in tumor cells from treated-animals when compared with non-treated groups, which suggests an inhibition of tumor proliferation rate and angiogenic process associated with tumor growth. Compounds 9 and 13 were the most potent compounds in tumor necrosis without liver necrosis. At the same time, treatment with compound 9 resulted in liver degeneration.
|
Inhibition of NF-kappaB-mediated TNF expression in human Jurkat T cells coexpressing GFP reporter gene at 100 uM by flow cytometry
|
Homo sapiens
|
6.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : New thalidomide analogues derived through Sonogashira or Suzuki reactions and their TNF expression inhibition profiles.
Year : 2010
Volume : 18
Issue : 2
First Page : 650
Last Page : 662
Authors : Stewart SG, Braun CJ, Ng SL, Polomska ME, Karimi M, Abraham LJ.
Abstract : A library of new thalidomide C4/5 analogues containing either a phenyl or alkyne tether were synthesized using Sonogashira or Suzuki cross coupling reactions from their aryl halogenated precursors. All thalidomide analogues were tested for their ability to inhibit the expression of the proinflammatory cytokine Tumor Necrosis Factor (TNF). More explicitly the use of a novel reporter system utilizing the promoter region of the TNF gene in a human T-cell line provided a rapid and effective measure of NFkappaB transcriptional activity. Several compounds either containing either an aryl-isobutyl or aryl-isopropoxy group were the most effective in inhibiting TNF expression, and were several times more active than thalidomide itself. Five of the more active derivatives indicated an apoptotic response while one of these compounds, containing an aldehyde tether, showed possible influence of cell cycling effects.
|
Inhibition of NF-kappaB-mediated TNF expression in human Jurkat T cells coexpressing GFP reporter gene at 10 uM by flow cytometry
|
Homo sapiens
|
4.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : New thalidomide analogues derived through Sonogashira or Suzuki reactions and their TNF expression inhibition profiles.
Year : 2010
Volume : 18
Issue : 2
First Page : 650
Last Page : 662
Authors : Stewart SG, Braun CJ, Ng SL, Polomska ME, Karimi M, Abraham LJ.
Abstract : A library of new thalidomide C4/5 analogues containing either a phenyl or alkyne tether were synthesized using Sonogashira or Suzuki cross coupling reactions from their aryl halogenated precursors. All thalidomide analogues were tested for their ability to inhibit the expression of the proinflammatory cytokine Tumor Necrosis Factor (TNF). More explicitly the use of a novel reporter system utilizing the promoter region of the TNF gene in a human T-cell line provided a rapid and effective measure of NFkappaB transcriptional activity. Several compounds either containing either an aryl-isobutyl or aryl-isopropoxy group were the most effective in inhibiting TNF expression, and were several times more active than thalidomide itself. Five of the more active derivatives indicated an apoptotic response while one of these compounds, containing an aldehyde tether, showed possible influence of cell cycling effects.
|
Inhibition of human FAAH at 1 uM
|
Homo sapiens
|
14.19
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Mining biologically-active molecules for inhibitors of fatty acid amide hydrolase (FAAH): identification of phenmedipham and amperozide as FAAH inhibitors.
Year : 2009
Volume : 19
Issue : 23
First Page : 6793
Last Page : 6796
Authors : Vincent F, Nguyen MT, Emerling DE, Kelly MG, Duncton MA.
Abstract : The screening of known medicinal agents against new biological targets has been shown to be a valuable approach for revealing new pharmacology of marketed compounds. Recently, carbamate, urea and ketone inhibitors of fatty acid amide hydrolase (FAAH) have been described as promising treatments for pain, anxiety, depression and other CNS-related conditions. In order to find novel FAAH inhibitors, a focused screen of molecules containing potentially reactive moieties or having in vivo effects that are possibly relevant to the biology of FAAH was conducted. These studies revealed phenmedipham 13 and amperozide 14 to be inhibitors of human FAAH, with an IC(50) of 377 nM and 1.34 microM, respectively.
|
Inhibition of okadaic acid-induced TNFalpha production in human HL60 cells at 30 uM after 16 hrs by ELISA relative to control
|
Homo sapiens
|
164.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovering a new analogue of thalidomide which may be used as a potent modulator of TNF-alpha production.
