|
Inhibition of human recombinant MAOA before repeated washing at 500 uM
|
Homo sapiens
|
86.75
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, stereochemical identification, and selective inhibitory activity against human monoamine oxidase-B of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones.
Year : 2008
Volume : 51
Issue : 16
First Page : 4874
Last Page : 4880
Authors : Chimenti F, Maccioni E, Secci D, Bolasco A, Chimenti P, Granese A, Carradori S, Alcaro S, Ortuso F, Yáñez M, Orallo F, Cirilli R, Ferretti R, La Torre F.
Abstract : A series of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones have been investigated for their ability to inhibit selectively the activity of the human A and B isoforms of monoamine oxidase (MAO). The target compounds, which present a stereogenic center on the cyclohexane ring, were obtained as pure (R) and (S) enantiomers by enantioselective HPLC. The absolute configuration of homochiral forms isolated on a semipreparative scale was obtained by a combined strategy based on chemical correlation and single-crystal X-ray diffraction. All compounds showed higher activity against the human MAO-B isoform with IC50 values ranging between 26.81 +/- 2.74 microM and 14.20 +/- 0.26 nM, and the assays carried out on the pure enantiomers showed higher activity for the (R) form. A computational study was performed by molecular mechanics, DFT-based quantomechanics, and docking techniques on the most active and human MAO-B selective inhibitor 8.
|
Inhibition of human recombinant MAOA after washing at 500 uM by centrifugation-ultrafiltration method
|
Homo sapiens
|
10.26
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, stereochemical identification, and selective inhibitory activity against human monoamine oxidase-B of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones.
Year : 2008
Volume : 51
Issue : 16
First Page : 4874
Last Page : 4880
Authors : Chimenti F, Maccioni E, Secci D, Bolasco A, Chimenti P, Granese A, Carradori S, Alcaro S, Ortuso F, Yáñez M, Orallo F, Cirilli R, Ferretti R, La Torre F.
Abstract : A series of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones have been investigated for their ability to inhibit selectively the activity of the human A and B isoforms of monoamine oxidase (MAO). The target compounds, which present a stereogenic center on the cyclohexane ring, were obtained as pure (R) and (S) enantiomers by enantioselective HPLC. The absolute configuration of homochiral forms isolated on a semipreparative scale was obtained by a combined strategy based on chemical correlation and single-crystal X-ray diffraction. All compounds showed higher activity against the human MAO-B isoform with IC50 values ranging between 26.81 +/- 2.74 microM and 14.20 +/- 0.26 nM, and the assays carried out on the pure enantiomers showed higher activity for the (R) form. A computational study was performed by molecular mechanics, DFT-based quantomechanics, and docking techniques on the most active and human MAO-B selective inhibitor 8.
|
Antagonist activity at human 5HT3A receptor expressed in HEK293 cells assessed as inhibition of serotonin-induced inward Na+ current at >= 10 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Molecular properties of psychopharmacological drugs determining non-competitive inhibition of 5-HT3A receptors.
Year : 2009
Volume : 44
Issue : 6
First Page : 2667
Last Page : 2672
Authors : Kornhuber J, Terfloth L, Bleich S, Wiltfang J, Rupprecht R.
Abstract : We developed a structure-property-activity relationship (SPAR)-model for psychopharmacological drugs acting as non-competitive 5-HT(3A) receptor antagonists by using a decision-tree learner provided by the RapidMiner machine learning tool. A single molecular descriptor, namely the molecular dipole moment per molecular weight (mu/MW), predicts whether or not a substance non-competitively antagonizes 5-HT-induced Na(+) currents. A low mu/MW is compatible with drug-cumulation in apolar lipid rafts. This study confirms that size-intensive descriptors allow the development of compact SPAR models.
|
NOVARTIS: Inhibition of Plasmodium falciparum 3D7 (drug-susceptible) proliferation in erythrocyte-based infection assay
|
Plasmodium falciparum
|
740.0
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.
|
Competitive inhibition of MAOA in rat liver homogenate by spectrophotometrically
|
Rattus norvegicus
|
5.53
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and molecular modeling of some novel hexahydroindazole derivatives as potent monoamine oxidase inhibitors.
Year : 2009
Volume : 17
Issue : 18
First Page : 6761
Last Page : 6772
Authors : Gökhan-Kelekçi N, Simşek OO, Ercan A, Yelekçi K, Sahin ZS, Işik S, Uçar G, Bilgin AA.
