|
Antifungal activity against Aspergillus fumigatus
|
Aspergillus fumigatus
|
10.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Fold decrease in IC50 vs beta-lactamase on pre-incubation
|
Escherichia coli
|
2.0
|
|
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.
|
Antifungal activity against Candida albicans
|
Candida albicans
|
10.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Antifungal activity against Candida tropicalis
|
Candida tropicalis
|
100.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
In vitro inhibition of human Cytochrome P450 17A1 activity
|
Homo sapiens
|
243.0
nM
|
|
Journal : J. Med. Chem.
Title : Three dimensional pharmacophore modeling of human CYP17 inhibitors. Potential agents for prostate cancer therapy.
Year : 2003
Volume : 46
Issue : 12
First Page : 2345
Last Page : 2351
Authors : Clement OO, Freeman CM, Hartmann RW, Handratta VD, Vasaitis TS, Brodie AM, Njar VC.
Abstract : We report here a molecular modeling investigation of steroidal and nonsteroidal inhibitors of human cytochrome P450 17alpha-hydroxylase-17,20-lyase (CYP17). Using the pharmacophore perception technique, we have generated common-feature pharmacophore model(s) to explain the putative binding requirements for two classes of human CYP17 inhibitors. Common chemical features in the steroid and nonsteroid human CYP17 enzyme inhibitors, as deduced by the Catalyst/HipHop program, are one to two hydrogen bond acceptors (HBAs) and three hydrophobic groups. For azole-steroidal ligands, the 3beta-OH group of ring A and the N-3 of the azole ring attached to ring D at C-17 act as hydrogen bond acceptors. A model that permits hydrogen bond interaction between the azole functionality on ring D and the enzyme is consistent with experimental deductions for type II CYP17 inhibitors where a sixth ligating atom interacts with Fe(II) of heme. In general, pharmacophore models derived for steroid and nonsteroidal compounds bear striking similarities to all azole sites mapping the HBA functionality and to three hydrophobic features describing the hydrophobic interactions between the ligands and the enzyme. Using the pharmacophore model derived for azole-steroidal inhibitors as a 3D search query against several 3D multiconformational Catalyst formatted databases, we identified several steroidal compounds with potential inhibition of this enzyme. Biological testing of some of these compounds show low to high inhibitory potency against the human CYP17 enzyme. This shows the potential of our pharmacophore model in identifying new and potent CYP17 inhibitors. Further refinement of the model is in progress with a view to identifying and optimizing new leads.
|
In vitro inhibition of cytochrome P450 19A1 by rat ovarian microsomes incubated with [3H]androstenedione and NADPH-generating system.
|
None
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Aromatase inhibition by 5-substituted pyrimidines and dihydropyrimidines.
Year : 1987
Volume : 30
Issue : 8
First Page : 1359
Last Page : 1365
Authors : Taylor HM, Jones CD, Davenport JD, Hirsch KS, Kress TJ, Weaver D.
Abstract : The inhibition of estrogen biosynthesis has been suggested to be an effective treatment of hormone-dependent diseases, particularly breast cancer. Several series of 5-substituted pyrimidine derivatives have been synthesized and tested for their ability to inhibit the enzyme aromatase (estrogen synthetase). Compounds were evaluated in an in vitro assay that measured the inhibition of rat ovarian microsomal aromatase activity. Greatest inhibitory activity was achieved in the cases of diarylpyrimidinemethanols and diarylpyrimidinyl methanes which were substituted in the 4- and 4'-positions with electron-withdrawing substituents, particularly Cl.
|
Antifungal activity against Cryptococcus neoformans
|
Cryptococcus neoformans
|
1.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Inhibition of human cytochrome P450 3A4
|
None
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Antibacterial activity against Erysipelothrix insidiosa
|
Erysipelothrix rhusiopathiae
|
1.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Inhibition of Vaginal Candida (C-43 strain) infection in Hamsters, estimated as Percent Area under curve at 0.25 % concentration after 8 days of administration
|
Cricetulus griseus
|
69.0
%
|
|
Journal : J. Med. Chem.
Title : Isobenzofurans as conformationally constrained miconazole analogues with improved antifungal potency.
Year : 1992
Volume : 35
Issue : 22
First Page : 4221
Last Page : 4229
Authors : Lovey RG, Elliott AJ, Kaminski JJ, Loebenberg D, Parmegiani RM, Rane DF, Girijavallabhan VM, Pike RE, Guzik H, Antonacci B.
Abstract : A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.
|
Inhibition of Vaginal Candida (C-60 strain) infection in Hamsters, estimated as Percent Area under curve at 0.01 % concentration after 4 days of administration
|
Cricetulus griseus
|
33.0
%
|
|
Journal : J. Med. Chem.
Title : Isobenzofurans as conformationally constrained miconazole analogues with improved antifungal potency.
Year : 1992
Volume : 35
Issue : 22
First Page : 4221
Last Page : 4229
Authors : Lovey RG, Elliott AJ, Kaminski JJ, Loebenberg D, Parmegiani RM, Rane DF, Girijavallabhan VM, Pike RE, Guzik H, Antonacci B.
Abstract : A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.
|
Inhibition of Vaginal Candida (C-60 strain) infection in Hamsters, estimated as Percent Area under curve at 0.25 % concentration after 4 days of administration
|
Cricetulus griseus
|
63.0
%
|
|
Journal : J. Med. Chem.
Title : Isobenzofurans as conformationally constrained miconazole analogues with improved antifungal potency.
Year : 1992
Volume : 35
Issue : 22
First Page : 4221
Last Page : 4229
Authors : Lovey RG, Elliott AJ, Kaminski JJ, Loebenberg D, Parmegiani RM, Rane DF, Girijavallabhan VM, Pike RE, Guzik H, Antonacci B.
Abstract : A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.
|
Inhibition of Vaginal Candida (C-60 strain) infection in Hamsters, estimated as Percent Area under curve at 0.25 % concentration after 8 days of administration
|
Cricetulus griseus
|
63.0
%
|
|
Journal : J. Med. Chem.