Year : 2009
Volume : 44
Issue : 9
First Page : 3533
Last Page : 3542
Authors : Fernández Braña M, Acero N, Añorbe L, Muñoz Mingarro D, Llinares F, Domínguez G.
Abstract : A new series of imide derivatives related to thalidomide were synthesized and evaluated as modulators of TNF-alpha production. These derivatives enhance TNF-alpha production using human leukemia HL-60 cells induced with 12-O-tetradecanoylphorbol 13-acetate (TPA), while inhibiting TNF-alpha production induced with okadaic acid (OA) in the same cell line. The diphenylmaleimide derivative 2f, was found to be the most active product, producing a strong modulation of the cytokine level.
|
Antinociceptive activity in Swiss mouse assessed as inhibition of acetic acid-induced abdominal constrictions at 100 umol/kg, po administered 40 mins before acetic acid challenge measured for 25 mins relative to control
|
Mus musculus
|
73.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological evaluation of pyrazine N-acylhydrazone derivatives designed as novel analgesic and anti-inflammatory drug candidates.
Year : 2010
Volume : 18
Issue : 14
First Page : 5007
Last Page : 5015
Authors : da Silva YK, Augusto CV, de Castro Barbosa ML, de Albuquerque Melo GM, de Queiroz AC, de Lima Matos Freire Dias T, Júnior WB, Barreiro EJ, Lima LM, Alexandre-Moreira MS.
Abstract : In this paper, we report the synthesis and pharmacological evaluation of pyrazine N-acylhydrazone (NAH) derivatives (2a-s) designed as novel analgesic and anti-inflammatory drug candidates. This series was planned by molecular simplification of prototype 1 (LASSBio-1018), previously described as a non-selective cyclooxygenase inhibitor. Derivatives 2a-s were evaluated in several animal models of pain and inflammation, standing-out compound 2o (2-N'-[(E)-(3,4,5-trimethoxyphenyl) methylidene]-2-pyrazinecarbohydrazide; LASSBio-1181), that was also active in a murine model of chronic inflammation (i.e., adjuvant-induced arthritis test in rats) and can be considered a new analgesic and anti-inflammatory lead for drug development.
|
Analgesic activity against formalin-induced acute pain in Swiss mouse assessed inhibition of nociception at 100 umol/kg, po administered 40 mins before formalin challenge measured for 15 to 30 mins relative to control
|
Mus musculus
|
66.7
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological evaluation of pyrazine N-acylhydrazone derivatives designed as novel analgesic and anti-inflammatory drug candidates.
Year : 2010
Volume : 18
Issue : 14
First Page : 5007
Last Page : 5015
Authors : da Silva YK, Augusto CV, de Castro Barbosa ML, de Albuquerque Melo GM, de Queiroz AC, de Lima Matos Freire Dias T, Júnior WB, Barreiro EJ, Lima LM, Alexandre-Moreira MS.
Abstract : In this paper, we report the synthesis and pharmacological evaluation of pyrazine N-acylhydrazone (NAH) derivatives (2a-s) designed as novel analgesic and anti-inflammatory drug candidates. This series was planned by molecular simplification of prototype 1 (LASSBio-1018), previously described as a non-selective cyclooxygenase inhibitor. Derivatives 2a-s were evaluated in several animal models of pain and inflammation, standing-out compound 2o (2-N'-[(E)-(3,4,5-trimethoxyphenyl) methylidene]-2-pyrazinecarbohydrazide; LASSBio-1181), that was also active in a murine model of chronic inflammation (i.e., adjuvant-induced arthritis test in rats) and can be considered a new analgesic and anti-inflammatory lead for drug development.
|
Antiinflammatory activity against zymosan A-induced peritonitis in Swiss mouse assessed as inhibition of granulocyte infiltration in to peritoneal cavity at 100 mg/kg, po administered 40 mins before zymosan A challenge measured after 6 hrs relative to control
|
Mus musculus
|
61.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological evaluation of pyrazine N-acylhydrazone derivatives designed as novel analgesic and anti-inflammatory drug candidates.
