|
Percent inhibition of adenosine uptake by Plasmodium berghei
|
Plasmodium berghei
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : Syntheses of 9-acridine- and 2-phenanthridinemethanols as potential antimalarials.
Year : 1981
Volume : 24
Issue : 8
First Page : 1016
Last Page : 1018
Authors : Muth CW, Minigh HL, Chookruvong S, Hall LA, Chao HT.
Abstract : alpha-(1-Piperidinylmethyl)-9-acridinemethanol (3), alpha-[(dibutylamino)ethyl]-9-acridanmethanol (4a), and alpha-[(dibutylamino)methyl]-2-phenanthridinemethanol (5) have been made and all are ineffective as antimalarials against Plasmodium berghei in mice. 9-Acridinyloxirane showed no significant mutagenicity for strains TA 98 or TA 100 of Salmonella typhimurium.
|
Percent inhibition of hypoxanthine uptake by Plasmodium berghei
|
Plasmodium berghei
|
92.0
%
|
|
Journal : J. Med. Chem.
Title : Syntheses of 9-acridine- and 2-phenanthridinemethanols as potential antimalarials.
Year : 1981
Volume : 24
Issue : 8
First Page : 1016
Last Page : 1018
Authors : Muth CW, Minigh HL, Chookruvong S, Hall LA, Chao HT.
Abstract : alpha-(1-Piperidinylmethyl)-9-acridinemethanol (3), alpha-[(dibutylamino)ethyl]-9-acridanmethanol (4a), and alpha-[(dibutylamino)methyl]-2-phenanthridinemethanol (5) have been made and all are ineffective as antimalarials against Plasmodium berghei in mice. 9-Acridinyloxirane showed no significant mutagenicity for strains TA 98 or TA 100 of Salmonella typhimurium.
|
Inhibitory activity against synovial human recombinant phospholipase (hr-PLA2) at 1 mM concentration
|
None
|
48.9
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of 2'-hydroxychalcones and flavones as inhibitors of inflammatory mediators generation.
Year : 1995
Volume : 38
Issue : 14
First Page : 2794
Last Page : 2797
Authors : Ballesteros JF, Sanz MJ, Ubeda A, Miranda MA, Iborra S, Payá M, Alcaraz MJ.
Abstract : 2'-Hydroxy-3,4-dimethoxy-3',4'-dimethylchalcone (3a), 2'-hydroxy-3',4',3,4-tetramethoxychalcone (3b), and their corresponding flavones, 3',4'-dimethoxy-7,8-dimethylflavone (4a) and 3',4',7,8-tetramethoxyflavone (4b), were prepared from 3,4-dimethoxycinnamic acid and the respective phenol. The four compounds inhibited enzymic lipid peroxidation and showed weak peroxyl scavenging activity. They also reduced LTB4 release from human neutrophils stimulated by A23187. The chalcone 3b was the only compound able to inhibit in a concentration-dependent way, synovial human recombinant phospholipase A2 activity, human platelet TXB2 generation, and human neutrophil degranulation. This chalcone exerted topical antiinflammatory effects in mice.
|
Compound was tested for the percent inhibition of phospholipase A2 (PLA2) in rabbit heart membranes at a concentration of 100 uM.
|
Oryctolagus cuniculus
|
14.9
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of substituted benzenesulfonamides as novel potent membrane-bound phospholipase A2 inhibitors.
Year : 1991
Volume : 34
Issue : 7
First Page : 2260
Last Page : 2267
Authors : Oinuma H, Takamura T, Hasegawa T, Nomoto K, Naitoh T, Daiku Y, Hamano S, Kakisawa H, Minami N.
Abstract : A novel series of 4-[N-methyl-N-[(E)-3-[4-(methylsulfonyl)phenyl]-2- propenoyl]amino]benzenesulfonamides has been prepared and evaluated as membrane-bound phospholipase A2 inhibitors. A structure-activity relationship study indicated that the optimum potency was realized with the N-(phenylalkyl)piperidine derivatives 3 and 4. These compounds inhibited the liberation of arachidonic acid from the rabbit heart membrane fraction with IC30 values of 0.028 and 0.009 microM, respectively. Several compounds (3, 4, and 28), which proved to be potent inhibitors in vitro, significantly reduced the size of myocardial infarction in coronary occluded rats by iv administrations prior to the ligation. N-(1-Benzyl-4-piperidinyl)-4-[N-methyl-N-[(E)-3-[ 4-(methylsulfonyl)phenyl]-2-propenoyl]amino]-benzenesulfonamide (3, ER-3826), which showed the protective in vivo effects at doses higher than 0.3 mg/kg iv, was finally chosen as a leading candidate.
|
Half maximal inhibition of Prion protein PrPsc formation was assayed in ScN2a cells
|
None
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Antimalarial drug quinacrine binds to C-terminal helix of cellular prion protein.
Year : 2003
Volume : 46
Issue : 17
First Page : 3563
Last Page : 3564
Authors : Vogtherr M, Grimme S, Elshorst B, Jacobs DM, Fiebig K, Griesinger C, Zahn R.
Abstract : Using NMR spectroscopy we show that the cellular prion protein constitutes a target for binding of various acridine and phenothiazine derivatives. We unambiguously map the quinacrine binding site of recombinant human prion protein to residues Tyr225, Tyr226, and Gln227 of helix alpha3, which is located near the "protein X" epitope. The millimolar dissociation constant of the complex suggests that in vivo inhibition of prion propagation occurs after 10000-fold concentration of quinacrine within endolysosomes.
|
Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex at 10 uM
|
Cavia porcellus
|
73.3
%
|
|
Journal : J. Med. Chem.