Abstract : A novel series of 2-thiocarbamoyl-2,3,4,5,6,7-hexahydro-1H-indazole and 2-substituted thiocarbamoyl-3,3a,4,5,6,7-hexahydro-2H-indazoles derivatives were synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The target molecules were identified on the basis of satisfactory analytical and spectra data (IR, (1)H NMR, (13)C NMR, (2)D NMR, DEPT, EI-MASS techniques and elemental analysis). Synthesized compounds showed high activity against both the MAO-A (compounds 1d, 1e, 2c, 2d, 2e) and the MAO-B (compounds 1a, 1b, 1c, 2a, 2b) isoforms. In the discussion of the results, the influence of the structure on the biological activity of the prepared compounds was delineated. It was suggested that non-substituted and N-methyl/ethyl bearing compounds (except 2c) increased the inhibitory effect and selectivity toward MAO-B. The rest of the compounds, carrying N-allyl and N-phenyl, appeared to select the MAO-A isoform. The inhibition profile was found to be competitive and reversible for all compounds. A series of experimentally tested (1a-2e) compounds was docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The autodock 4.01 program was employed to perform automated molecular docking. In order to see the detailed interactions of the docked poses of the model inhibitors compounds 1a, 1d, 1e and 2e were chosen because of their ability to reversibly inhibit the MAO-B and MAO-A and the availability of experimental inhibition data. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Excellent to good correlations between the calculated and experimental K(i) values were obtained. In the docking of the MAO-A complex, the trans configuration of compound 1e made various very close interactions with the residues lining the active site cavity these interactions were much better than those of the other compounds tested in this study. This tight binding observation may be responsible for the nanomolar inhibition of form of MAOA. However, it binds slightly weaker (experimental K(i)=1.23 microM) to MAO-B than to MAO-A (experimental K(i)=4.22 nM).
|
Inhibition of MAO-A in rat liver homogenate by spectrophotometry-based Holt method
|
Rattus norvegicus
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Towards development of selective and reversible pyrazoline based MAO-inhibitors: Synthesis, biological evaluation and docking studies.
Year : 2010
Volume : 20
Issue : 1
First Page : 132
Last Page : 136
Authors : Sahoo A, Yabanoglu S, Sinha BN, Ucar G, Basu A, Jayaprakash V.
Abstract : Ten novel 3,5-diaryl pyrazolines were synthesized and investigated for their monoamine oxidase (MAO) inhibitory property. All the molecules were found to be reversible and selective inhibitor for either one of the isoform (MAO-A or MAO-B). Further insights in the theoretical evaluation of the possible interactions between the compounds and monoamine oxidases (MAO-A or MAO-B) have been developed through docking studies. The theoretical values are in congruence with their experimental values.
|
Inhibition of human recombinant MAOA expressed in BTI-TN-5B1-4 cells at 500 uM before washing by centrifugation-ultrafiltration method
|
Homo sapiens
|
84.75
%
|
|
Journal : Bioorg. Med. Chem.
Title : A new series of flavones, thioflavones, and flavanones as selective monoamine oxidase-B inhibitors.
Year : 2010
Volume : 18
Issue : 3
First Page : 1273
Last Page : 1279
Authors : Chimenti F, Fioravanti R, Bolasco A, Chimenti P, Secci D, Rossi F, Yáñez M, Orallo F, Ortuso F, Alcaro S, Cirilli R, Ferretti R, Sanna ML.
Abstract : A new series of synthetic flavones, thioflavones, and flavanones has been synthesized and evaluated as potential inhibitors of monoamine oxidase isoforms (MAO-A and -B). The most active series is the flavanone one with higher selective inhibitory activity against MAO-B. Some of these flavanones (mainly the most effective) have been separated and tested as single enantiomers. In order to investigate the MAOs recognition of the most active and selective compounds, a molecular modeling study has been performed using available Protein Data Bank (PDB) structures as receptor models for docking experiments.
|
Inhibition of human recombinant MAOA expressed in BTI-TN-5B1-4 cells at 500 uM after repeated washing by centrifugation-ultrafiltration method
|
Homo sapiens
|
10.26
%
|
|
Journal : Bioorg. Med. Chem.
Title : A new series of flavones, thioflavones, and flavanones as selective monoamine oxidase-B inhibitors.
Year : 2010
Volume : 18
Issue : 3
First Page : 1273
Last Page : 1279
Authors : Chimenti F, Fioravanti R, Bolasco A, Chimenti P, Secci D, Rossi F, Yáñez M, Orallo F, Ortuso F, Alcaro S, Cirilli R, Ferretti R, Sanna ML.