Year : 2010
Volume : 18
Issue : 14
First Page : 5007
Last Page : 5015
Authors : da Silva YK, Augusto CV, de Castro Barbosa ML, de Albuquerque Melo GM, de Queiroz AC, de Lima Matos Freire Dias T, Júnior WB, Barreiro EJ, Lima LM, Alexandre-Moreira MS.
Abstract : In this paper, we report the synthesis and pharmacological evaluation of pyrazine N-acylhydrazone (NAH) derivatives (2a-s) designed as novel analgesic and anti-inflammatory drug candidates. This series was planned by molecular simplification of prototype 1 (LASSBio-1018), previously described as a non-selective cyclooxygenase inhibitor. Derivatives 2a-s were evaluated in several animal models of pain and inflammation, standing-out compound 2o (2-N'-[(E)-(3,4,5-trimethoxyphenyl) methylidene]-2-pyrazinecarbohydrazide; LASSBio-1181), that was also active in a murine model of chronic inflammation (i.e., adjuvant-induced arthritis test in rats) and can be considered a new analgesic and anti-inflammatory lead for drug development.
|
Antiedematogenic activity in Swiss mouse assessed as inhibition of capsaicin-induced paw edema at 100 umol/kg, po administered 40 mins before capsaicin challenge measured after 30 mins relative to control
|
Mus musculus
|
25.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological evaluation of pyrazine N-acylhydrazone derivatives designed as novel analgesic and anti-inflammatory drug candidates.
Year : 2010
Volume : 18
Issue : 14
First Page : 5007
Last Page : 5015
Authors : da Silva YK, Augusto CV, de Castro Barbosa ML, de Albuquerque Melo GM, de Queiroz AC, de Lima Matos Freire Dias T, Júnior WB, Barreiro EJ, Lima LM, Alexandre-Moreira MS.
Abstract : In this paper, we report the synthesis and pharmacological evaluation of pyrazine N-acylhydrazone (NAH) derivatives (2a-s) designed as novel analgesic and anti-inflammatory drug candidates. This series was planned by molecular simplification of prototype 1 (LASSBio-1018), previously described as a non-selective cyclooxygenase inhibitor. Derivatives 2a-s were evaluated in several animal models of pain and inflammation, standing-out compound 2o (2-N'-[(E)-(3,4,5-trimethoxyphenyl) methylidene]-2-pyrazinecarbohydrazide; LASSBio-1181), that was also active in a murine model of chronic inflammation (i.e., adjuvant-induced arthritis test in rats) and can be considered a new analgesic and anti-inflammatory lead for drug development.
|
Inhibition of TNFalpha-induced NF-kappaB activation expressed in human HT-29 cells coexpressing hrGFP at 100 uM after 24 hrs by propidium iodide staining-based flow cytometric analysis relative to control
|
Homo sapiens
|
126.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl N-acylhydrazone derivatives.
Year : 2012
Volume : 20
Issue : 6
First Page : 2158
Last Page : 2171
Authors : Hernández P, Cabrera M, Lavaggi ML, Celano L, Tiscornia I, Rodrigues da Costa T, Thomson L, Bollati-Fogolín M, Miranda AL, Lima LM, Barreiro EJ, González M, Cerecetto H.
Abstract : We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities.
|
Inhibition of TNFalpha-induced NF-kappaB activation expressed in human HT-29 cells coexpressing hrGFP at 400 uM after 24 hrs by propidium iodide staining-based flow cytometric analysis relative to control
|
Homo sapiens
|
116.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl N-acylhydrazone derivatives.
Year : 2012
Volume : 20
Issue : 6
First Page : 2158
Last Page : 2171
Authors : Hernández P, Cabrera M, Lavaggi ML, Celano L, Tiscornia I, Rodrigues da Costa T, Thomson L, Bollati-Fogolín M, Miranda AL, Lima LM, Barreiro EJ, González M, Cerecetto H.
Abstract : We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities.
|
Inhibition of TNFalpha-induced NF-kappaB activation expressed in human HT-29 cells coexpressing hrGFP at 200 uM after 24 hrs by propidium iodide staining-based flow cytometric analysis relative to control
|
Homo sapiens
|
114.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl N-acylhydrazone derivatives.