Title : Isobenzofurans as conformationally constrained miconazole analogues with improved antifungal potency.
Year : 1992
Volume : 35
Issue : 22
First Page : 4221
Last Page : 4229
Authors : Lovey RG, Elliott AJ, Kaminski JJ, Loebenberg D, Parmegiani RM, Rane DF, Girijavallabhan VM, Pike RE, Guzik H, Antonacci B.
Abstract : A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.
|
Antifungal activity against Microsporum canis
|
Arthroderma otae
|
1.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Antifungal activity against Mucor species
|
mucor species
|
100.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Inhibition of P-gp was determined using rhodamine-assay in human CaCo-2 cells
|
None
|
22.0
%
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Antifungal activity against Phialophora verrucosa
|
Phialophora verrucosa
|
100.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Antifungal activity against Saprolegnia species
|
saprolegnia species
|
10.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Antifungal activity against Sporothrix schenck ii
|
Sporothrix schenckii
|
1.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Antibacterial against Staphylococcus hemolyticus
|
staphylococcus hemolyticus
|
10.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Antibacterial activity against Streptococcus pyogenes
|
Streptococcus pyogenes
|
1.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Antifungal activity against Trichophyton mentagrophytes
|
trychophyton mentagrophytes
|
1.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Antifungal activity against Trichophyton rubrum
|
Trichophyton rubrum
|
1.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.
Year : 1981
Volume : 24
Issue : 11
First Page : 1360
Last Page : 1364
Authors : Heeres J, Van Cutsem J.
Abstract : The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
|
Fold increase in IC50 vs beta-lactamase with 0.1 mg/mL saponin
|
Escherichia coli
|
50.0
|
|
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.
|
Fold increase in IC50 vs beta-lactamase with 10x increased enzyme
|
Escherichia coli
|
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 CYP450-mediated tangeretin demethylation in Aspergillus niger ATCC 9142 assessed as relative activity at 0.5 mM
|
Aspergillus niger
|
10.0
%
|
|
Journal : J. Nat. Prod.
Title : Biotransformation of polymethoxylated flavonoids: access to their 4'-O-demethylated metabolites.
Year : 2007
Volume : 70
Issue : 6
First Page : 1035
Last Page : 1038
Authors : Buisson D, Quintin J, Lewin G.
Abstract : Regioselective O-demethylation of the flavones tangeretin (1) and 3-hydroxytangeretin (6) into their 4'-O-demethylated metabolites was performed by using an Aspergillus niger strain. This method serves as a straightforward alternative to multistep synthesis or semisynthesis. The microbial approach is complementary to the chemical procedure, which furnishes a 5-O-demethylated product. P450 inhibitors prevented the biotransformation of tangeretin (1). These results suggest that a P450 oxidation system might be involved in this O-demethylation and demonstrate a consequent similarity in both microbial and mammalian metabolism of polymethoxylated flavones.
|
Inhibition of human CYP51 expressed in Topp 3 cells by lanosterol demethylase assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors.
Year : 2007
Volume : 35
Issue : 3
First Page : 493
Last Page : 500
Authors : Ekins S, Mankowski DC, Hoover DJ, Lawton MP, Treadway JL, Harwood HJ.
Abstract : CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential mono-oxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, whereas inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. To predict the interaction of inhibitors with the active site of human CYP51, a three-dimensional quantitative structure-activity relationship model was constructed. This pharmacophore model of the common structural features of CYP51 inhibitors was built using the program Catalyst from multiple inhibitors (n = 26) of recombinant human CYP51-mediated lanosterol 14alpha-demethylation. The pharmacophore, which consisted of one hydrophobe, one hydrogen bond acceptor, and two ring aromatic features, demonstrated a high correlation between observed and predicted IC(50) values (r = 0.92). Validation of this pharmacophore was performed by predicting the IC(50) of a test set of commercially available (n = 19) and CP-320626-related (n = 48) CYP51 inhibitors. Using predictions below 10 microM as a cutoff indicative of active inhibitors, 16 of 19 commercially available inhibitors (84%) and 38 of 48 CP-320626-related inhibitors (79.2%) were predicted correctly. To better understand how inhibitors fit into the enzyme, potent CYP51 inhibitors were used to build a Cerius(2) receptor surface model representing the volume of the active site. This study has demonstrated the potential for ligand-based computational pharmacophore modeling of human CYP51 and enables a high-throughput screening system for drug discovery and data base mining.
|
Antifungal activity against Candida albicans ATCC 26790
|
Candida albicans
|
8.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Two novel cyclic peptides with antifungal activity from the cyanobacterium Tolypothrix byssoidea (EAWAG 195).
Year : 2001
Volume : 64
Issue : 2
First Page : 154
Last Page : 158
Authors : Jaki B, Zerbe O, Heilmann J, Sticher O.
Abstract : Two novel cyclic tridecapeptides, tolybyssidins A (1) and B (2), were isolated from the culture medium of mass cultured cyanobacterium Tolypothrix byssoidea (EAWAG 195) by means of bioguided isolation. The gross structures of these peptides were determined by 1D and 2D NMR experiments and tandem mass spectrometry. Both peptides contain the nonnatural amino acid dehydrohomoalanine (Dhha) as well as proteinogenic amino acids albeit with D- or L-configuration. The compounds exhibit moderate antifungal activity against the yeast Candida albicans.
|
Inhibition of CYP3A4
|
None
|
851.14
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Comparative chemometric modeling of cytochrome 3A4 inhibitory activity of structurally diverse compounds using stepwise MLR, FA-MLR, PLS, GFA, G/PLS and ANN techniques.
Year : 2009
Volume : 44
Issue : 7
First Page : 2913
Last Page : 2922
Authors : Roy K, Pratim Roy P.