Title : [3H]Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs.
Year : 1985
Volume : 28
Issue : 3
First Page : 381
Last Page : 388
Authors : McNeal ET, Lewandowski GA, Daly JW, Creveling CR.
Abstract : [3H]Batrachotoxinin A benzoate ( [3H]BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of [3H]BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of [3H]BTX-B binding provides a rapid, quantitative, and facile method for the screening and investigation of local anesthetic activity.
|
Inhibition of purified telomerase of Euplotes aediculatus at 50 uM
|
Euplotes aediculatus
|
75.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
Year : 2004
Volume : 14
Issue : 13
First Page : 3467
Last Page : 3471
Authors : Dominick PK, Keppler BR, Legassie JD, Moon IK, Jarstfer MB.
Abstract : We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors.
|
Inhibition of telomerase after assembly using recombinant Tetraymena thermophilia TR and TERT at 50 uM
|
Tetrahymena thermophila
|
80.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
Year : 2004
Volume : 14
Issue : 13
First Page : 3467
Last Page : 3471
Authors : Dominick PK, Keppler BR, Legassie JD, Moon IK, Jarstfer MB.
Abstract : We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors.
|
Inhibition of telomerase before assembly using recombinant Tetraymena thermophilia TR and TERT at 50 uM
|
Tetrahymena thermophila
|
93.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
Year : 2004
Volume : 14
Issue : 13
First Page : 3467
Last Page : 3471
Authors : Dominick PK, Keppler BR, Legassie JD, Moon IK, Jarstfer MB.
Abstract : We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors.
|
Inhibition of human telomerase after assembly using recombinant hTR and hTERT at 50 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
Year : 2004
Volume : 14
Issue : 13
First Page : 3467
Last Page : 3471
Authors : Dominick PK, Keppler BR, Legassie JD, Moon IK, Jarstfer MB.
Abstract : We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors.
|
Inhibition of human telomerase before assembly using recombinant hTR and hTERT at 50 uM
|
Homo sapiens
|
82.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
Year : 2004
Volume : 14
Issue : 13
First Page : 3467
Last Page : 3471
Authors : Dominick PK, Keppler BR, Legassie JD, Moon IK, Jarstfer MB.
Abstract : We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors.
|
In vitro cytotoxicity against transformed chinese hamster fibroblast line UV4.
|
Cricetulus griseus
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : DNA-directed alkylating agents. 1. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the reactivity of the mustard.
Year : 1990
Volume : 33
Issue : 4
First Page : 1177
Last Page : 1186
Authors : Gourdie TA, Valu KK, Gravatt GL, Boritzki TJ, Baguley BC, Wakelin LP, Wilson WR, Woodgate PD, Denny WA.
Abstract : A series of DNA-targeted aniline mustards have been prepared, and their chemical reactivity and in vitro and in vivo cytotoxicity have been evaluated and compared with that of the corresponding simple aniline mustards. The alkylating groups were anchored to the DNA-intercalating 9-aminoacridine chromophore by an alkyl chain of fixed length attached at the mustard 4-position through a link group X, while the corresponding simple mustards possessed an electronically identical small group at this position. The link group was varied to provide a series of compounds of similar geometry but widely differing mustard reactivity. Variation in biological activity should then largely be a consequence of this varying reactivity. Rates of mustard hydrolysis in the two series related only to the electronic properties of the link group, with attachment of the intercalating chromophore having no effect. The cytotoxicities of the simple mustards correlated well with group electronic properties (with a 200-300-fold range in IC50S). The corresponding DNA-targeted mustards were much more potent (up to 100-fold), but their IC50 values varied much less with linker group electronic properties. Most of the DNA-targeted mustards showed in vivo antitumor activity, being both more active and more dose-potent than either the corresponding untargeted mustards and chlorambucil. These results show that targeting alkylating agents to DNA by attachment to DNA-affinic units may be a useful strategy.
|
Effective concentration against Plasmodium falciparum W2
|
Plasmodium falciparum
|
8.0
nM
|
|
Effective concentration against Plasmodium falciparum W2
|
Plasmodium falciparum
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities.
Year : 2005
Volume : 15
Issue : 4
First Page : 1015
Last Page : 1018
Authors : Madrid PB, Sherrill J, Liou AP, Weisman JL, Derisi JL, Guy RK.
Abstract : A simple two-step synthesis method was used to make 51 B-ring-substituted 4-hydroxyquinolines allowing analysis of the effect of ring substitutions on inhibition of growth of chloroquine sensitive and resistant strains of Plasmodium falciparum, the dominant cause of malaria morbidity. Substituted quinoline rings other than the 7-chloroquinoline ring found in chloroquine were found to have significant activity against the drug-resistant strain of P. falciparum W2.
|
Effective concentration for Plasmodium falciparum 3D7
|
Plasmodium falciparum
|
5.0
nM
|
|
Effective concentration for Plasmodium falciparum 3D7
|
Plasmodium falciparum
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities.
Year : 2005
Volume : 15
Issue : 4
First Page : 1015
Last Page : 1018
Authors : Madrid PB, Sherrill J, Liou AP, Weisman JL, Derisi JL, Guy RK.