Year : 2012
Volume : 20
Issue : 6
First Page : 2158
Last Page : 2171
Authors : Hernández P, Cabrera M, Lavaggi ML, Celano L, Tiscornia I, Rodrigues da Costa T, Thomson L, Bollati-Fogolín M, Miranda AL, Lima LM, Barreiro EJ, González M, Cerecetto H.
Abstract : We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities.
|
Inhibition of NF-kappaB activation expressed in human HT-29 cells assessed as inhibition of TNFalpha-stimulated IL8 release at 100 uM after 24 hrs by flow cytometric analysis relative to control
|
Homo sapiens
|
63.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl N-acylhydrazone derivatives.
Year : 2012
Volume : 20
Issue : 6
First Page : 2158
Last Page : 2171
Authors : Hernández P, Cabrera M, Lavaggi ML, Celano L, Tiscornia I, Rodrigues da Costa T, Thomson L, Bollati-Fogolín M, Miranda AL, Lima LM, Barreiro EJ, González M, Cerecetto H.
Abstract : We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities.
|
Inhibition of NF-kappaB activation expressed in human HT-29 cells assessed as inhibition of TNFalpha-stimulated IL8 release at 400 uM after 24 hrs by flow cytometric analysis relative to control
|
Homo sapiens
|
57.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl N-acylhydrazone derivatives.
Year : 2012
Volume : 20
Issue : 6
First Page : 2158
Last Page : 2171
Authors : Hernández P, Cabrera M, Lavaggi ML, Celano L, Tiscornia I, Rodrigues da Costa T, Thomson L, Bollati-Fogolín M, Miranda AL, Lima LM, Barreiro EJ, González M, Cerecetto H.
Abstract : We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities.
|
Inhibition of NF-kappaB activation expressed in human HT-29 cells assessed as inhibition of TNFalpha-stimulated IL8 release at 200 uM after 24 hrs by flow cytometric analysis relative to control
|
Homo sapiens
|
77.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl N-acylhydrazone derivatives.
Year : 2012
Volume : 20
Issue : 6
First Page : 2158
Last Page : 2171
Authors : Hernández P, Cabrera M, Lavaggi ML, Celano L, Tiscornia I, Rodrigues da Costa T, Thomson L, Bollati-Fogolín M, Miranda AL, Lima LM, Barreiro EJ, González M, Cerecetto H.
Abstract : We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities.
|
Inhibition of iNOS in Mus musculus (mouse) RAW 264.7 cells assessed as inhibition of LPS-induced nitrite production pretreated for 24 hr before stimulation with LPS measured after 18 hr by ELISA
|
Mus musculus
|
28.2
%
|
|
Journal : Med Chem Res
Title : Study on synthesis of thalidomide analogues and their bioactivities; inhibition on iNOS pathway and cytotoxic effects
Year : 2012
Volume : 21
Issue : 7
First Page : 953
Last Page : 963
Authors : Yeh C, Lin P, Hwang J, Su C, Yeh Y, Yang S, Chou M
|
Antiinflammatory activity in carrageenan-induced air pouch mouse model assessed as inhibition of leukocyte migration from blood circulation into air pouches at 10 mg/kg, po administered 1 hr before carrageenan challenge measured after 6 hrs relative to control
|
Mus musculus
|
76.3
%
|
|
Journal : Med Chem Res
Title : Phthaloyl amino acids as anti-inflammatory and immunomodulatory prototypes
Year : 2013
First Page : 1
Last Page : 8
Authors : Leite ACL, Barbosa FF, Cardoso MVdO, Moreira DRM, Coelho LCD, da Silva EB, Filho GBdO, de Souza VMO, Pereira VRA, de C. Reis L, Ferreira PMP, Pessoa C, Wanderley AG, Mota FVB, da Silva TG
|
Antiinflammatory activity in carrageenan-induced air pouch mouse model assessed as inhibition of leukocyte migration from blood circulation into air pouches at 100 mg/kg, po administered 1 hr before carrageenan challenge measured after 6 hrs relative to control
|
Mus musculus
|
72.1
%
|
|