Abstract : Twenty-eight structurally diverse cytochrome 3A4 (CYP3A4) inhibitors have been subjected to quantitative structure-activity relationship (QSAR) studies. The analyses were performed with electronic, spatial, topological, and thermodynamic descriptors calculated using Cerius 2 version 10 software. The statistical tools used were linear [multiple linear regression with factor analysis as preprocessing step (FA-MLR), stepwise MLR, partial least squares (PLS), genetic function algorithm (GFA), genetic PLS (G/PLS)] and non-linear methods [artificial neural network (ANN)]. All the five linear modeling methods indicate the importance of n-octanol/water partition coefficient (logP) along with different topological and electronic parameters. The best model obtained from the training set (stepwise regression) based on highest external predictive R(2) value and lowest RMSEP value also showed good internal predictive power. Other models like FA-MLR, PLS, GFA and G/PLS are also of statistically significant internal and external validation characteristics. The best model [according to r(m)(2) for the test set, as defined by P.P. Roy, K. Roy, QSAR Comb. Sci. 27 (2008) 302-313] obtained from ANN showed a good r(2) value (determination coefficient between observed and predicted values) for the test set compounds, which was superior to those of other statistical models except the stepwise regression derived model. However, based upon the r(m)(2) value (test set), which penalizes a model for large differences between observed and predicted values, the stepwise MLR model was found to be inferior to other methods except PLS. Considering r(m)(2) value for the whole set, the G/PLS derived model appears to be the best predictive model for this data set. For choosing the best predictive model from among comparable models, r(m)(2) for the whole set calculated based on leave-one-out predicted values of the training set and model-derived predicted values for the test set compounds is suggested to be a good criterion.
|
Inhibition of human placental microsome CYP19
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacophore modeling strategies for the development of novel nonsteroidal inhibitors of human aromatase (CYP19).
Year : 2010
Volume : 20
Issue : 10
First Page : 3050
Last Page : 3064
Authors : Muftuoglu Y, Mustata G.
Abstract : The present study utilizes for the first time the structural information of aromatase, an important pharmacological target in anti-breast cancer therapy, to extract the pharmacophoric features important for interactions between the enzyme and its substrate, androstenedione. A ligand-based pharmacophore model developed from the most comprehensive list of nonsteroidal aromatase inhibitors (AIs) is described and explained, as well. This study demonstrates that the ligand-based pharmacophore model contributes to efficacy while the structure-based model contributes to specificity. It is also shown that a 'merged' model (i.e., a merged structure-based and ligand-based model) can successfully identify known AIs and differentiate between active and inactive inhibitors. Therefore, this model can be effectively used to identify the next generation of highly specific and less toxic aromatase inhibitors for breast cancer treatment.
|
Antimicrobial activity against Plasmodium yoelii 265 liver infected in mammalian hepatocytes after 48 hrs
|
Plasmodium yoelii yoelii
|
2.03
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : New active drugs against liver stages of Plasmodium predicted by molecular topology.
Year : 2008
Volume : 52
Issue : 4
First Page : 1215
Last Page : 1220
Authors : Mahmoudi N, Garcia-Domenech R, Galvez J, Farhati K, Franetich JF, Sauerwein R, Hannoun L, Derouin F, Danis M, Mazier D.
Abstract : We conducted a quantitative structure-activity relationship (QSAR) study based on a database of 127 compounds previously tested against the liver stage of Plasmodium yoelii in order to develop a model capable of predicting the in vitro antimalarial activities of new compounds. Topological indices were used as structural descriptors, and their relation to antimalarial activity was determined by using linear discriminant analysis. A topological model consisting of two discriminant functions was created. The first function discriminated between active and inactive compounds, and the second identified the most active among the active compounds. The model was then applied sequentially to a large database of compounds with unknown activity against liver stages of Plasmodium. Seventeen drugs that were predicted to be active or inactive were selected for testing against the hepatic stage of P. yoelii in vitro. Antiretroviral, antifungal, and cardiotonic drugs were found to be highly active (nanomolar 50% inhibitory concentration values), and two ionophores completely inhibited parasite development. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed on hepatocyte cultures for all compounds, and none of these compounds were toxic in vitro. For both ionophores, the same in vitro assay as those for P. yoelii has confirmed their in vitro activities on Plasmodium falciparum. A similar topological model was used to estimate the octanol/water partition of each compound. These results demonstrate the utility of the QSAR and molecular topology approaches for identifying new drugs that are active against the hepatic stage of malaria parasites. We also show the remarkable efficacy of some drugs that were not previously reported to have antiparasitic activity.
|
Binding affinity to Mycobacterium smegmatis ATCC 700084 CYP51 in presence of 0.5 M NaCl at pH7.5
|
Mycobacterium smegmatis
|
940.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification, characterization, and azole-binding properties of Mycobacterium smegmatis CYP164A2, a homolog of ML2088, the sole cytochrome P450 gene of Mycobacterium leprae.
Year : 2009
Volume : 53
Issue : 3
First Page : 1157
Last Page : 1164
Authors : Warrilow AG, Jackson CJ, Parker JE, Marczylo TH, Kelly DE, Lamb DC, Kelly SL.
Abstract : The genome sequence of Mycobacterium leprae revealed a single open reading frame, ML2088 (CYP164A1), encoding a putative full-length cytochrome P450 monooxygenase and 12 pseudogenes. We have identified a homolog of ML2088 in Mycobacterium smegmatis and report here the cloning, expression, purification, and azole-binding characteristics of this cytochrome P450 (CYP164A2). CYP164A2 is 1,245 bp long and encodes a protein of 414 amino acids and molecular mass of 45 kDa. CYP164A2 has 60% identity with Mycobacterium leprae CYP161A1 and 66 to 69% identity with eight other mycobacterial CYP164A1 homologs, with three identified highly conserved motifs. Recombinant CYP164A2 has the typical spectral characteristics of a cytochrome P450 monooxygenase, predominantly in the ferric low-spin state. Unusually, the spin state was readily modulated by increasing ionic strength at pH 7.5, with 50% high-spin occupancy achieved with 0.14 M NaCl. CYP164A2 bound clotrimazole, econazole, and miconazole strongly (K(d), 1.2 to 2.5 muM); however, strong binding with itraconazole, ketoconazole, and voriconazole was only observed in the presence of 0.5 M NaCl. Fluconazole did not bind to CYP164A2 at pH 7.5 and no discernible type II binding spectrum was observed.
|
Binding affinity to Mycobacterium tuberculosis CYP51
|
Mycobacterium tuberculosis
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification, characterization, and azole-binding properties of Mycobacterium smegmatis CYP164A2, a homolog of ML2088, the sole cytochrome P450 gene of Mycobacterium leprae.