Abstract : A new series of synthetic flavones, thioflavones, and flavanones has been synthesized and evaluated as potential inhibitors of monoamine oxidase isoforms (MAO-A and -B). The most active series is the flavanone one with higher selective inhibitory activity against MAO-B. Some of these flavanones (mainly the most effective) have been separated and tested as single enantiomers. In order to investigate the MAOs recognition of the most active and selective compounds, a molecular modeling study has been performed using available Protein Data Bank (PDB) structures as receptor models for docking experiments.
|
Inhibition of human MAOA at 500 uM
|
Homo sapiens
|
86.75
%
|
|
Journal : Bioorg. Med. Chem.
Title : Investigations on the 2-thiazolylhydrazyne scaffold: synthesis and molecular modeling of selective human monoamine oxidase inhibitors.
Year : 2010
Volume : 18
Issue : 15
First Page : 5715
Last Page : 5723
Authors : Chimenti F, Bolasco A, Secci D, Chimenti P, Granese A, Carradori S, Yáñez M, Orallo F, Ortuso F, Alcaro S.
Abstract : A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71-99%) and characterized by elemental analysis and (1)H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) inhibitory activity and selectivity and most of them showed IC(50) values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the CN, displayed IC(50)=3.81+/-0.12 nM and selectivity ratio=119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the enzyme-inhibitor interaction toward hMAO isoforms and to explain the structure-activity relationship of this kind of inhibitors.
|
Reversible inhibition of human MAOA at 500 uM by centrifugation-ultrafiltration method
|
Homo sapiens
|
10.26
%
|
|
Journal : Bioorg. Med. Chem.
Title : Investigations on the 2-thiazolylhydrazyne scaffold: synthesis and molecular modeling of selective human monoamine oxidase inhibitors.
Year : 2010
Volume : 18
Issue : 15
First Page : 5715
Last Page : 5723
Authors : Chimenti F, Bolasco A, Secci D, Chimenti P, Granese A, Carradori S, Yáñez M, Orallo F, Ortuso F, Alcaro S.
Abstract : A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71-99%) and characterized by elemental analysis and (1)H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) inhibitory activity and selectivity and most of them showed IC(50) values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the CN, displayed IC(50)=3.81+/-0.12 nM and selectivity ratio=119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the enzyme-inhibitor interaction toward hMAO isoforms and to explain the structure-activity relationship of this kind of inhibitors.
|
Inhibition of human recombinant MAOA expressed in baculovirus infected BTI-TN-5B1-4 insect cells assessed as hydrogen peroxide production from p-tyramine at 500 uM after 15 mins
|
Homo sapiens
|
86.75
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, semipreparative HPLC separation, biological evaluation, and 3D-QSAR of hydrazothiazole derivatives as human monoamine oxidase B inhibitors.
Year : 2010
Volume : 18
Issue : 14
First Page : 5063
Last Page : 5070
Authors : Chimenti F, Secci D, Bolasco A, Chimenti P, Granese A, Carradori S, Maccioni E, Cardia MC, Yáñez M, Orallo F, Alcaro S, Ortuso F, Cirilli R, Ferretti R, Distinto S, Kirchmair J, Langer T.
Abstract : The present study reports on synthesis in high yields (70-99%), HPLC enantioseparation, inhibitory activity against human monoamino oxidases, and molecular modeling including 3D-QSAR studies, of a large series of (4-aryl-thiazol-2-yl)hydrazones (1-45). Most of the synthesized compounds proved to be potent and selective inhibitors of hMAO-B isoform in the micromolar or nanomolar range, thus demonstrating that hydrazothiazole could be considered a good pharmacophore to design new hMAO-B inhibitors. Due to the presence in some derivatives of a chiral center, we also performed a semipreparative chromatographic enantioseparation of these compounds obtained by a stereoconservative pattern. The separated enantiomers were submitted to in vitro biological evaluation to point out the stereorecognition of the active site of the enzyme towards these structures. Finally, a 3D-QSAR study was carried out using Comparative Molecular Field Analysis (CoMFA), aiming to deduce rational guidelines for the further structural modification of these lead compounds.
|
Irreversible inhibition of human recombinant MAOA expressed in baculovirus infected BTI-TN-5B1-4 insect cells assessed as hydrogen peroxide production from p-tyramine at 500 uM measured after repeated washing by centrifugation-ultrafiltration method
|
Homo sapiens
|
10.26
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, semipreparative HPLC separation, biological evaluation, and 3D-QSAR of hydrazothiazole derivatives as human monoamine oxidase B inhibitors.
Year : 2010
Volume : 18
Issue : 14
First Page : 5063
Last Page : 5070
Authors : Chimenti F, Secci D, Bolasco A, Chimenti P, Granese A, Carradori S, Maccioni E, Cardia MC, Yáñez M, Orallo F, Alcaro S, Ortuso F, Cirilli R, Ferretti R, Distinto S, Kirchmair J, Langer T.