Journal : Med Chem Res
Title : Phthaloyl amino acids as anti-inflammatory and immunomodulatory prototypes
Year : 2013
First Page : 1
Last Page : 8
Authors : Leite ACL, Barbosa FF, Cardoso MVdO, Moreira DRM, Coelho LCD, da Silva EB, Filho GBdO, de Souza VMO, Pereira VRA, de C. Reis L, Ferreira PMP, Pessoa C, Wanderley AG, Mota FVB, da Silva TG
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
82.94
%
|
|
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
|
101.03
%
|
|
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 NFkappaB in human FRT-Jurkat cells expressing GFP assessed as reduction of TNF expression at 10 uM after 24 hrs by flow cytometry relative to control
|
Homo sapiens
|
2.0
%
|
|
Journal : MedChemComm
Title : Novel thalidomide analogues with potent NFB and TNF expression inhibition
Year : 2011
Volume : 2
Issue : 11
First Page : 1073
Last Page : 1078
Authors : Yeung SY, Kampmann S, Stubbs KA, Skelton BW, Kaskow BJ, Abraham LJ, Stewart SG
|
Inhibition of NFkappaB in human FRT-Jurkat cells expressing GFP assessed as reduction of TNF expression at 100 uM after 24 hrs by flow cytometry relative to control
|
Homo sapiens
|
4.0
%
|
|
Journal : MedChemComm
Title : Novel thalidomide analogues with potent NFB and TNF expression inhibition
Year : 2011
Volume : 2
Issue : 11
First Page : 1073
Last Page : 1078
Authors : Yeung SY, Kampmann S, Stubbs KA, Skelton BW, Kaskow BJ, Abraham LJ, Stewart SG
|
Antinociceptive effect in mouse assessed as inhibition of acetic acid-induced abdominal constriction at 100 uM/kg, po
|
Mus musculus
|
42.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of novel dapsone-thalidomide hybrids for the treatment of type 2 leprosy reactions.
Year : 2014
Volume : 24
Issue : 14
First Page : 3084
Last Page : 3087
Authors : Yamasaki PR, do Nascimento DC, Chelucci RC, de Faria Fernandes Belone A, Rosa PS, Diório SM, de Melo TR, Barbieri KP, Placeres MC, Carlos IZ, Chung MC, dos Santos JL.
Abstract : We synthesized a series of novel dapsone-thalidomide hybrids (3a-i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125 μM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions.
|
Antiinflammatory activity against mouse L929 cells assessed as inhibition of LPS-induced TNFalpha production at 125 uM after 48 hrs
|
Mus musculus
|
42.81
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of novel dapsone-thalidomide hybrids for the treatment of type 2 leprosy reactions.
Year : 2014
Volume : 24
Issue : 14
First Page : 3084
Last Page : 3087
Authors : Yamasaki PR, do Nascimento DC, Chelucci RC, de Faria Fernandes Belone A, Rosa PS, Diório SM, de Melo TR, Barbieri KP, Placeres MC, Carlos IZ, Chung MC, dos Santos JL.
Abstract : We synthesized a series of novel dapsone-thalidomide hybrids (3a-i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125 μM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions.
|
Antiinflammatory activity against mouse L929 cells assessed as inhibition of LPS-induced TNFalpha production at 15.625 uM after 48 hrs
|
Mus musculus
|
35.38
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of novel dapsone-thalidomide hybrids for the treatment of type 2 leprosy reactions.
Year : 2014
Volume : 24
Issue : 14
First Page : 3084
Last Page : 3087
Authors : Yamasaki PR, do Nascimento DC, Chelucci RC, de Faria Fernandes Belone A, Rosa PS, Diório SM, de Melo TR, Barbieri KP, Placeres MC, Carlos IZ, Chung MC, dos Santos JL.
Abstract : We synthesized a series of novel dapsone-thalidomide hybrids (3a-i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125 μM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions.