Year : 2009
Volume : 53
Issue : 3
First Page : 1157
Last Page : 1164
Authors : Warrilow AG, Jackson CJ, Parker JE, Marczylo TH, Kelly DE, Lamb DC, Kelly SL.
Abstract : The genome sequence of Mycobacterium leprae revealed a single open reading frame, ML2088 (CYP164A1), encoding a putative full-length cytochrome P450 monooxygenase and 12 pseudogenes. We have identified a homolog of ML2088 in Mycobacterium smegmatis and report here the cloning, expression, purification, and azole-binding characteristics of this cytochrome P450 (CYP164A2). CYP164A2 is 1,245 bp long and encodes a protein of 414 amino acids and molecular mass of 45 kDa. CYP164A2 has 60% identity with Mycobacterium leprae CYP161A1 and 66 to 69% identity with eight other mycobacterial CYP164A1 homologs, with three identified highly conserved motifs. Recombinant CYP164A2 has the typical spectral characteristics of a cytochrome P450 monooxygenase, predominantly in the ferric low-spin state. Unusually, the spin state was readily modulated by increasing ionic strength at pH 7.5, with 50% high-spin occupancy achieved with 0.14 M NaCl. CYP164A2 bound clotrimazole, econazole, and miconazole strongly (K(d), 1.2 to 2.5 muM); however, strong binding with itraconazole, ketoconazole, and voriconazole was only observed in the presence of 0.5 M NaCl. Fluconazole did not bind to CYP164A2 at pH 7.5 and no discernible type II binding spectrum was observed.
|
Antifungal activity against 5 x 10'6 CFU/ml Microsporum canis B68128 by resazurin based fluorimetry assay
|
Arthroderma otae
|
230.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antifungal activity against 5 x 10'6 CFU/ml Trichophyton mentagrophytes B70554 by resazurin based fluorimetry assay
|
Trichophyton mentagrophytes
|
400.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antifungal activity against 5 x 10'6 CFU/ml Trichophyton rubrum B68183 by resazurin based fluorimetry assay
|
Trichophyton rubrum
|
330.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antifungal activity against 5 x 10'6 CFU/ml Trichophyton rubrum J941704 by resazurin based fluorimetry assay
|
Trichophyton rubrum
|
140.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antifungal activity against 5 x 10'6 CFU/ml Trichophyton quinckeanum B68683 by resazurin based fluorimetry assay
|
Trichophyton quinckeanum
|
790.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antifungal activity against 5 x 10'6 CFU/ml Candida albicans B59163 by resazurin based fluorimetry assay
|
Candida albicans
|
300.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antifungal activity against 5 x 10'6 CFU/ml Candida glabrata B63155 by resazurin based fluorimetry assay
|
Candida glabrata
|
120.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antifungal activity against 5 x 10'6 CFU/ml Candida kefyr B46120 by resazurin based fluorimetry assay
|
Kluyveromyces marxianus
|
30.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antipromastigote activity against Leishmania donovani MHOM/IN/80/Dd8 promastigotes assessed as luciferase activity of viable cells at 20 uM after 72 hrs by luminometry
|
Leishmania donovani
|
100.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and evaluation of new furanyl and thiophenyl azoles as antileishmanial agents.
Year : 2011
Volume : 46
Issue : 5
First Page : 1694
Last Page : 1700
Authors : Marrapu VK, Mittal M, Shivahare R, Gupta S, Bhandari K.
Abstract : A series of benzyloxy furanyl and benzyloxy thiophenyl azoles were synthesized and screened for their in vitro antileishmanial activity against Leishmania donovani. Among all, 16 compounds have shown more than 90% inhibition against promastigotes at 20 μM while 11 compounds exhibited IC50 in the range of 3.04-9.39 μM against amastigotes. Compound 4, a 3-chlorobenzyloxy furanyl imidazole emerged as the most active compound in the series with IC50 value of 3.04 μM and SI value of 19.80, and was several folds more potent than the reference drugs miltefosine and miconazole.
|
DRUGMATRIX: Muscarinic M1 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
956.0
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: Muscarinic M3 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
668.0
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: Muscarinic M4 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
446.0
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: Transporter, Serotonin (5-Hydroxytryptamine) (SERT) radioligand binding (ligand: [3H] Paroxetine)
|
None
|
778.0
nM
|
|
DRUGMATRIX: Transporter, Serotonin (5-Hydroxytryptamine) (SERT) radioligand binding (ligand: [3H] Paroxetine)
|
None
|
414.0
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: Thromboxane Synthetase enzyme inhibition (substrate: PGH2)
|
Homo sapiens
|
263.0
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: CYP450, 2C19 enzyme inhibition (substrate: 3-Cyano-7-ethoxycoumarin)
|
None
|
16.0
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: CYP450, 2C9 enzyme inhibition (substrate: 3-Cyano-7-ethoxycoumarin)
|
None
|
200.0
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: CYP450, 3A4 enzyme inhibition (substrate: 7-Benzyloxy-4-(trifluoromethyl)-coumarin)
|
None
|
100.0
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
|
Inhibition of mouse Tdo2 transfected in HEK293T cells using L-tryptophan as substrate assessed as kynurenine formation at 100 uM after 45 mins by spectrophotometric analysis relative to control
|
Mus musculus
|
95.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.
Year : 2012
Volume : 22
Issue : 24
First Page : 7641
Last Page : 7646
Authors : Bakmiwewa SM, Fatokun AA, Tran A, Payne RJ, Hunt NH, Ball HJ.