Abstract : A simple two-step synthesis method was used to make 51 B-ring-substituted 4-hydroxyquinolines allowing analysis of the effect of ring substitutions on inhibition of growth of chloroquine sensitive and resistant strains of Plasmodium falciparum, the dominant cause of malaria morbidity. Substituted quinoline rings other than the 7-chloroquinoline ring found in chloroquine were found to have significant activity against the drug-resistant strain of P. falciparum W2.
|
Inhibition of PrPSc accumulation in mouse ScN2a cell line relative to control
|
Mus musculus
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-activity relationship study of 9-aminoacridine compounds in scrapie-infected neuroblastoma cells.
Year : 2006
Volume : 16
Issue : 18
First Page : 4913
Last Page : 4916
Authors : May BC, Witkop J, Sherrill J, Anderson MO, Madrid PB, Zorn JA, Prusiner SB, Cohen FE, Guy RK.
Abstract : A focused library of variously substituted 9-aminoacridine compounds was screened for bioactivity against accumulation of the infectious prion protein isoform, denoted PrP(Sc), in a cell model of prion replication. The efficacy of compounds against PrP(Sc) accumulation was influenced by both substituents of the distal tertiary amine and acridine heterocycle, while cellular cytotoxicity was encoded in the acridine heterocycle substituents.
|
Inhibition of protease-resistant scrapie prion protein activity in ScN2a cells
|
Mus musculus
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : A chimeric ligand approach leading to potent antiprion active acridine derivatives: design, synthesis, and biological investigations.
Year : 2006
Volume : 49
Issue : 22
First Page : 6591
Last Page : 6595
Authors : Dollinger S, Löber S, Klingenstein R, Korth C, Gmeiner P.
Abstract : Human transmissible neurodegenerations including Creutzfeldt-Jakob disease are unique, since they are caused by prions, an infectious agent that replicates without nucleic acids but instead by inducing conversion of a host-resident normal prion protein to a misfolded conformational isoform. For pharmacotherapy of these unusual diseases, tricyclic heterocyclic compounds such as quinacrine have been considered, but with ambiguous success in vivo, so far. On the basis of the synergistic antiprion effects of quinacrine and iminodibenzyl derivatives, we introduce a novel class of potential pharmaceuticals representing structural chimeras of quinacrine and imipramine analogues. We describe the chemical synthesis and bioassays of a focused library of these compounds. The most potent target compound 2a revealed an EC(50) value of 20 nM determined with a cell model of prion disease, thus substantially improving the antiprion efficacy of quinacrine.
|
Reduction of PrPSC accumulation in ScN2a cells
|
Mus musculus
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship study of prion inhibition by 2-aminopyridine-3,5-dicarbonitrile-based compounds: parallel synthesis, bioactivity, and in vitro pharmacokinetics.
Year : 2007
Volume : 50
Issue : 1
First Page : 65
Last Page : 73
Authors : May BC, Zorn JA, Witkop J, Sherrill J, Wallace AC, Legname G, Prusiner SB, Cohen FE.
Abstract : 2-Aminopyridine-3,5-dicarbonitrile compounds were previously identified as mimetics of dominant-negative prion protein mutants and inhibit prion replication in cultured cells. Here, we report findings from a comprehensive structure-activity relationship study of the 6-aminopyridine-3,5-dicarbonitrile scaffold. We identify compounds with significantly improved bioactivity (approximately 40-fold) against replication of the infectious prion isoform (PrPSc) and suitable pharmacokinetic profiles to warrant evaluation in animal models of prion disease.
|
Antimicrobial activity against chloroquine-sensitive Plasmodium falciparum 3D7 after 72 hrs
|
Plasmodium falciparum
|
11.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Bis-acridines as lead antiparasitic agents: structure-activity analysis of a discrete compound library in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2164
Last Page : 2172
Authors : Caffrey CR, Steverding D, Swenerton RK, Kelly B, Walshe D, Debnath A, Zhou YM, Doyle PS, Fafarman AT, Zorn JA, Land KM, Beauchene J, Schreiber K, Moll H, Ponte-Sucre A, Schirmeister T, Saravanamuthu A, Fairlamb AH, Cohen FE, McKerrow JH, Weisman JL, May BC.
Abstract : Parasitic diseases are of enormous public health significance in developing countries-a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 A. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC(50)) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC(50) values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.
|
Antimicrobial activity against chloroquine-resistant Plasmodium falciparum W2 after 72 hrs
|
Plasmodium falciparum
|
33.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Bis-acridines as lead antiparasitic agents: structure-activity analysis of a discrete compound library in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2164
Last Page : 2172
Authors : Caffrey CR, Steverding D, Swenerton RK, Kelly B, Walshe D, Debnath A, Zhou YM, Doyle PS, Fafarman AT, Zorn JA, Land KM, Beauchene J, Schreiber K, Moll H, Ponte-Sucre A, Schirmeister T, Saravanamuthu A, Fairlamb AH, Cohen FE, McKerrow JH, Weisman JL, May BC.
Abstract : Parasitic diseases are of enormous public health significance in developing countries-a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 A. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC(50)) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC(50) values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.
|
Activity at androgen receptor ligand binding domain assessed as inhibition of SRC2-3 interaction at 50 uM after 2 hrs by fluorescence polarization assay
|
None
|
72.0
%
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : A surface on the androgen receptor that allosterically regulates coactivator binding.
