|
Inhibition of human aquaporin 4 M23 isoform expressed in Xenopus laevis oocytes at 20 uM
|
Homo sapiens
|
3.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of aquaporin 4 inhibitors using in vitro and in silico methods.
Year : 2009
Volume : 17
Issue : 1
First Page : 411
Last Page : 417
Authors : Huber VJ, Tsujita M, Nakada T.
Abstract : The in vitro inhibitory effects and in silico docking energies of 18 compounds with respect to aquaporin 4 (AQP4) were investigated. More than half of the compounds tested showed inhibitory activity in the in vitro functional assay and included the 5-HT(1B/1D) agonists sumatriptan, and rizatriptan. Moreover, the observed inhibitory activity of the compounds used in this study at 20 microM showed a strong correlation with their in silico docking energies, r(2)=0.64, which was consistent with that found in previous studies. The AQP4 inhibitory IC(50) values of three compounds, 2-(nicotinamido)-1,3,4-thiadiazole, sumatriptan and rizatriptan, were subsequently found to be 3, 11, and 2 microM, respectively.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Ra at 50 ug/ml after 6 days by microplate alamar blue assay
|
Mycobacterium tuberculosis H37Ra
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : 3'-bromo analogues of pyrimidine nucleosides as a new class of potent inhibitors of Mycobacterium tuberculosis.
Year : 2010
Volume : 53
Issue : 10
First Page : 4130
Last Page : 4140
Authors : Shakya N, Srivastav NC, Desroches N, Agrawal B, Kunimoto DY, Kumar R.
Abstract : Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2'- or 3'-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and evaluated for antimycobacterial activities. Among the compounds tested, 3'-bromo-3'-deoxy-arabinofuranosylthymine (33) was the most effective antituberculosis agent in the in vitro assays against wild-type M. tuberculosis strain (H37Ra) (MIC(50) = 1 microg/mL) as well as drug-resistant (H37Rv) (rifampicin-resistant and isoniazid-resistant) strains of M. tuberculosis (MIC(50) = 1-2 microg/mL). Compound 33 also inhibited intracellular M. tuberculosis in a human monocytic cell line infected with H37Ra, demonstrating higher activity against intramacrophagic mycobacteria (80% reduction at 10 microg/mL concentration) than extracellular mycobacteria (75% reduction at 10 microg/mL concentration). In contrast, pyrimidine nucleosides possessing 5-fluorouracil base were weak inhibitors of M. tuberculosis. No cytotoxicity was found up to the highest concentration of compounds tested (CC(50) > 100-200 microg/mL) against a human cell line. Overall, these encouraging results substantiate the potential of this new class of compounds as promising antituberculosis agents.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Ra at 25 ug/ml after 6 days by microplate alamar blue assay
|
Mycobacterium tuberculosis H37Ra
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : 3'-bromo analogues of pyrimidine nucleosides as a new class of potent inhibitors of Mycobacterium tuberculosis.
Year : 2010
Volume : 53
Issue : 10
First Page : 4130
Last Page : 4140
Authors : Shakya N, Srivastav NC, Desroches N, Agrawal B, Kunimoto DY, Kumar R.
Abstract : Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2'- or 3'-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and evaluated for antimycobacterial activities. Among the compounds tested, 3'-bromo-3'-deoxy-arabinofuranosylthymine (33) was the most effective antituberculosis agent in the in vitro assays against wild-type M. tuberculosis strain (H37Ra) (MIC(50) = 1 microg/mL) as well as drug-resistant (H37Rv) (rifampicin-resistant and isoniazid-resistant) strains of M. tuberculosis (MIC(50) = 1-2 microg/mL). Compound 33 also inhibited intracellular M. tuberculosis in a human monocytic cell line infected with H37Ra, demonstrating higher activity against intramacrophagic mycobacteria (80% reduction at 10 microg/mL concentration) than extracellular mycobacteria (75% reduction at 10 microg/mL concentration). In contrast, pyrimidine nucleosides possessing 5-fluorouracil base were weak inhibitors of M. tuberculosis. No cytotoxicity was found up to the highest concentration of compounds tested (CC(50) > 100-200 microg/mL) against a human cell line. Overall, these encouraging results substantiate the potential of this new class of compounds as promising antituberculosis agents.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Ra at 5 ug/ml after 6 days by microplate alamar blue assay
|
Mycobacterium tuberculosis H37Ra
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : 3'-bromo analogues of pyrimidine nucleosides as a new class of potent inhibitors of Mycobacterium tuberculosis.
Year : 2010
Volume : 53
Issue : 10
First Page : 4130
Last Page : 4140
Authors : Shakya N, Srivastav NC, Desroches N, Agrawal B, Kunimoto DY, Kumar R.