Abstract : The kynurenine pathway is responsible for the breakdown of the majority of the essential amino acid, tryptophan (Trp). The first and rate-limiting step of the kynurenine pathway can be independently catalysed by tryptophan 2,3-dioxygenase (Tdo2), indoleamine 2,3-dioxygenase 1 (Ido1) or indoleamine 2,3-dioxygenase 2 (Ido2). Tdo2 or Ido1 enzymatic activity has been implicated in a number of actions of the kynurenine pathway, including immune evasion by tumors. IDO2 is expressed in several human pancreatic cancer cell lines, suggesting it also may play a role in tumorigenesis. Although Ido2 was originally suggested to be a target of the chemotherapeutic agent dextro-1-methyl-tryptophan, subsequent studies suggest this compound does not inhibit Ido2 activity. The development of selective Ido2 inhibitors could provide valuable tools for investigating its activity in tumor development and normal physiology. In this study, a library of Food and Drug Administration-approved drugs was screened for inhibition of mouse Ido2 enzymatic activity. A number of candidates were identified and IC(50) values of each compound for Ido1 and Ido2 were estimated. The Ido2 inhibitors were also tested for inhibition of Tdo2 activity. Our results showed that compounds from a class of drugs used to inhibit proton pumps were the most potent and selective Ido2 inhibitors identified in the library screen. These included tenatoprazole, which exhibited an IC(50) value of 1.8μM for Ido2 with no inhibition of Ido1 or Tdo2 activity detected at a concentration of 100μM tenatoprazole. These highly-selective Ido2 inhibitors will be useful for defining the distinct biological roles of the three Trp-catabolizing enzymes.
|
Inhibition of mouse Ido2 transfected in HEK293T cells using L-tryptophan as substrate assessed as kynurenine formation at 20 uM after 45 mins by spectrophotometric analysis relative to control
|
Mus musculus
|
55.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.
Year : 2012
Volume : 22
Issue : 24
First Page : 7641
Last Page : 7646
Authors : Bakmiwewa SM, Fatokun AA, Tran A, Payne RJ, Hunt NH, Ball HJ.
Abstract : The kynurenine pathway is responsible for the breakdown of the majority of the essential amino acid, tryptophan (Trp). The first and rate-limiting step of the kynurenine pathway can be independently catalysed by tryptophan 2,3-dioxygenase (Tdo2), indoleamine 2,3-dioxygenase 1 (Ido1) or indoleamine 2,3-dioxygenase 2 (Ido2). Tdo2 or Ido1 enzymatic activity has been implicated in a number of actions of the kynurenine pathway, including immune evasion by tumors. IDO2 is expressed in several human pancreatic cancer cell lines, suggesting it also may play a role in tumorigenesis. Although Ido2 was originally suggested to be a target of the chemotherapeutic agent dextro-1-methyl-tryptophan, subsequent studies suggest this compound does not inhibit Ido2 activity. The development of selective Ido2 inhibitors could provide valuable tools for investigating its activity in tumor development and normal physiology. In this study, a library of Food and Drug Administration-approved drugs was screened for inhibition of mouse Ido2 enzymatic activity. A number of candidates were identified and IC(50) values of each compound for Ido1 and Ido2 were estimated. The Ido2 inhibitors were also tested for inhibition of Tdo2 activity. Our results showed that compounds from a class of drugs used to inhibit proton pumps were the most potent and selective Ido2 inhibitors identified in the library screen. These included tenatoprazole, which exhibited an IC(50) value of 1.8μM for Ido2 with no inhibition of Ido1 or Tdo2 activity detected at a concentration of 100μM tenatoprazole. These highly-selective Ido2 inhibitors will be useful for defining the distinct biological roles of the three Trp-catabolizing enzymes.
|
Antimicrobial activity against Fusarium solani at 200 ug/ml after 7 days by agar plate method
|
Fusarium solani
|
90.0
%
|
|
Journal : Med Chem Res
Title : Synthesis and antimicrobial evaluation of novel benzo[b]thiophenes comprising -lactam nucleus
Year : 2012
Volume : 21
Issue : 7
First Page : 1471
Last Page : 1479
Authors : Trivedi AR, Desai JM, Dholariya BH, Dodiya DK, Shah VH
|
Antimicrobial activity against Arthroderma otae at 200 ug/ml after 7 days by agar plate method
|
Arthroderma otae
|
90.0
%
|
|
Journal : Med Chem Res
Title : Synthesis and antimicrobial evaluation of novel benzo[b]thiophenes comprising -lactam nucleus
Year : 2012
Volume : 21
Issue : 7
First Page : 1471
Last Page : 1479
Authors : Trivedi AR, Desai JM, Dholariya BH, Dodiya DK, Shah VH
|
Antimicrobial activity against Trichophyton longifusum at 200 ug/ml after 7 days by agar plate method
|
Trichophyton longifusum
|
100.0
%
|
|
Journal : Med Chem Res
Title : Synthesis and antimicrobial evaluation of novel benzo[b]thiophenes comprising -lactam nucleus
Year : 2012
Volume : 21
Issue : 7
First Page : 1471
Last Page : 1479
Authors : Trivedi AR, Desai JM, Dholariya BH, Dodiya DK, Shah VH
|
Antimicrobial activity against Candida albicans at 200 ug/ml after 7 days by agar plate method
|
Candida albicans
|
90.0
%
|
|
Journal : Med Chem Res
Title : Synthesis and antimicrobial evaluation of novel benzo[b]thiophenes comprising -lactam nucleus
Year : 2012
Volume : 21
Issue : 7
First Page : 1471
Last Page : 1479
Authors : Trivedi AR, Desai JM, Dholariya BH, Dodiya DK, Shah VH
|
Antileishmanial activity against amastigotes of Leishmania donovani assessed as inhibition of parasite growth at 40 uM after 72 hrs by luciferase reporter assay
|
Leishmania donovani
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Chemotherapy of leishmaniasis. Part XII: design, synthesis and bioevaluation of novel triazole integrated phenyl heteroterpenoids as antileishmanial agents.
Year : 2013
Volume : 23
Issue : 10
First Page : 2925
Last Page : 2928
Authors : Suryawanshi SN, Tiwari A, Kumar S, Shivahare R, Mittal M, Kant P, Gupta S.