|
Inhibition of TNFalpha expression in human Jurkat cells containing GFP gene under control of TNF gene promoter at 100 uM incubated for 24 hrs
|
Homo sapiens
|
5.0
%
|
|
Journal : MedChemComm
Title : Novel phthalimide derivatives with TNF- and IL-1 expression inhibitory and apoptotic inducing properties
Year : 2014
Volume : 5
Issue : 6
First Page : 758
Last Page : 765
Authors : Coelho LCD, Cardoso MVdO, Moreira DRM, Gomes PATdM, Cavalcanti SMT, Oliveira AR, Filho GBdO, Siqueira LRPd, Barbosa MdO, Borba EFdO, Silva TGd, Kaskow B, Karimi M, Abraham LJ, Leite ACL
|
Inhibition of TNFalpha expression in human Jurkat cells containing GFP gene under control of TNF gene promoter at 10 uM incubated for 24 hrs
|
Homo sapiens
|
5.0
%
|
|
Journal : MedChemComm
Title : Novel phthalimide derivatives with TNF- and IL-1 expression inhibitory and apoptotic inducing properties
Year : 2014
Volume : 5
Issue : 6
First Page : 758
Last Page : 765
Authors : Coelho LCD, Cardoso MVdO, Moreira DRM, Gomes PATdM, Cavalcanti SMT, Oliveira AR, Filho GBdO, Siqueira LRPd, Barbosa MdO, Borba EFdO, Silva TGd, Kaskow B, Karimi M, Abraham LJ, Leite ACL
|
Inhibition of LPS-induced TNFalpha production in Swiss albino mouse macrophages at 50 uM after 24 hrs by ELISA relative to control
|
Mus musculus
|
31.7
%
|
|
Journal : Eur J Med Chem
Title : Discovery of phenylsulfonylfuroxan derivatives as gamma globin inducers by histone acetylation.
Year : 2018
Volume : 154
First Page : 341
Last Page : 353
Authors : Melo TRF, Kumkhaek C, Fernandes GFDS, Lopes Pires ME, Chelucci RC, Barbieri KP, Coelho F, Capote TSO, Lanaro C, Carlos IZ, Marcondes S, Chegaev K, Guglielmo S, Fruttero R, Chung MC, Costa FF, Rodgers GP, Dos Santos JL.
Abstract : N-oxide derivatives 5(a-b), 8(a-b), and 11(a-c) were designed, synthesized and evaluated in vitro and in vivo as potential drugs that are able to ameliorate sickle cell disease (SCD) symptoms. All of the compounds demonstrated the capacity to releasing nitric oxide at different levels ranging from 0.8 to 30.1%, in vivo analgesic activity and ability to reduce TNF-α levels in the supernatants of monocyte cultures. The most active compound (8b) protected 50.1% against acetic acid-induced abdominal constrictions, while dipyrone, which was used as a control only protected 35%. Compounds 8a and 8b inhibited ADP-induced platelet aggregation by 84% and 76.1%, respectively. Both compounds increased γ-globin in K562 cells at 100 μM. The mechanisms involved in the γ-globin increase are related to the acetylation of histones H3 and H4 that is induced by these compounds. In vitro, the most promising compound (8b) was not cytotoxic, mutagenic and genotoxic.
|
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
|
9.61
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-2.18
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
3.28
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
8.64
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
24.03
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
3.62
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-0.8
%
|
|
|
Inhibition of TPA-induced TNFalpha production in human THP1 cells at 3 uM by ELISA relative to control
|
Homo sapiens
|
32.0
%
|
|
Journal : J Med Chem
Title : De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives.
Year : 2019
Volume : 62
Issue : 14
First Page : 6615
Last Page : 6629
Authors : Heim C, Pliatsika D, Mousavizadeh F, Bär K, Hernandez Alvarez B, Giannis A, Hartmann MD.
Abstract : Targeted protein degradation via cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase complex, is an increasingly important strategy in various clinical settings, in which the substrate specificity of CRBN is altered via the binding of small-molecule effectors. To date, such effectors are derived from thalidomide and confer a broad substrate spectrum that is far from being fully characterized. Here, we employed a rational and modular approach to design novel and minimalistic CRBN effectors. In this approach, we took advantage of the binding modes of hydrolyzed metabolites of several thalidomide-derived effectors, which we elucidated via crystallography. These yielded key insights for the optimization of the minimal core binding moiety and its linkage to a chemical moiety that imparts substrate specificity. Based on this scaffold, we present a first active de-novo CRBN effector that is able to degrade the neo-substrate IKZF3 in the cell culture.
|
Binding affinity to human CRBN (1 to 442 residues)/N-terminal 6His-tagged human DDB1 (1 to 1140 residues) expressed in baculovirus infected BTI-TN-5B1-4 insect cells after 30 mins by cy5 probe based fluorescence polarization assay
|
Homo sapiens
|
250.0
nM
|
|
Journal : J Med Chem
Title : From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1).