Abstract : Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2'- or 3'-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and evaluated for antimycobacterial activities. Among the compounds tested, 3'-bromo-3'-deoxy-arabinofuranosylthymine (33) was the most effective antituberculosis agent in the in vitro assays against wild-type M. tuberculosis strain (H37Ra) (MIC(50) = 1 microg/mL) as well as drug-resistant (H37Rv) (rifampicin-resistant and isoniazid-resistant) strains of M. tuberculosis (MIC(50) = 1-2 microg/mL). Compound 33 also inhibited intracellular M. tuberculosis in a human monocytic cell line infected with H37Ra, demonstrating higher activity against intramacrophagic mycobacteria (80% reduction at 10 microg/mL concentration) than extracellular mycobacteria (75% reduction at 10 microg/mL concentration). In contrast, pyrimidine nucleosides possessing 5-fluorouracil base were weak inhibitors of M. tuberculosis. No cytotoxicity was found up to the highest concentration of compounds tested (CC(50) > 100-200 microg/mL) against a human cell line. Overall, these encouraging results substantiate the potential of this new class of compounds as promising antituberculosis agents.
|
Antitubercular activity against Mycobacterium bovis BCG at 10 ug/ml after 6 days by microplate alamar blue assay
|
Mycobacterium bovis BCG
|
71.0
%
|
|
Journal : J. Med. Chem.
Title : Inhibition of mycobacterial replication by pyrimidines possessing various C-5 functionalities and related 2'-deoxynucleoside analogues using in vitro and in vivo models.
Year : 2010
Volume : 53
Issue : 16
First Page : 6180
Last Page : 6187
Authors : Srivastav NC, Rai D, Tse C, Agrawal B, Kunimoto DY, Kumar R.
Abstract : Tuberculosis (TB) has become an increasing problem since the emergence of human immunodeficiency virus and increasing appearance of drug-resistant strains. There is an urgent need to advance our knowledge and discover a new class of agents that are distinct than current therapies. Antimycobacterial activities of several 5-alkyl, 5-alkynyl, furanopyrimidines and related 2'-deoxynucleosides were investigated against Mycobacterium tuberculosis. Compounds with 5-arylalkynyl substituents (23-26, 33, 35) displayed potent in vitro antitubercular activity against Mycobacterium bovis and Mycobacterium tuberculosis. The in vivo activity of 5-(2-pyridylethynyl)-uracil (26) and its 2'-deoxycytidine analogue, 5-(2-pyridylethynyl)-2'-deoxycytidine (35), was assessed in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds 26 and 35 given at a dose of 50 mg/kg for 5 weeks showed promising in vivo efficacy in a mouse model, with the 2'-deoxycytidine derivative being more effective than the uracil analogue and a reference drug d-cycloserine. These data indicated that there is a significant potential in this class of compounds.
|
Antitubercular activity against Mycobacterium bovis BCG at 5 ug/ml after 6 days by microplate alamar blue assay
|
Mycobacterium bovis BCG
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Inhibition of mycobacterial replication by pyrimidines possessing various C-5 functionalities and related 2'-deoxynucleoside analogues using in vitro and in vivo models.
Year : 2010
Volume : 53
Issue : 16
First Page : 6180
Last Page : 6187
Authors : Srivastav NC, Rai D, Tse C, Agrawal B, Kunimoto DY, Kumar R.
Abstract : Tuberculosis (TB) has become an increasing problem since the emergence of human immunodeficiency virus and increasing appearance of drug-resistant strains. There is an urgent need to advance our knowledge and discover a new class of agents that are distinct than current therapies. Antimycobacterial activities of several 5-alkyl, 5-alkynyl, furanopyrimidines and related 2'-deoxynucleosides were investigated against Mycobacterium tuberculosis. Compounds with 5-arylalkynyl substituents (23-26, 33, 35) displayed potent in vitro antitubercular activity against Mycobacterium bovis and Mycobacterium tuberculosis. The in vivo activity of 5-(2-pyridylethynyl)-uracil (26) and its 2'-deoxycytidine analogue, 5-(2-pyridylethynyl)-2'-deoxycytidine (35), was assessed in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds 26 and 35 given at a dose of 50 mg/kg for 5 weeks showed promising in vivo efficacy in a mouse model, with the 2'-deoxycytidine derivative being more effective than the uracil analogue and a reference drug d-cycloserine. These data indicated that there is a significant potential in this class of compounds.
|
Antitubercular activity against Mycobacterium tuberculosis H37Ra at 10 ug/ml after 6 days by microplate alamar blue assay
|
Mycobacterium tuberculosis H37Ra
|
67.0
%
|
|
Journal : J. Med. Chem.
Title : Inhibition of mycobacterial replication by pyrimidines possessing various C-5 functionalities and related 2'-deoxynucleoside analogues using in vitro and in vivo models.