Abstract : The present study reports on synthesis in high yields (70-99%), HPLC enantioseparation, inhibitory activity against human monoamino oxidases, and molecular modeling including 3D-QSAR studies, of a large series of (4-aryl-thiazol-2-yl)hydrazones (1-45). Most of the synthesized compounds proved to be potent and selective inhibitors of hMAO-B isoform in the micromolar or nanomolar range, thus demonstrating that hydrazothiazole could be considered a good pharmacophore to design new hMAO-B inhibitors. Due to the presence in some derivatives of a chiral center, we also performed a semipreparative chromatographic enantioseparation of these compounds obtained by a stereoconservative pattern. The separated enantiomers were submitted to in vitro biological evaluation to point out the stereorecognition of the active site of the enzyme towards these structures. Finally, a 3D-QSAR study was carried out using Comparative Molecular Field Analysis (CoMFA), aiming to deduce rational guidelines for the further structural modification of these lead compounds.
|
Inhibition of human recombinant MAO-A expressed in baculovirus infected BTI-TN-5B1-4 insect sells assessed as hydrogen peroxide production at 500 uM by fluorimetric method
|
Homo sapiens
|
85.98
%
|
|
Journal : J. Med. Chem.
Title : Homoisoflavonoids: natural scaffolds with potent and selective monoamine oxidase-B inhibition properties.
Year : 2011
Volume : 54
Issue : 7
First Page : 2155
Last Page : 2164
Authors : Desideri N, Bolasco A, Fioravanti R, Monaco LP, Orallo F, Yáñez M, Ortuso F, Alcaro S.
Abstract : A series of homoisoflavonoids [(E)-3-benzylidenechroman-4-ones 1a-w, 3-benzyl-4H-chromen-4-ones 2a-g, and 3-benzylchroman-4-ones 3a-e] have been synthesized and tested in vitro as inhibitors of human monoamine oxidase isoforms A and B (hMAO-A and hMAO-B). Most of the compounds were found to be potent and selective MAO-B inhibitors. In general, the (E)-3-benzylidenechroman-4-ones 1a-w showed activities in the nano- or micromolar range coupled with high selectivity against hMAO-B. The reduction of the exocyclic double bond results in compounds 3a-e selective against isoform B and active in the micromolar range. In contrast, the endocyclic migration of the double bond (compounds 2a-g) generally produces the loss of the inhibitory activity or a marked reduction in potency. (E)-3-(4-(Dimethylamino)benzylidene)chroman-4-one (1l) and (E)-5,7-dihydroxy-3-(4-hydroxybenzylidene)chroman-4-one (1h) were the most interesting compounds of the entire series of inhibitors, showing hMAO-B affinity better than the selective inhibitor selegiline. Molecular modeling studies have been carried out to explain the selectivity of the most active homoisoflavonoids 1h and 1l.
|
Inhibition of human recombinant MAO-A expressed in baculovirus infected BTI-TN-5B1-4 insect sells assessed as hydrogen peroxide production at 500 uM measured after repeated washing by fluorimetric method
|
Homo sapiens
|
11.45
%
|
|
Journal : J. Med. Chem.
Title : Homoisoflavonoids: natural scaffolds with potent and selective monoamine oxidase-B inhibition properties.
Year : 2011
Volume : 54
Issue : 7
First Page : 2155
Last Page : 2164
Authors : Desideri N, Bolasco A, Fioravanti R, Monaco LP, Orallo F, Yáñez M, Ortuso F, Alcaro S.
Abstract : A series of homoisoflavonoids [(E)-3-benzylidenechroman-4-ones 1a-w, 3-benzyl-4H-chromen-4-ones 2a-g, and 3-benzylchroman-4-ones 3a-e] have been synthesized and tested in vitro as inhibitors of human monoamine oxidase isoforms A and B (hMAO-A and hMAO-B). Most of the compounds were found to be potent and selective MAO-B inhibitors. In general, the (E)-3-benzylidenechroman-4-ones 1a-w showed activities in the nano- or micromolar range coupled with high selectivity against hMAO-B. The reduction of the exocyclic double bond results in compounds 3a-e selective against isoform B and active in the micromolar range. In contrast, the endocyclic migration of the double bond (compounds 2a-g) generally produces the loss of the inhibitory activity or a marked reduction in potency. (E)-3-(4-(Dimethylamino)benzylidene)chroman-4-one (1l) and (E)-5,7-dihydroxy-3-(4-hydroxybenzylidene)chroman-4-one (1h) were the most interesting compounds of the entire series of inhibitors, showing hMAO-B affinity better than the selective inhibitor selegiline. Molecular modeling studies have been carried out to explain the selectivity of the most active homoisoflavonoids 1h and 1l.
|
Inhibition of human MAO-A expressed in BTI insect cells using p-tyramine as substrate after 60 mins
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrazoline based MAO inhibitors: synthesis, biological evaluation and SAR studies.