Abstract : A novel series of triazole integrated phenyl heteroterpenoids have been synthesized and screened for their in vitro activity against intracellular amastigote form of Leishmania donovani. Among all tested compounds, compound 3a was found to be the most active with IC50 6.4μM and better selectivity index (SI) 18 as compared to reference drugs, miltefosine and miconazole. When evaluated in vivo in L. donovani/hamster model, 3a has exhibited 79±11% inhibition of parasite multiplication at 50mgkg(-1)×5days on day 7 post treatment.
|
Inhibition of IDO1 (unknown origin) at highest soluble concentration using L-tryptophan substrate incubated for 60 mins by HPLC
|
Homo sapiens
|
77.2
%
|
|
Journal : Eur. J. Med. Chem.
Title : Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.
Year : 2014
Volume : 84
First Page : 284
Last Page : 301
Authors : Röhrig UF, Majjigapu SR, Chambon M, Bron S, Pilotte L, Colau D, Van den Eynde BJ, Turcatti G, Vogel P, Zoete V, Michielin O.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 μM under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 inhibitor scaffold, the imidazole antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity.
|
Inhibition of recombinant human CYP2C19 preincubated at 10 uM for 5 mins before fluorescent substrate addition by fluorescence assay
|
Homo sapiens
|
8.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3234
Last Page : 3237
Authors : Yun J, Han M, Song C, Cheon SH, Choi K, Hahn HG.
Abstract : We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.
|
DNDI: Chagas in Vitro, 96 hour
|
Trypanosoma cruzi
|
40.0
nM
|
|
Title : Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning
Authors : Kaiser M, Mäser P, Tadoori LP, Ioset JR, Brun R.
Abstract : In this study, a set of 100 registered drugs with drug repositioning potential for neglected tropical diseases was assembled. The compound collection was systematically screened against protozoan parasites, namely T. b. rhodesiense, L. donovani, T. cruzi and P. falciparum. Several drugs and drug classes exhibited in vitro activity and selectivity against one of the protozoan parasites. The results offer opportunities for drug repurposing and the identified compound classes could also be a starting point for new drug discovery projects. See also publication: Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning. PLoS One. 2015 10(8): e0135556.
|
DNDI: Malaria in Vitro, 72 hour
|
Plasmodium falciparum
|
490.0
nM
|
|
Title : Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning
Authors : Kaiser M, Mäser P, Tadoori LP, Ioset JR, Brun R.
Abstract : In this study, a set of 100 registered drugs with drug repositioning potential for neglected tropical diseases was assembled. The compound collection was systematically screened against protozoan parasites, namely T. b. rhodesiense, L. donovani, T. cruzi and P. falciparum. Several drugs and drug classes exhibited in vitro activity and selectivity against one of the protozoan parasites. The results offer opportunities for drug repurposing and the identified compound classes could also be a starting point for new drug discovery projects. See also publication: Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning. PLoS One. 2015 10(8): e0135556.
|
Fungicidal activity against Microsporum canis B68128
|
Microsporum canis
|
0.02
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : 2-(2-oxo-morpholin-3-yl)-acetamide derivatives as broad-spectrum antifungal agents.
Year : 2015
Volume : 58
Issue : 3
First Page : 1502
Last Page : 1512
Authors : Bardiot D, Thevissen K, De Brucker K, Peeters A, Cos P, Taborda CP, McNaughton M, Maes L, Chaltin P, Cammue BP, Marchand A.
Abstract : From a fungicidal screen, we identified 2-(2-oxo-morpholin-3-yl)-acetamide derivatives as fungicidal agents against Candida species, additionally characterized by antifungal activity against Aspergillus species. However, development of this series was hampered by low plasmatic stability. Introduction of a gem-dimethyl on the 6-position of the morpholin-2-one core led to considerable improvement in plasmatic stability while maintaining in vitro antifungal activity. Further optimization of the series resulted in the discovery of N-(biphenyl-3-ylmethyl)-2-(4-ethyl-6,6-dimethyl-2-oxomorpholin-3-yl)acetamide (87), which, in addition to fungicidal activity against Candida species, shows promising and broad antifungal in vitro activity against various fungi species, such as molds and dermatophytes. In vivo efficacy was also demonstrated in a murine model of systemic Candida albicans infection with a significant fungal load reduction in kidneys.
|
Fungicidal activity against Sporothrix schenckii B62482
|
Sporothrix schenckii
|
0.12
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : 2-(2-oxo-morpholin-3-yl)-acetamide derivatives as broad-spectrum antifungal agents.
Year : 2015
Volume : 58
Issue : 3
First Page : 1502
Last Page : 1512
Authors : Bardiot D, Thevissen K, De Brucker K, Peeters A, Cos P, Taborda CP, McNaughton M, Maes L, Chaltin P, Cammue BP, Marchand A.
Abstract : From a fungicidal screen, we identified 2-(2-oxo-morpholin-3-yl)-acetamide derivatives as fungicidal agents against Candida species, additionally characterized by antifungal activity against Aspergillus species. However, development of this series was hampered by low plasmatic stability. Introduction of a gem-dimethyl on the 6-position of the morpholin-2-one core led to considerable improvement in plasmatic stability while maintaining in vitro antifungal activity. Further optimization of the series resulted in the discovery of N-(biphenyl-3-ylmethyl)-2-(4-ethyl-6,6-dimethyl-2-oxomorpholin-3-yl)acetamide (87), which, in addition to fungicidal activity against Candida species, shows promising and broad antifungal in vitro activity against various fungi species, such as molds and dermatophytes. In vivo efficacy was also demonstrated in a murine model of systemic Candida albicans infection with a significant fungal load reduction in kidneys.
|
Inhibition of CYP2J2 in human liver microsomes using 7 probe cocktail containing phenacetin, paclitaxel, diclofenac, S-mephenytoin, dextromethorphan, astemizole and midazolam after 8 mins by LC-MS/MS analysis
|
Homo sapiens
|
640.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Identifying a selective substrate and inhibitor pair for the evaluation of CYP2J2 activity.