Year : 2007
Volume : 104
Issue : 41
First Page : 16074
Last Page : 16079
Authors : Estébanez-Perpiñá E, Arnold LA, Nguyen P, Rodrigues ED, Mar E, Bateman R, Pallai P, Shokat KM, Baxter JD, Guy RK, Webb P, Fletterick RJ.
Abstract : Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.
|
Antiprion activity against scrapie prion protein RML infected mouse ScN2a cells assessed as reduction of scrapie prion protein accumulation by immunoblot analysis
|
None
|
230.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiprion activity of functionalized 9-aminoacridines related to quinacrine.
Year : 2008
Volume : 16
Issue : 14
First Page : 6737
Last Page : 6746
Authors : Nguyen TH, Lee CY, Teruya K, Ong WY, Doh-ura K, Go ML.
Abstract : A library of functionalized 6-chloro-2-methoxy-(N(9)-substituted)acridin-9-amines structurally related to quinacrine were synthesized and evaluated for antiprion activity on four different cell models persistently infected with scrapie prion strains (ScN2a, N167, Ch2) or a human disease prion strain (F3). Most of the compounds were distinguished by the side chain attached to 9-amino of the acridine ring. These were dialkylaminoalkyl and phenyl with basic groups on the phenyl ring. The most promising compound was 6-chloro-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)acridin-9-amine (15) which had submicromolar EC(50) values (0.1-0.7microM) on all cell models, was able to clear PrP(Sc) at non-toxic concentrations of 1.2-2.5microM, and was more active than quinacrine in terms of EC(50) values. Other promising compounds were 14 (a regioisomer of 15) and 17 which had a 1-benzylpiperidin-4-yl substituent attached to the 9-amino function. Activity was strongly dependent on the presence of a substituted acridine ring, which in this library comprised 6-chloro-2-methoxy substituents on the acridine ring. The side chains of 14, 15, and 17 have not been previously associated with antiprion activity and are interesting leads for further optimization of antiprion activity.
|
Antiprion activity against scrapie prion protein 22L infected mouse N167 cells assessed as reduction of scrapie prion protein accumulation
|
None
|
590.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiprion activity of functionalized 9-aminoacridines related to quinacrine.
Year : 2008
Volume : 16
Issue : 14
First Page : 6737
Last Page : 6746
Authors : Nguyen TH, Lee CY, Teruya K, Ong WY, Doh-ura K, Go ML.
Abstract : A library of functionalized 6-chloro-2-methoxy-(N(9)-substituted)acridin-9-amines structurally related to quinacrine were synthesized and evaluated for antiprion activity on four different cell models persistently infected with scrapie prion strains (ScN2a, N167, Ch2) or a human disease prion strain (F3). Most of the compounds were distinguished by the side chain attached to 9-amino of the acridine ring. These were dialkylaminoalkyl and phenyl with basic groups on the phenyl ring. The most promising compound was 6-chloro-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)acridin-9-amine (15) which had submicromolar EC(50) values (0.1-0.7microM) on all cell models, was able to clear PrP(Sc) at non-toxic concentrations of 1.2-2.5microM, and was more active than quinacrine in terms of EC(50) values. Other promising compounds were 14 (a regioisomer of 15) and 17 which had a 1-benzylpiperidin-4-yl substituent attached to the 9-amino function. Activity was strongly dependent on the presence of a substituted acridine ring, which in this library comprised 6-chloro-2-methoxy substituents on the acridine ring. The side chains of 14, 15, and 17 have not been previously associated with antiprion activity and are interesting leads for further optimization of antiprion activity.
|
Antiprion activity against scrapie prion protein RML infected mouse Ch2 cells assessed as reduction of scrapie prion protein accumulation
|
None
|
460.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiprion activity of functionalized 9-aminoacridines related to quinacrine.
Year : 2008
Volume : 16
Issue : 14
First Page : 6737
Last Page : 6746
Authors : Nguyen TH, Lee CY, Teruya K, Ong WY, Doh-ura K, Go ML.
Abstract : A library of functionalized 6-chloro-2-methoxy-(N(9)-substituted)acridin-9-amines structurally related to quinacrine were synthesized and evaluated for antiprion activity on four different cell models persistently infected with scrapie prion strains (ScN2a, N167, Ch2) or a human disease prion strain (F3). Most of the compounds were distinguished by the side chain attached to 9-amino of the acridine ring. These were dialkylaminoalkyl and phenyl with basic groups on the phenyl ring. The most promising compound was 6-chloro-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)acridin-9-amine (15) which had submicromolar EC(50) values (0.1-0.7microM) on all cell models, was able to clear PrP(Sc) at non-toxic concentrations of 1.2-2.5microM, and was more active than quinacrine in terms of EC(50) values. Other promising compounds were 14 (a regioisomer of 15) and 17 which had a 1-benzylpiperidin-4-yl substituent attached to the 9-amino function. Activity was strongly dependent on the presence of a substituted acridine ring, which in this library comprised 6-chloro-2-methoxy substituents on the acridine ring. The side chains of 14, 15, and 17 have not been previously associated with antiprion activity and are interesting leads for further optimization of antiprion activity.
|
Inhibition of snake venom phospholipase A2 at 5.800 mM assessed as oxygen consumption for 3 mins
|
Naja naja
|
85.5
%
|
|
Journal : J. Nat. Prod.