Year : 2011
Volume : 21
Issue : 14
First Page : 4296
Last Page : 4300
Authors : Jagrat M, Behera J, Yabanoglu S, Ercan A, Ucar G, Sinha BN, Sankaran V, Basu A, Jayaprakash V.
Abstract : Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5-16) were found to be potent inhibitors of hMAO-A isoform with SI(MAO-A) in the order 10(3) and 10(4). Ten molecules with unsubstituted ring A and without ring C (21-30), in which eight molecules (21, 23-26, and 28-30) were selective for hMAO-A, one for hMAO-B (22) and the other one non-selective (27). Presence of ring C increases potency as well as SI towards hMAO-A; however its absence decreases both potency and SI towards hMAO-A and hMAO-B.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
1.7
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-3.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
27.5
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of MAO-B in Sprague-Dawley rat brain mitochondrial suspension using kynuramine as substrate at 10 uM incubated for 5 mins prior to substrate addition measured for 5 mins by spectrophotometry
|
Rattus norvegicus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery, biological evaluation, and structure-activity and -selectivity relationships of 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-methylacetamides, a novel class of potent and selective monoamine oxidase inhibitors.
Year : 2013
Volume : 56
Issue : 6
First Page : 2651
Last Page : 2664
Authors : Pisani L, Barletta M, Soto-Otero R, Nicolotti O, Mendez-Alvarez E, Catto M, Introcaso A, Stefanachi A, Cellamare S, Altomare C, Carotti A.
Abstract : The use of selective inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B) holds a therapeutic relevance in the treatment of depressive disorders and Parkinson's disease (PD), respectively. Here, the discovery of a new class of compounds acting as monoamine oxidase inhibitors (MAO-Is) and bearing a 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide skeleton is reported. 6'-Sulfonyloxy derivatives exhibited outstanding affinities to MAO-A (7.0 nM < IC50 < 49 nM, much higher than moclobemide) and a pronounced MAO-A/B selectivity. The corresponding 6'-benzyloxy derivatives showed potent MAO-B inhibition and inverted selectivity profile. The rigid E-geometry of the exocyclic double bond allowed a more efficient binding conformation compared to more flexible and less active 2-(1-benzofuran-3-yl)-N-methylacetamide isomers and 4-N-methylcarboxamidomethylcoumarin analogues. Focused structural modifications and docking simulations enabled the identification of key molecular determinants for high affinity toward both MAO isoforms. These novel MAO-Is may represent promising hits for the development of safer therapeutic agents with a potential against depression, PD, and other age-related neurodegenerative pathologies.
|
Reversible inhibition of human recombinant MAO-A expressed in baculovirus infected BT1 insect cells at 300 nM incubated for 1 hr followed by compound washout by centrifugation-ultrafiltration method
|
Homo sapiens
|
9.56
%
|
|
Journal : Eur. J. Med. Chem.
Title : Monoamine oxidase inhibitory activity of 3,5-biaryl-4,5-dihydro-1H-pyrazole-1-carboxylate derivatives.
Year : 2013
Volume : 69
First Page : 762
Last Page : 767
Authors : Vishnu Nayak B, Ciftci-Yabanoglu S, Jadav SS, Jagrat M, Sinha BN, Ucar G, Jayaprakash V.
Abstract : Ethyl and phenyl carbamate derivatives of pyrazoline (3a-3h) were synthesized and tested for their MAO inhibitory activity. All the compounds were found to be selective towards MAO-A. Phenyl carbamates (3e-3h) were better than ethyl carbamates (3a-3d) and displayed the best selectivity index. Compound 3f (KiMAO-A; 4.96 ± 0.21 nM) was found to be equally potent as that of standard drug, Moclobemide (KiMAO-A; 5.01 ± 0.13 nM) but with best selectivity index (8.86 × 10(-5)). Molecular docking studies with R &S conformer of 3f revealed S-enantiomer is better than R-enantiomer as reported earlier by other groups. It is proposed that VdW's radii of the substitution (bulkiness) in ring B determine the potency of phenyl carbamates.
|
Reversible inhibition of human recombinant MAO-A expressed in baculovirus infected BT1 insect cells at 300 nM after 1 hr by centrifugation-ultrafiltration method
|
Homo sapiens
|
89.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Monoamine oxidase inhibitory activity of 3,5-biaryl-4,5-dihydro-1H-pyrazole-1-carboxylate derivatives.