Year : 2010
Volume : 53
Issue : 16
First Page : 6180
Last Page : 6187
Authors : Srivastav NC, Rai D, Tse C, Agrawal B, Kunimoto DY, Kumar R.
Abstract : Tuberculosis (TB) has become an increasing problem since the emergence of human immunodeficiency virus and increasing appearance of drug-resistant strains. There is an urgent need to advance our knowledge and discover a new class of agents that are distinct than current therapies. Antimycobacterial activities of several 5-alkyl, 5-alkynyl, furanopyrimidines and related 2'-deoxynucleosides were investigated against Mycobacterium tuberculosis. Compounds with 5-arylalkynyl substituents (23-26, 33, 35) displayed potent in vitro antitubercular activity against Mycobacterium bovis and Mycobacterium tuberculosis. The in vivo activity of 5-(2-pyridylethynyl)-uracil (26) and its 2'-deoxycytidine analogue, 5-(2-pyridylethynyl)-2'-deoxycytidine (35), was assessed in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds 26 and 35 given at a dose of 50 mg/kg for 5 weeks showed promising in vivo efficacy in a mouse model, with the 2'-deoxycytidine derivative being more effective than the uracil analogue and a reference drug d-cycloserine. These data indicated that there is a significant potential in this class of compounds.
|
Antitubercular activity against Mycobacterium tuberculosis H37Ra at 5 ug/ml after 6 days by microplate alamar blue assay
|
Mycobacterium tuberculosis H37Ra
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Inhibition of mycobacterial replication by pyrimidines possessing various C-5 functionalities and related 2'-deoxynucleoside analogues using in vitro and in vivo models.
Year : 2010
Volume : 53
Issue : 16
First Page : 6180
Last Page : 6187
Authors : Srivastav NC, Rai D, Tse C, Agrawal B, Kunimoto DY, Kumar R.
Abstract : Tuberculosis (TB) has become an increasing problem since the emergence of human immunodeficiency virus and increasing appearance of drug-resistant strains. There is an urgent need to advance our knowledge and discover a new class of agents that are distinct than current therapies. Antimycobacterial activities of several 5-alkyl, 5-alkynyl, furanopyrimidines and related 2'-deoxynucleosides were investigated against Mycobacterium tuberculosis. Compounds with 5-arylalkynyl substituents (23-26, 33, 35) displayed potent in vitro antitubercular activity against Mycobacterium bovis and Mycobacterium tuberculosis. The in vivo activity of 5-(2-pyridylethynyl)-uracil (26) and its 2'-deoxycytidine analogue, 5-(2-pyridylethynyl)-2'-deoxycytidine (35), was assessed in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds 26 and 35 given at a dose of 50 mg/kg for 5 weeks showed promising in vivo efficacy in a mouse model, with the 2'-deoxycytidine derivative being more effective than the uracil analogue and a reference drug d-cycloserine. These data indicated that there is a significant potential in this class of compounds.
|
Cytotoxicity against african green monkey Vero cells after 72 hrs by MTT assay
|
Chlorocebus sabaeus
|
62.5
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents.
Year : 2013
Volume : 23
Issue : 5
First Page : 1383
Last Page : 1386
Authors : Wei AC, Ali MA, Yoon YK, Ismail R, Choon TS, Kumar RS.
Abstract : A series of fourteen dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions and were screened for their antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv in HTS (High Throughput Screen). Most of the compounds showed moderate to good activity with MIC of less than 20 μM. Compound 4'-(4-bromophenyl)-1'-methyldispiro[acenaphthylene-1,2'-pyrrolidine-3',2″-indane]-2,1″(1H)-dione (4c) was found to be the most active with MIC of 12.50 μM.
|
Cytotoxicity against african green monkey Vero cells after 72 hrs by MTS-PMS assay
|
Chlorocebus sabaeus
|
100.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Chlorinated coumarins from the polypore mushroom Fomitopsis officinalis and their activity against Mycobacterium tuberculosis.
Year : 2013
Volume : 76
Issue : 10
First Page : 1916
Last Page : 1922
Authors : Hwang CH, Jaki BU, Klein LL, Lankin DC, McAlpine JB, Napolitano JG, Fryling NA, Franzblau SG, Cho SH, Stamets PE, Wang Y, Pauli GF.