Title : Two fungal lanostane derivatives as phospholipase A2 inhibitors.
Year : 1996
Volume : 59
Issue : 10
First Page : 977
Last Page : 979
Authors : Cuélla MJ, Giner RM, Recio MC, Just MJ, Máñez S, Ríos JL.
Abstract : The hydroalcoholic extract of Poria cocos and two lanostane derivatives isolated from it, pachymic acid (1) and dehydrotumulosic acid (2), were active as inhibitors of phospholipase A2 from snake venom when a polarographic method was used. Dehydrotumulosic acid exhibited an IC50 of 0.845 mM. These two compounds are structurally related to certain triterpenoids from Ganoderma and Schinus that have previously been described as competitive inhibitors of phospholipase A2. These comprise a new group of natural potential antiinflammatory agents due to their interaction with that enzyme.
|
Inhibition of secretagogue-induced histamine release in Sprague-Dawley rat peritoneal mast cells at 30 uM treated 30 mins before secretagogue challenge measured after 15 mins
|
Rattus norvegicus
|
18.4
%
|
|
Journal : J. Nat. Prod.
Title : Two phenanthraquinones from Dendrobium moniliforme.
Year : 2001
Volume : 64
Issue : 8
First Page : 1084
Last Page : 1086
Authors : Lin TH, Chang SJ, Chen CC, Wang JP, Tsao LT.
Abstract : Two phenanthraquinones were isolated from the stems of Dendrobium moniliforme. They were identified by interpretation of spectral data as 2,6-dimethoxy-1,4,5,8-phenanthradiquinone and 5-hydroxy-3,7-dimethoxy-1,4-phenanthraquinone, named moniliformin (1) and denbinobin (2), respectively. This is the first report of compound 1, which possesses a novel 1,4,5,8-diquinone moiety in the phenanthraquinone skeleton. Compound 2 showed potent antiinflammatory effects in vitro.
|
Inhibition of secretagogue-induced beta-glucuronidase release in Sprague-Dawley rat peritoneal mast cells at 30 uM treated 30 mins before secretagogue challenge measured after 15 mins
|
Rattus norvegicus
|
8.7
%
|
|
Journal : J. Nat. Prod.
Title : Two phenanthraquinones from Dendrobium moniliforme.
Year : 2001
Volume : 64
Issue : 8
First Page : 1084
Last Page : 1086
Authors : Lin TH, Chang SJ, Chen CC, Wang JP, Tsao LT.
Abstract : Two phenanthraquinones were isolated from the stems of Dendrobium moniliforme. They were identified by interpretation of spectral data as 2,6-dimethoxy-1,4,5,8-phenanthradiquinone and 5-hydroxy-3,7-dimethoxy-1,4-phenanthraquinone, named moniliformin (1) and denbinobin (2), respectively. This is the first report of compound 1, which possesses a novel 1,4,5,8-diquinone moiety in the phenanthraquinone skeleton. Compound 2 showed potent antiinflammatory effects in vitro.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum K1 after 48 hrs by [G-3H]hypoxanthine uptake
|
Plasmodium falciparum K1
|
43.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Pharmacophore based discovery of potential antimalarial agent targeting haem detoxification pathway.
Year : 2008
Volume : 43
Issue : 12
First Page : 2840
Last Page : 2852
Authors : Acharya BN, Saraswat D, Kaushik MP.
Abstract : Pharmacophore hypotheses were generated from molecules having putative antimalarial activities targeting haem detoxification pathway of malarial parasite. A training set consisting of 33 compounds, whose activities were evaluated for haem polymerization inhibition and against chloroquine resistant (K1) strain of Plasmodium falciparum, was optimized to generate hypotheses. The hypothesis showing optimum correlation between actual and estimated activities was validated by Fischer's randomization test at 95% confidence level and used as a model to screen our in-house compound database. Nicotinic acid [trans-3-(4-ethoxy-3-methoxy-phenyl)-1-(4-hydroxy-phenyl)-allylidene]-hydrazide (ALH5) was obtained as a hit. The compound was synthesized and evaluated against chloroquine sensitive (MRC-02) and resistant (RKL9) strains of malarial parasite P. falciparum. The compound showed antimalarial activity in nanomolar range and was found comparable with chloroquine.
|
Antiprion activity against Scrapie prion protein-mediated scrapie in mouse SMB cells assessed as remaining PrP-Sc level after 5 days by Bradford assay
|
None
|
420.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and structure-activity relationship of indole-3-glyoxylamide libraries possessing highly potent activity in a cell line model of prion disease.
Year : 2009
Volume : 52
Issue : 23
First Page : 7503
Last Page : 7511
Authors : Thompson MJ, Borsenberger V, Louth JC, Judd KE, Chen B.
Abstract : Transmissible spongiform encephalopathies (TSEs) are a family of invariably fatal neurodegenerative disorders for which no effective curative therapy currently exists. We report here the synthesis of a library of indole-3-glyoxylamides and their evaluation as potential antiprion agents. A number of compounds demonstrated submicromolar activity in a cell line model of prion disease together with a defined structure-activity relationship, permitting the design of more potent compounds that effected clearance of scrapie in the low nanomolar range. Thus, the indole-3-glyoxylamides described herein constitute ideal candidates to progress to further development as potential therapeutics for the family of human prion disorders.
|
Antiprion activity against Scrapie prion protein-mediated scrapie in RML mouse ScN2a cells assessed as reduction of PrP-Sc level after 6 days by immunoblotting
|
None
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and structure-activity relationship of indole-3-glyoxylamide libraries possessing highly potent activity in a cell line model of prion disease.