Year : 2012
Volume : 40
Issue : 5
First Page : 943
Last Page : 951
Authors : Lee CA, Jones JP, Katayama J, Kaspera R, Jiang Y, Freiwald S, Smith E, Walker GS, Totah RA.
Abstract : CYP2J2, an arachidonic acid epoxygenase, is recognized for its role in the first-pass metabolism of astemizole and ebastine. To fully assess the role of CYP2J2 in drug metabolism, a selective substrate and potent specific chemical inhibitor are essential. In this study, we report amiodarone 4-hydoxylation as a specific CYP2J2-catalyzed reaction with no CYP3A4, or other drug-metabolizing enzyme, involvement. Amiodarone 4-hydroxylation enabled the determination of liver relative activity factor and intersystem extrapolation factor for CYP2J2. Amiodarone 4-hydroxylation correlated with astemizole O-demethylation but not with CYP2J2 protein content in a sample of human liver microsomes. To identify a specific CYP2J2 inhibitor, 138 drugs were screened using terfenadine and astemizole as probe substrates with recombinant CYP2J2. Forty-two drugs inhibited CYP2J2 activity by ≥50% at 30 μM, but inhibition was substrate-dependent. Of these, danazol was a potent inhibitor of both hydroxylation of terfenadine (IC(50) = 77 nM) and O-demethylation of astemizole (K(i) = 20 nM), and inhibition was mostly competitive. Danazol inhibited CYP2C9, CYP2C8, and CYP2D6 with IC(50) values of 1.44, 1.95, and 2.74 μM, respectively. Amiodarone or astemizole were included in a seven-probe cocktail for cytochrome P450 (P450) drug-interaction screening potential, and astemizole demonstrated a better profile because it did not appreciably interact with other P450 probes. Thus, danazol, amiodarone, and astemizole will facilitate the ability to determine the metabolic role of CYP2J2 in hepatic and extrahepatic tissues.
|
Inhibition of CYP2J2-mediated astemizole O-demethylation in human liver microsomes after 8 mins by LC-MS/MS analysis
|
Homo sapiens
|
580.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Identifying a selective substrate and inhibitor pair for the evaluation of CYP2J2 activity.
Year : 2012
Volume : 40
Issue : 5
First Page : 943
Last Page : 951
Authors : Lee CA, Jones JP, Katayama J, Kaspera R, Jiang Y, Freiwald S, Smith E, Walker GS, Totah RA.
Abstract : CYP2J2, an arachidonic acid epoxygenase, is recognized for its role in the first-pass metabolism of astemizole and ebastine. To fully assess the role of CYP2J2 in drug metabolism, a selective substrate and potent specific chemical inhibitor are essential. In this study, we report amiodarone 4-hydoxylation as a specific CYP2J2-catalyzed reaction with no CYP3A4, or other drug-metabolizing enzyme, involvement. Amiodarone 4-hydroxylation enabled the determination of liver relative activity factor and intersystem extrapolation factor for CYP2J2. Amiodarone 4-hydroxylation correlated with astemizole O-demethylation but not with CYP2J2 protein content in a sample of human liver microsomes. To identify a specific CYP2J2 inhibitor, 138 drugs were screened using terfenadine and astemizole as probe substrates with recombinant CYP2J2. Forty-two drugs inhibited CYP2J2 activity by ≥50% at 30 μM, but inhibition was substrate-dependent. Of these, danazol was a potent inhibitor of both hydroxylation of terfenadine (IC(50) = 77 nM) and O-demethylation of astemizole (K(i) = 20 nM), and inhibition was mostly competitive. Danazol inhibited CYP2C9, CYP2C8, and CYP2D6 with IC(50) values of 1.44, 1.95, and 2.74 μM, respectively. Amiodarone or astemizole were included in a seven-probe cocktail for cytochrome P450 (P450) drug-interaction screening potential, and astemizole demonstrated a better profile because it did not appreciably interact with other P450 probes. Thus, danazol, amiodarone, and astemizole will facilitate the ability to determine the metabolic role of CYP2J2 in hepatic and extrahepatic tissues.
|
Binding affinity to Mycobacterium tuberculosis H37Rv wild type CYP121 by titration assay
|
Mycobacterium tuberculosis H37Rv
|
73.0
nM
|
|
Journal : J. Med. Chem.
Title : Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors.
Year : 2016
Volume : 59
Issue : 7
First Page : 3272
Last Page : 3302
Authors : Kavanagh ME, Coyne AG, McLean KJ, James GG, Levy CW, Marino LB, de Carvalho LP, Chan DS, Hudson SA, Surade S, Leys D, Munro AW, Abell C.
Abstract : The essential enzyme CYP121 is a target for drug development against antibiotic resistant strains of Mycobacterium tuberculosis. A triazol-1-yl phenol fragment 1 was identified to bind to CYP121 using a cascade of biophysical assays. Synthetic merging and optimization of 1 produced a 100-fold improvement in binding affinity, yielding lead compound 2 (KD = 15 μM). Deconstruction of 2 into its component retrofragments allowed the group efficiency of structural motifs to be assessed, the identification of more LE scaffolds for optimization and highlighted binding affinity hotspots. Structure-guided addition of a metal-binding pharmacophore onto LE retrofragment scaffolds produced low nanomolar (KD = 15 nM) CYP121 ligands. Elaboration of these compounds to target binding hotspots in the distal active site afforded compounds with excellent selectivity against human drug-metabolizing P450s. Analysis of the factors governing ligand potency and selectivity using X-ray crystallography, UV-vis spectroscopy, and native mass spectrometry provides insight for subsequent drug development.
|
Cytotoxicity against human MRC5 cells incubated for 48 hrs by MTT assay
|
Homo sapiens
|
61.7
ug.mL-1
|
|
Journal : MedChemComm
Title : Design, synthesis, and antimicrobial evaluation of 1,4-dihydroindeno[1,2-<i>c</i>]pyrazole tethered carbohydrazide hybrids: exploring their <i>in silico</i> ADMET, ergosterol inhibition and ROS inducing potential.
Year : 2019
Volume : 10
Issue : 5
First Page : 806
Last Page : 813
Authors : Shareef MA, Sirisha K, Khan I, Sayeed IB, Jadav SS, Ramu G, Kumar CG, Kamal A, Babu BN.