Year : 2013
Volume : 69
First Page : 762
Last Page : 767
Authors : Vishnu Nayak B, Ciftci-Yabanoglu S, Jadav SS, Jagrat M, Sinha BN, Ucar G, Jayaprakash V.
Abstract : Ethyl and phenyl carbamate derivatives of pyrazoline (3a-3h) were synthesized and tested for their MAO inhibitory activity. All the compounds were found to be selective towards MAO-A. Phenyl carbamates (3e-3h) were better than ethyl carbamates (3a-3d) and displayed the best selectivity index. Compound 3f (KiMAO-A; 4.96 ± 0.21 nM) was found to be equally potent as that of standard drug, Moclobemide (KiMAO-A; 5.01 ± 0.13 nM) but with best selectivity index (8.86 × 10(-5)). Molecular docking studies with R &S conformer of 3f revealed S-enantiomer is better than R-enantiomer as reported earlier by other groups. It is proposed that VdW's radii of the substitution (bulkiness) in ring B determine the potency of phenyl carbamates.
|
Competitive reversible inhibition of human recombinant MAO-A expressed in baculovirus infected BT1 insect cells using p-tyramine as substrate assessed as H2O2 production after 15 mins by fluorimetric analysis
|
Homo sapiens
|
5.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Monoamine oxidase inhibitory activity of 3,5-biaryl-4,5-dihydro-1H-pyrazole-1-carboxylate derivatives.
Year : 2013
Volume : 69
First Page : 762
Last Page : 767
Authors : Vishnu Nayak B, Ciftci-Yabanoglu S, Jadav SS, Jagrat M, Sinha BN, Ucar G, Jayaprakash V.
Abstract : Ethyl and phenyl carbamate derivatives of pyrazoline (3a-3h) were synthesized and tested for their MAO inhibitory activity. All the compounds were found to be selective towards MAO-A. Phenyl carbamates (3e-3h) were better than ethyl carbamates (3a-3d) and displayed the best selectivity index. Compound 3f (KiMAO-A; 4.96 ± 0.21 nM) was found to be equally potent as that of standard drug, Moclobemide (KiMAO-A; 5.01 ± 0.13 nM) but with best selectivity index (8.86 × 10(-5)). Molecular docking studies with R &S conformer of 3f revealed S-enantiomer is better than R-enantiomer as reported earlier by other groups. It is proposed that VdW's radii of the substitution (bulkiness) in ring B determine the potency of phenyl carbamates.
|
Inhibition of human recombinant MAOA expressed in BTI-TN-5B1-4 cells using p-tyramine substrate assessed as reduction in H2O2 production
|
Homo sapiens
|
361.38
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent and selective MAO-B inhibitory activity: amino- versus nitro-3-arylcoumarin derivatives.
Year : 2015
Volume : 25
Issue : 3
First Page : 642
Last Page : 648
Authors : Matos MJ, Rodríguez-Enríquez F, Vilar S, Santana L, Uriarte E, Hripcsak G, Estrada M, Rodríguez-Franco MI, Viña D.
Abstract : In this study we synthesized and evaluated a new series of amino and nitro 3-arylcoumarins as hMAO-A and hMAO-B inhibitors. Compounds 2, 3, 5 and 6 presented a better activity and selectivity profile against the hMAO-B isoform (IC50 values between 2 and 6nM) than selegiline. In general, the amino derivatives (4-6) proved to be more selective against MAO-B than the nitro derivatives (1-3). Additionally, a theoretical study of some physicochemical properties, PAMPA and reversibility assays for the most potent derivative, and molecular docking simulations were carried out to further explain the pharmacological results, and to identify the hypothetical binding mode for the compounds inside the hMAO-B.
|
Inhibition of human MAOA expressed in baculovirus-infected BTI insect cells assessed as H2O2 production by resorufin dye based fluorimetric method
|
Homo sapiens
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of some novel hydrazone and 2-pyrazoline derivatives: monoamine oxidase inhibitory activities and docking studies.
Year : 2014
Volume : 24
Issue : 15
First Page : 3278
Last Page : 3284
Authors : Evranos-Aksöz B, Yabanoğlu-Çiftçi S, Uçar G, Yelekçi K, Ertan R.