Year : 2009
Volume : 52
Issue : 23
First Page : 7503
Last Page : 7511
Authors : Thompson MJ, Borsenberger V, Louth JC, Judd KE, Chen B.
Abstract : Transmissible spongiform encephalopathies (TSEs) are a family of invariably fatal neurodegenerative disorders for which no effective curative therapy currently exists. We report here the synthesis of a library of indole-3-glyoxylamides and their evaluation as potential antiprion agents. A number of compounds demonstrated submicromolar activity in a cell line model of prion disease together with a defined structure-activity relationship, permitting the design of more potent compounds that effected clearance of scrapie in the low nanomolar range. Thus, the indole-3-glyoxylamides described herein constitute ideal candidates to progress to further development as potential therapeutics for the family of human prion disorders.
|
NOVARTIS: Inhibition of Plasmodium falciparum 3D7 (drug-susceptible) proliferation in erythrocyte-based infection assay
|
Plasmodium falciparum
|
8.13
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen.
Year : 2008
Volume : 105
Issue : 26
First Page : 9059
Last Page : 9064
Authors : Plouffe D, Brinker A, McNamara C, Henson K, Kato N, Kuhen K, Nagle A, Adrián F, Matzen JT, Anderson P, Nam TG, Gray NS, Chatterjee A, Janes J, Yan SF, Trager R, Caldwell JS, Schultz PG, Zhou Y, Winzeler EA.
Abstract : The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximately 1.7 million compounds, we identified a diverse collection of approximately 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 microM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.
|
NOVARTIS: Inhibition of Plasmodium falciparum W2 (drug-resistant) proliferation in erythrocyte-based infection assay
|
Plasmodium falciparum
|
14.22
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen.
Year : 2008
Volume : 105
Issue : 26
First Page : 9059
Last Page : 9064
Authors : Plouffe D, Brinker A, McNamara C, Henson K, Kato N, Kuhen K, Nagle A, Adrián F, Matzen JT, Anderson P, Nam TG, Gray NS, Chatterjee A, Janes J, Yan SF, Trager R, Caldwell JS, Schultz PG, Zhou Y, Winzeler EA.
Abstract : The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximately 1.7 million compounds, we identified a diverse collection of approximately 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 microM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.
|
Antiproliferative activity against mouse neural precursor cells by MTT assay
|
Mus musculus
|
936.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical genetics reveals a complex functional ground state of neural stem cells.
Year : 2007
Volume : 3
Issue : 5
First Page : 268
Last Page : 273
Authors : Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EK, Ward RJ, Jamieson LG, Tyers M, Dirks PB.
Abstract : The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
|
Inhibition of bovine erythrocyte AChE using acetylthiocholine iodide as a substrate at 10 uM after 20 mins by Ellman's assay
|
Bos taurus
|
49.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Quinolizidinyl derivatives of bi- and tricyclic systems as potent inhibitors of acetyl- and butyrylcholinesterase with potential in Alzheimer's disease.
Year : 2011
Volume : 46
Issue : 6
First Page : 2170
Last Page : 2184
Authors : Tasso B, Catto M, Nicolotti O, Novelli F, Tonelli M, Giangreco I, Pisani L, Sparatore A, Boido V, Carotti A, Sparatore F.
Abstract : On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi- and tricyclic (hetero)aromatic systems were studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC50 values for most of them (e.g. 15: IC50 versus BChE=0.15 μM; SI=47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e.g. 46: IC50 versus AChE=0.35 μM; SI=0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer's disease, and may, therefore, represent hits for the development of interesting single-entity multi-target drugs.
|
NOVARTIS: Antimalarial liver stage activity measured as reduction in Plasmodium yoelii schizont area in HepG2-A16-CD81 cells by immuno-fluorescence, and median schizont size at 10uM compound concentration
|
Plasmodium yoelii
|
165.7
nM
|
|
Journal : Science
Title : Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery.
Year : 2011
Volume : 334
Issue : 6061
First Page : 1372
Last Page : 1377
Authors : Meister S, Plouffe DM, Kuhen KL, Bonamy GM, Wu T, Barnes SW, Bopp SE, Borboa R, Bright AT, Che J, Cohen S, Dharia NV, Gagaring K, Gettayacamin M, Gordon P, Groessl T, Kato N, Lee MC, McNamara CW, Fidock DA, Nagle A, Nam TG, Richmond W, Roland J, Rottmann M, Zhou B, Froissard P, Glynne RJ, Mazier D, Sattabongkot J, Schultz PG, Tuntland T, Walker JR, Zhou Y, Chatterjee A, Diagana TT, Winzeler EA.