Abstract : A series of new 1,4-dihydroindeno[1,2-<i>c</i>]pyrazole tethered carbohydrazide hybrids (<b>5a-u</b>) were designed, synthesized and evaluated for their antimicrobial activity. Compounds <b>5d</b>, <b>5g</b>, <b>5j</b>, <b>5k</b> and <b>5q</b> demonstrated significant activity against the entire panel of test pathogens. Further, compounds <b>5d</b> and <b>5g</b> exhibited significant anti-<i>Candida</i> activity. These potential hybrids (<b>5d</b> and <b>5g</b>) also exhibited promising ergosterol biosynthesis inhibition against <i>Candida albicans</i>, which was further validated through molecular docking studies. Furthermore, compounds <b>5d</b> and <b>5g</b> caused intracellular ROS accumulation in <i>C. albicans</i> MTCC 3017 and were non-toxic to normal human lung cell line MRC5. <i>In silico</i> studies revealed that they demonstrated drug likeness and an appreciable pharmacokinetic profile. Overall, the findings demonstrate that <b>5d</b> and <b>5g</b> may be considered as promising leads for further development of new antifungal drugs.
|
Inhibition of transglutaminase in human keratinocytes in presence of 10 uM retinal relative to retinal alone
|
Homo sapiens
|
278.0
nM
|
|
Title : Method for treating skin with retinoids and retinoid boosters
|
Inhibition of cytochrome P450 in Sprague-Dawley rat liver microsomes assessed as inhibition of NADPH-dependent retinoic acid oxidation at 10 uM incubated for 5 mins followed by retinoic acid addition and further incubated for 60 mins by HPLC analysis relative to control
|
Rattus norvegicus
|
74.0
%
|
|
Title : Method for treating skin with retinoids and retinoid boosters
|
Inhibition of cytochrome P450 in Sprague-Dawley rat liver microsomes assessed as inhibition of NADPH-dependent retinoic acid oxidation at 100 uM incubated for 5 mins followed by retinoic acid addition and further incubated for 60 mins by HPLC analysis relative to control
|
Rattus norvegicus
|
86.0
%
|
|
Title : Method for treating skin with retinoids and retinoid boosters
|
Inhibition of CYP3A4 (unknown origin)
|
Homo sapiens
|
850.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Strategies for the development of highly selective cytochrome P450 inhibitors: Several CYP targets in current research.
Year : 2019
Volume : 29
Issue : 16
First Page : 2016
Last Page : 2024
Authors : Zhao L, Sun N, Tian L, Zhao S, Sun B, Sun Y, Zhao D.
Abstract : Cytochromes P450 (CYPs) play an important role in the metabolism of endogenic and xenobiotic substances, especially drugs. In addition, many CYPs may serve as targets for disease treatment. However, due to the presence of a common heme, the hydrophobicity of the CYP binding cavity, and the high homology within the binding pocket, most CYP inhibitors lack selectivity, which often leads to drug-drug interactions. Therefore, it is meaningful to develop highly selective CYP inhibitors. In this review, we summarize some of the strategies that have been used to develop highly selective CYP inhibitors, such as the weakening of the heme-binding group interaction, reduction of molecular lipophilicity and introduction of small structural changes within compounds.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.26
%
|
|
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
|
-0.27
%
|
|
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
|
-0.27
%
|
|
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.
|
Antimalarial activity against chloroquine resistant Plasmodium falciparum
|
Plasmodium falciparum
|
200.0
nM
|
|
Journal : RSC Med Chem
Title : An epigrammatic status of the azole-based antimalarial drugs
Year : 2020
Volume : 11
Issue : 2
First Page : 184
Last Page : 211
Authors : Sharma, Mousmee, Prasher, Parteek
Abstract : The development of multidrug resistance in the malarial parasite has sabotaged majority of the eradication efforts by restraining the inhibition profile of first line as well as second line antimalarial drugs, thus necessitating the development of novel pharmaceutics constructed on appropriate scaffolds with superior potency against the drug-resistant and drug-susceptible Plasmodium parasite. Over the past decades, the infectious malarial parasite has developed resistance against most of the contemporary therapeutics, thus necessitating the rational development of novel approaches principally focused on MDR malaria. This review presents an epigrammatic collation of the epidemiology and the contemporary antimalarial therapeutics based on the 'azole' motif.
|
Antimalarial activity against chloroquine sensitive Plasmodium falciparum
|
Plasmodium falciparum
|
200.0
nM
|
|
Journal : RSC Med Chem
Title : An epigrammatic status of the azole-based antimalarial drugs
Year : 2020
Volume : 11
Issue : 2
First Page : 184
Last Page : 211
Authors : Sharma, Mousmee, Prasher, Parteek
Abstract : The development of multidrug resistance in the malarial parasite has sabotaged majority of the eradication efforts by restraining the inhibition profile of first line as well as second line antimalarial drugs, thus necessitating the development of novel pharmaceutics constructed on appropriate scaffolds with superior potency against the drug-resistant and drug-susceptible Plasmodium parasite. Over the past decades, the infectious malarial parasite has developed resistance against most of the contemporary therapeutics, thus necessitating the rational development of novel approaches principally focused on MDR malaria. This review presents an epigrammatic collation of the epidemiology and the contemporary antimalarial therapeutics based on the 'azole' motif.
|
Cytotoxicity against human HL-60 cells assessed as reduction in cell viability incubated for 96 hrs by MTT assay
|
Homo sapiens
|
800.0
nM
|
|
|
Anti-biofilm activity in Candida albicans CPCC400616 assessed as inhibition of biofilm formation at 32 ug/ml incubated for 24 hrs with 3 hrs precultured fungal suspension by XTT assay relative to control
|
Candida albicans
|
50.0
%
|
|
|
Inhibition of CYP3A4 in human liver microsome using Nifedipine as a substrate incubated for 10 mins in the presence of NADPH by LC-MS/MS analysis
|
Homo sapiens
|
74.2
nM
|
|