Year : 2019
Volume : 62
Issue : 11
First Page : 5522
Last Page : 5540
Authors : Papatzimas JW, Gorobets E, Maity R, Muniyat MI, MacCallum JL, Neri P, Bahlis NJ, Derksen DJ.
Abstract : Protein-protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. An ideal PPI-based target is the protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor in cancers such as multiple myeloma where MCL1 levels directly correlate to disease progression. Current strategies for halting the antiapoptotic properties of MCL1 revolve around inhibiting its sequestration of proapoptotic factors. Existing inhibitors disrupt endogenous regulatory proteins; however, this strategy actually leads to an increase of MCL1 protein levels. Here, we show the development of hetero-bifunctional small molecules capable of selectively targeting MCL1 using a proteolysis targeting chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon ubiquitination pathway, making these PROTACs a first step toward a new class of antiapoptotic B-cell lymphoma 2 family protein degraders.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
17.51
%
|
|
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
|
0.09
%
|
|
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
|
0.09
%
|
|
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.
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Antiinflammatory activity in human monocytes assessed as inhibition of LPS-induced TNFaplha production at 50 uM preincubated for 15 mins followed by LPS addition and measured after 4 hrs by ELISA relative to control
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Homo sapiens
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15.0
%
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Journal : Bioorg Med Chem
Title : Insights of synthetic analogues of anti-leprosy agents.
Year : 2019
Volume : 27
Issue : 13
First Page : 2689
Last Page : 2717
Authors : Bera S, Mondal D.
Abstract : Today, the emergence of the phenomenon of drug or multidrug-resistance for community-associated diseases represents a major concern in the world. In these contexts, the chronic infectious disease, leprosy, grounded by a slow-growing bacterium called Mycobacterium leprae or Mycobacterium lepromatosis is a leadingcause of severe disfiguring skin sores and nerve damage in the arms, legs, and skin areas around the body. Even, over 200,000 new leprosy cases are being accounted every year along with the relapsed leprosy cases. Nonetheless, this has been considered a curable disease with a higher dose of multidrug therapy (MDT) for a long period of time. The prolonged action of a high dose of combination drugs administration may cause an adverse reaction that can significantly affect patient compliance, particularly the outbreak of multidrug-resistance in the infected person. To overcome these shortfalls or prevent the resistance-associated problems, researchers are diligently involved in the structural modifications of the clinically used anti-leprosy drugs or the allied compounds for the structure-antimycobacterial activity relationship study. This review article described the detailed synthesis and biological assays of different anti-leprosy compounds reported by several research groups.
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Antiinflammatory activity in human monocytes assessed as inhibition of LPS-induced TNFaplha production at 25 uM preincubated for 15 mins followed by LPS addition and measured after 4 hrs by ELISA relative to control
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Homo sapiens
|
10.0
%
|
|
Journal : Bioorg Med Chem
Title : Insights of synthetic analogues of anti-leprosy agents.
Year : 2019
Volume : 27
Issue : 13
First Page : 2689
Last Page : 2717
Authors : Bera S, Mondal D.
Abstract : Today, the emergence of the phenomenon of drug or multidrug-resistance for community-associated diseases represents a major concern in the world. In these contexts, the chronic infectious disease, leprosy, grounded by a slow-growing bacterium called Mycobacterium leprae or Mycobacterium lepromatosis is a leadingcause of severe disfiguring skin sores and nerve damage in the arms, legs, and skin areas around the body. Even, over 200,000 new leprosy cases are being accounted every year along with the relapsed leprosy cases. Nonetheless, this has been considered a curable disease with a higher dose of multidrug therapy (MDT) for a long period of time. The prolonged action of a high dose of combination drugs administration may cause an adverse reaction that can significantly affect patient compliance, particularly the outbreak of multidrug-resistance in the infected person. To overcome these shortfalls or prevent the resistance-associated problems, researchers are diligently involved in the structural modifications of the clinically used anti-leprosy drugs or the allied compounds for the structure-antimycobacterial activity relationship study. This review article described the detailed synthesis and biological assays of different anti-leprosy compounds reported by several research groups.