Abstract : Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.
|
DRUGMATRIX: Muscarinic M1 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
359.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M2 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
964.0
nM
|
|
DRUGMATRIX: Muscarinic M2 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
343.0
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
|
266.0
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
|
277.0
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: Serotonin (5-Hydroxytryptamine) 5-HT2A radioligand binding (ligand: [3H] Ketanserin)
|
None
|
761.0
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: Alpha-2A adrenergic receptor radioligand binding (ligand: MK-912)
|
None
|
855.0
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: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
833.0
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: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
560.0
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: Calcium Channel Type L, Benzothiazepine radioligand binding (ligand: [3H] Diltiazem)
|
Rattus norvegicus
|
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: Calcium Channel Type L, Phenylalkylamine radioligand binding (ligand: [3H] (-)-Desmethoxyverapamil (D-888))
|
Rattus norvegicus
|
739.0
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Phenylalkylamine radioligand binding (ligand: [3H] (-)-Desmethoxyverapamil (D-888))
|
Rattus norvegicus
|
719.0
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: Dopamine D3 radioligand binding (ligand: [3H] Spiperone)
|
None
|
448.0
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
|
Binding affinity to chicken riboflavin binding protein assessed as dissociation constant at pH 7.4 in phosphate buffer by isothermal titration calorimetric assay
|
Gallus gallus
|
264.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Bioanalytical Screening of Riboflavin Antagonists for Targeted Drug Delivery - A Thermodynamic and Kinetic Study.
Year : 2011
Volume : 2
Issue : 5
First Page : 363
Last Page : 367
Authors : Plantinga A, Witte A, Li MH, Harmon A, Choi SK, Banaszak Holl MM, Orr BG, Baker JR, Sinniah K.
Abstract : The present study screened riboflavin mimicking small molecules to determine their binding activity for the riboflavin binding protein. We performed thermodynamic and kinetic binding studies of these molecules using a combination of two analytical approaches; isothermal titration calorimetry and surface plasmon resonance spectroscopy. Screening of a biased set of non-riboflavin based small molecules by microcalorimetry led to the discovery of two known drug molecules, quinacrine and chloroquine, as favorable ligands for the riboflavin receptor with K(D) value of 264, and 2100 nM, respectively. We further demonstrated that quinacrine is a competitive ligand for the receptor as measured by surface plasmon resonance. Thus this study describes the identification of a novel class of dual acting riboflavin antagonists that target riboflavin receptor for cellular uptake and display multifunctional activities upon cellular entry.
|
Antiprion activity against mouse prion protein RML infected mouse ScN2a cells assessed as reduction of PrPSc level by Western blot method
|
Mus musculus
|
230.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position.
Year : 2011
Volume : 46
Issue : 7
First Page : 2917
Last Page : 2929
Authors : Nguyen T, Sakasegawa Y, Doh-Ura K, Go ML.
Abstract : In this paper, we report the synthesis and cell-based anti-prion activity of quinacrine analogs derived by replacing the basic alkyl side chain of quinacrine with 4-(4-methylpiperazin-I-yl)phenyl, (1-benzylpiperidin-4-yl) and their structural variants. Several promising analogs were found that have a more favorable anti-prion profile than quinacrine in terms of potency and activity across different prion-infected murine cell models. They also exhibited greater binding affinities for a human prion protein fragment (hPrP(121-231)) than quinacrine, and had permeabilities on the PAMPA-BBB assay that fall within the range of CNS permeant candidates. When evaluated on bidirectional assays on a Pgp overexpressing cell line, one analog was less susceptible to Pgp efflux activity compared to quinacrine. Taken together, the results point to an important role for the substituted 9-amino side chain attached to the acridine, tetrahydroacridine and quinoline scaffolds. The nature of this side chain influenced cell-based potency, PAMPA permeability and binding affinity to hPrP(121-231).
|
Antiprion activity against mouse prion protein 22L infected mouse N167 cells assessed as reduction of PrPSc level by Western blot method
|
Mus musculus
|
590.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position.
Year : 2011
Volume : 46
Issue : 7
First Page : 2917
Last Page : 2929
Authors : Nguyen T, Sakasegawa Y, Doh-Ura K, Go ML.
Abstract : In this paper, we report the synthesis and cell-based anti-prion activity of quinacrine analogs derived by replacing the basic alkyl side chain of quinacrine with 4-(4-methylpiperazin-I-yl)phenyl, (1-benzylpiperidin-4-yl) and their structural variants. Several promising analogs were found that have a more favorable anti-prion profile than quinacrine in terms of potency and activity across different prion-infected murine cell models. They also exhibited greater binding affinities for a human prion protein fragment (hPrP(121-231)) than quinacrine, and had permeabilities on the PAMPA-BBB assay that fall within the range of CNS permeant candidates. When evaluated on bidirectional assays on a Pgp overexpressing cell line, one analog was less susceptible to Pgp efflux activity compared to quinacrine. Taken together, the results point to an important role for the substituted 9-amino side chain attached to the acridine, tetrahydroacridine and quinoline scaffolds. The nature of this side chain influenced cell-based potency, PAMPA permeability and binding affinity to hPrP(121-231).
|
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.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum K1 assessed as incorporation of [3H]hypoxanthine after 48 hr microdilution method
|
Plasmodium falciparum K1
|
43.0
nM
|
|
Journal : Med Chem Res
Title : Pharmacophore-based predictive model generation for potent antimalarials targeting haem detoxification pathway
Year : 2007
Volume : 16
Issue : 5
First Page : 213
Last Page : 229
Authors : Acharya BN, Kaushik MP
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 assessed as incorporation of [3H]hypoxanthine after 48 hr microdilution method
|
Plasmodium falciparum 3D7
|
13.0
nM
|
|
Journal : Med Chem Res
Title : Pharmacophore-based predictive model generation for potent antimalarials targeting haem detoxification pathway
Year : 2007
Volume : 16
Issue : 5
First Page : 213
Last Page : 229
Authors : Acharya BN, Kaushik MP
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Antiprion activity against scrapie prion protein (unknown origin) infected in mouse ScGT1 cells assessed as inhibition of PrPSc replication by ELISA
|
Not specified
|
400.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : A Fluorescent Styrylquinoline with Combined Therapeutic and Diagnostic Activities against Alzheimer's and Prion Diseases.