Abstract : A novel series of 2-pyrazoline and hydrazone derivatives were synthesized and investigated for their human monoamine oxidase (hMAO) inhibitory activity. All compounds inhibited the hMAO isoforms (MAO-A or MAO-B) competitively and reversibly. With the exception of 5i, which was a selective MAO-B inhibitor, all derivatives inhibited hMAO-A potently and selectively. According to the experimental Ki values, compounds 6e and 6h exhibited the highest inhibitory activity towards the hMAO-A, whereas compound 5j, which carries a bromine atom at R(4) of the A ring of the pyrazoline, appeared to be the most selective MAO-A inhibitor. Tested compounds were docked computationally into the active site of the hMAO-A and hMAO-B isozymes. The computationally obtained results were in good agreement with the corresponding experimental values.
|
Inhibition of recombinant human MAO-A using p-tyramine as substrate assessed as H2O2 production preincubated for 15 mins followed by substrate addition measured for 15 mins by amplex red assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Monoamine Oxidase Inhibitory Activity of Novel Pyrazoline Analogues: Curcumin Based Design and Synthesis.
Year : 2016
Volume : 7
Issue : 1
First Page : 56
Last Page : 61
Authors : Badavath VN, Baysal İ, Ucar G, Sinha BN, Jayaprakash V.
Abstract : A series of new 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenolderivatives, 4-13, were synthesized and tested for their human MAO inhibitory activity. All the compounds were found to be selective and reversible toward hMAO-A except 4, a selective inhibitor of hMAO-B and 12, a nonselective inhibitor. Compound 7 was found to be a potent inhibitor of hMAO-A with Ki = 0.06 ± 0.003 μM and was having selectivity index of (SI = 1.02 × 10(-5)). It was found to be better than standard drug, Moclobemide (hMAO-A with Ki = 0.11 ± 0.01 μM) with selectivity index of SI = 0.049. Molecular docking simulation was carried out to understand the crucial interactions responsible for selectivity and potency.
|
Displacement of [3H](+)-pentazocine from S1R in human Jurkat cell membranes after 2 hrs by liquid scintillation counting
|
Homo sapiens
|
100.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and pharmacological evaluation of benzamide derivatives as potent and selective sigma-1 protein ligands.
Year : 2017
Volume : 138
First Page : 964
Last Page : 978
Authors : Donnier-Maréchal M, Carato P, Larchanché PE, Ravez S, Boulahjar R, Barczyk A, Oxombre B, Vermersch P, Melnyk P.
Abstract : A series of novel benzamide-derived compounds was designed, synthesized and pharmacologically evaluated. Among all 37 synthesized compounds, two series were developed with the modulation of the nature, the position of atoms or groups on the benzamide scaffold, but also the nature of the amine group separated from the benzamide with 2, 3 or 4 methylene groups. In vitro competition binding assays against sigma proteins (sigma-1 S1R and sigma-2 S2R) revealed that most of them conferred S2R/S1R selectivity toward without cytotoxic effects on SY5Y cells, especially with the first series with compounds 7a-z. Some selected compounds were also evaluated for their agonist and antagonist activities on a panel of 40 receptors. Results showed the importance of the nature and the position with halogeno atom on the benzamide scaffold, the length chain but also the contribution of the hydrophobic part on the amine group. Among them, compounds 7i, w, y with Cl, CN or NO2 groups at the 4-position of the benzamide scaffold showed excellent affinity for S1R (Ki = 1.2-3.6 nM), selectivity for S2R (Ki up to 1400 nM) and high selectivity index (IC50(SY5Y)/Ki(S1R) ratio from 28 000 to 83 000). Futhermore, these compounds presented an excellent safety profile over 40 other receptors. These derivatives will be selected for further biological investigations.
|
Displacement of [3H]-DTG from S2R in human Jurkat cell membranes after 1 hr in presence of (+)-pentazocine by liquid scintillation counting
|
Homo sapiens
|
200.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and pharmacological evaluation of benzamide derivatives as potent and selective sigma-1 protein ligands.
Year : 2017
Volume : 138
First Page : 964
Last Page : 978
Authors : Donnier-Maréchal M, Carato P, Larchanché PE, Ravez S, Boulahjar R, Barczyk A, Oxombre B, Vermersch P, Melnyk P.