Year : 2013
Volume : 4
Issue : 2
First Page : 225
Last Page : 229
Authors : Staderini M, Aulić S, Bartolini M, Tran HN, González-Ruiz V, Pérez DI, Cabezas N, Martínez A, Martín MA, Andrisano V, Legname G, Menéndez JC, Bolognesi ML.
Abstract : (E)-6-Methyl-4'-amino-2-styrylquinoline (3) is a small molecule with the proper features to potentially diagnose, deliver therapy and monitor response to therapy in protein misfolding diseases. These features include compound fluorescent emission in the NIR region and its ability to interact with both Aβ and prion fibrils, staining them with high selectivity. Styrylquinoline 3 also inhibits Aβ self-aggregation in vitro and prion replication in the submicromolar range in a cellular context. Furthermore, it is not toxic and is able to cross the blood brain barrier in vitro (PAMPA test).
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Antimalarial activity against multidrug-resistant Plasmodium falciparum Dd2 infected in human erythrocytes by SYBR green 1-based fluorescence assay
|
Plasmodium falciparum
|
29.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.
Year : 2019
Volume : 62
Issue : 7
First Page : 3475
Last Page : 3502
Authors : Dodean RA, Kancharla P, Li Y, Melendez V, Read L, Bane CE, Vesely B, Kreishman-Deitrick M, Black C, Li Q, Sciotti RJ, Olmeda R, Luong TL, Gaona H, Potter B, Sousa J, Marcsisin S, Caridha D, Xie L, Vuong C, Zeng Q, Zhang J, Zhang P, Lin H, Butler K, Roncal N, Gaynor-Ohnstad L, Leed SE, Nolan C, Huezo SJ, Rasmussen SA, Stephens MT, Tan JC, Cooper RA, Smilkstein MJ, Pou S, Winter RW, Riscoe MK, Kelly JX.
Abstract : Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.
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Antimalarial activity against drug-resistant Plasmodium falciparum Dd2 harboring V259L mutant infected in human erythrocytes after 72 hrs by SYBR green 1-based fluorescence assay
|
Plasmodium falciparum
|
18.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.
Year : 2019
Volume : 62
Issue : 7
First Page : 3475
Last Page : 3502
Authors : Dodean RA, Kancharla P, Li Y, Melendez V, Read L, Bane CE, Vesely B, Kreishman-Deitrick M, Black C, Li Q, Sciotti RJ, Olmeda R, Luong TL, Gaona H, Potter B, Sousa J, Marcsisin S, Caridha D, Xie L, Vuong C, Zeng Q, Zhang J, Zhang P, Lin H, Butler K, Roncal N, Gaynor-Ohnstad L, Leed SE, Nolan C, Huezo SJ, Rasmussen SA, Stephens MT, Tan JC, Cooper RA, Smilkstein MJ, Pou S, Winter RW, Riscoe MK, Kelly JX.
Abstract : Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.
|
Antimalarial activity against drug-resistant Plasmodium falciparum Dd2 harboring M133I/A138T double mutant infected in human erythrocytes after 72 hrs by SYBR green 1-based fluorescence assay
|
Plasmodium falciparum
|
29.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.
Year : 2019
Volume : 62
Issue : 7
First Page : 3475
Last Page : 3502
Authors : Dodean RA, Kancharla P, Li Y, Melendez V, Read L, Bane CE, Vesely B, Kreishman-Deitrick M, Black C, Li Q, Sciotti RJ, Olmeda R, Luong TL, Gaona H, Potter B, Sousa J, Marcsisin S, Caridha D, Xie L, Vuong C, Zeng Q, Zhang J, Zhang P, Lin H, Butler K, Roncal N, Gaynor-Ohnstad L, Leed SE, Nolan C, Huezo SJ, Rasmussen SA, Stephens MT, Tan JC, Cooper RA, Smilkstein MJ, Pou S, Winter RW, Riscoe MK, Kelly JX.
Abstract : Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.
|
Antimalarial activity against drug-resistant Plasmodium falciparum Dd2 harboring M133I mutant infected in human erythrocytes after 72 hrs by SYBR green 1-based fluorescence assay
|
Plasmodium falciparum
|
23.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.
Year : 2019
Volume : 62
Issue : 7
First Page : 3475
Last Page : 3502
Authors : Dodean RA, Kancharla P, Li Y, Melendez V, Read L, Bane CE, Vesely B, Kreishman-Deitrick M, Black C, Li Q, Sciotti RJ, Olmeda R, Luong TL, Gaona H, Potter B, Sousa J, Marcsisin S, Caridha D, Xie L, Vuong C, Zeng Q, Zhang J, Zhang P, Lin H, Butler K, Roncal N, Gaynor-Ohnstad L, Leed SE, Nolan C, Huezo SJ, Rasmussen SA, Stephens MT, Tan JC, Cooper RA, Smilkstein MJ, Pou S, Winter RW, Riscoe MK, Kelly JX.
Abstract : Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-4.1
%
|
|
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
|
-0.24
%
|
|
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
|
-0.24
%
|
|
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.