Abstract : A series of novel benzamide-derived compounds was designed, synthesized and pharmacologically evaluated. Among all 37 synthesized compounds, two series were developed with the modulation of the nature, the position of atoms or groups on the benzamide scaffold, but also the nature of the amine group separated from the benzamide with 2, 3 or 4 methylene groups. In vitro competition binding assays against sigma proteins (sigma-1 S1R and sigma-2 S2R) revealed that most of them conferred S2R/S1R selectivity toward without cytotoxic effects on SY5Y cells, especially with the first series with compounds 7a-z. Some selected compounds were also evaluated for their agonist and antagonist activities on a panel of 40 receptors. Results showed the importance of the nature and the position with halogeno atom on the benzamide scaffold, the length chain but also the contribution of the hydrophobic part on the amine group. Among them, compounds 7i, w, y with Cl, CN or NO2 groups at the 4-position of the benzamide scaffold showed excellent affinity for S1R (Ki = 1.2-3.6 nM), selectivity for S2R (Ki up to 1400 nM) and high selectivity index (IC50(SY5Y)/Ki(S1R) ratio from 28 000 to 83 000). Futhermore, these compounds presented an excellent safety profile over 40 other receptors. These derivatives will be selected for further biological investigations.
|
Inhibition of recombinant human MAO-A assessed as reduction in H2O2 production preincubated for 30 mins followed by p-tyramine substrate addition measured after 30 mins by amplex red reagent based fluorescence assay
|
Homo sapiens
|
102.0
nM
|
|
Journal : MedChemComm
Title : Curcumin-based pyrazoline analogues as selective inhibitors of human monoamine oxidase A.
Year : 2018
Volume : 9
Issue : 7
First Page : 1164
Last Page : 1171
Authors : Nath C, Badavath VN, Thakur A, Ucar G, Acevedo O, Mohd Siddique MU, Jayaprakash V.
Abstract : A series of 2-methoxy-4-(5-phenyl-4,5-dihydro-1<i>H</i>-pyrazol-3-yl)phenol (pyrazoline) derivatives (<b>2-6</b>) have been synthesized and tested for human monoamine oxidase (hMAO) inhibitory activity. The most active derivative (<b>2</b>) behaved as a competitive hMAO-A inhibitor, with an inhibition constant value of 0.08 μM and a strong hMAO-A selectivity (<i>K</i><sub>i</sub>(hMAO-B)/<i>K</i><sub>i</sub>(hMAO-A) > 1751). In addition, <b>2</b> exhibited little to no cytotoxic effects up to a 25 μM concentration and provided the best blood-brain barrier permeability among the derivatives synthesized. Molecular dynamics simulations revealed that a chlorine substituent at the <i>para</i>-position of the phenyl ring in <b>2</b> enabled a π-π stacking interaction with Tyr407 and Tyr444 that resulted in the formation of an "aromatic sandwich" structure. Consequently, this tight-binding aromatic cage culminated in a dramatically reduced active site volume that is believed to be the origin of the observed selectivity between the hMAO-A and hMAO-B isozymes. Removal of the chlorine from <b>2</b> disrupted the favorable intermolecular interactions and resulted in a selectivity change towards hMAO-B.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
3.95
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
0.74
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
9.06
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
7.86
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
4.07
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
3.1
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-2.98
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-1.36
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.94
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
3.102
%
|
|
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
|
-0.06
%
|
|
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
|
0.01
%
|
|
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
|
-0.06
%
|
|
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
|
0.01
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of human recombinant MAO-A at 1 mM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
95.3
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of human recombinant MAO-A at 100 uM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
83.14
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of human recombinant MAO-A at 10 uM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
62.44
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of human recombinant MAO-A at 1 uM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
35.76
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of human recombinant MAO-A at 0.1 uM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
24.47
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of human recombinant MAO-A at 0.01 uM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
19.64
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of human recombinant MAO-A at 1 nM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
15.42
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of human recombinant MAO-A at 0.1 nM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
12.85
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of human recombinant MAO-A at 0.01 nM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
7.251
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of recombinant human MAO-A expressed in baculovirus infected BTI insect cells using p-tyramine as substrate incubated for 30 mins by Amplex red reagent based fluorescence analysis
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Med Chem
Title : New 2-Pyrazoline and Hydrazone Derivatives as Potent and Selective Monoamine Oxidase A Inhibitors.
Year : 2021
Volume : 64
Issue : 4.0
First Page : 1989
Last Page : 2009
Authors : Salgin-Goksen U,Telli G,Erikci A,Dedecengiz E,Tel BC,Kaynak FB,Yelekci K,Ucar G,Gokhan-Kelekci N
Abstract : Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having N'-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the in vitro results. Five compounds, 6 (0.008 μM, Selectivity Index (SI): 9.70 × 10), 7 (0.009 μM, SI: 4.55 × 10), 14 (0.001 μM, SI: 8.00 × 10), 21 (0.009 μM, SI: 1.37 × 10), and 42 (0.010 μM, SI: 5.40 × 10), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood-brain barrier according to parallel artificial membrane permeation assay. Compounds 14, 21, and 42 exhibited an ex vivo MAO-A profile, which is highly consistent with the in vitro data.