Abstract : An EtOH extract of the polypore mushroom Fomitopsis officinalis afforded two new naturally occurring chlorinated coumarins, which were identified as the previously synthesized compounds 6-chloro-4-phenyl-2H-chromen-2-one (1) and ethyl 6-chloro-2-oxo-4-phenyl-2H-chromen-3-carboxylate (2). The structures of the two isolates were deduced by ab initio spectroscopic methods and confirmed by chemical synthesis. In addition, an analogue of each was synthesized as 7-chloro-4-phenyl-2H-chromen-2-one (3) and ethyl 7-chloro-2-oxo-4-phenyl-2H-chromen-3-carboxylate (4). All four compounds were characterized physicochemically, and their antimicrobial activity profiles revealed a narrow spectrum of activity with lowest MICs against the Mycobacterium tuberculosis complex.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27294 after 7 days by microplate Alamar blue assay
|
Mycobacterium tuberculosis H37Rv
|
12.47
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Antimycobacterial activity of nitrogen heterocycles derivatives: bipyridine derivatives. Part III.
Year : 2014
Volume : 74
First Page : 664
Last Page : 670
Authors : Danac R, Mangalagiu II.
Abstract : Three classes of fused bipyridine heterocycles were designed, synthesized and evaluated for their antimycobacterial activities. The method for preparation of fused bipyridine derivatives is straight and efficient. The primary antimycobacterial screening reveals that mono-indolizine mono-salts are displaying potency superior to the second-line antitubercular drugs Cycloserine and Pyrimethamine and, equal as the first line anti-TB Ethambutol. The data from Cycle-2 screening assay (MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation) confirm the promising anti-TB results from Cycle-1 for mono-indolizine mono-salts. These data indicate that mono-indolizine mono-salt 6d is a potent compound against both replicating and non-replicating Mycobacterium tuberculosis, is active against both extracellular and intracellular organisms, has a bacteriostatic mechanism of action and has basically no toxicity. We see no influence concerning the anti-TB activity of the fused-pyridine substituents.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27294 at 12.5 ug/ml after 7 days by microplate Alamar blue assay relative to control
|
Mycobacterium tuberculosis H37Rv
|
51.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Antimycobacterial activity of nitrogen heterocycles derivatives: bipyridine derivatives. Part III.
Year : 2014
Volume : 74
First Page : 664
Last Page : 670
Authors : Danac R, Mangalagiu II.
Abstract : Three classes of fused bipyridine heterocycles were designed, synthesized and evaluated for their antimycobacterial activities. The method for preparation of fused bipyridine derivatives is straight and efficient. The primary antimycobacterial screening reveals that mono-indolizine mono-salts are displaying potency superior to the second-line antitubercular drugs Cycloserine and Pyrimethamine and, equal as the first line anti-TB Ethambutol. The data from Cycle-2 screening assay (MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation) confirm the promising anti-TB results from Cycle-1 for mono-indolizine mono-salts. These data indicate that mono-indolizine mono-salt 6d is a potent compound against both replicating and non-replicating Mycobacterium tuberculosis, is active against both extracellular and intracellular organisms, has a bacteriostatic mechanism of action and has basically no toxicity. We see no influence concerning the anti-TB activity of the fused-pyridine substituents.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27294 at 25 ug/ml after 7 days by microplate Alamar blue assay relative to control
|
Mycobacterium tuberculosis H37Rv
|
93.9
%
|
|
Journal : Eur. J. Med. Chem.
Title : Antimycobacterial activity of nitrogen heterocycles derivatives: bipyridine derivatives. Part III.
Year : 2014
Volume : 74
First Page : 664
Last Page : 670
Authors : Danac R, Mangalagiu II.
Abstract : Three classes of fused bipyridine heterocycles were designed, synthesized and evaluated for their antimycobacterial activities. The method for preparation of fused bipyridine derivatives is straight and efficient. The primary antimycobacterial screening reveals that mono-indolizine mono-salts are displaying potency superior to the second-line antitubercular drugs Cycloserine and Pyrimethamine and, equal as the first line anti-TB Ethambutol. The data from Cycle-2 screening assay (MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation) confirm the promising anti-TB results from Cycle-1 for mono-indolizine mono-salts. These data indicate that mono-indolizine mono-salt 6d is a potent compound against both replicating and non-replicating Mycobacterium tuberculosis, is active against both extracellular and intracellular organisms, has a bacteriostatic mechanism of action and has basically no toxicity. We see no influence concerning the anti-TB activity of the fused-pyridine substituents.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27294 at 50 ug/ml after 7 days by microplate Alamar blue assay relative to control
|
Mycobacterium tuberculosis H37Rv
|
96.3
%
|
|
Journal : Eur. J. Med. Chem.
Title : Antimycobacterial activity of nitrogen heterocycles derivatives: bipyridine derivatives. Part III.
Year : 2014
Volume : 74
First Page : 664
Last Page : 670
Authors : Danac R, Mangalagiu II.
Abstract : Three classes of fused bipyridine heterocycles were designed, synthesized and evaluated for their antimycobacterial activities. The method for preparation of fused bipyridine derivatives is straight and efficient. The primary antimycobacterial screening reveals that mono-indolizine mono-salts are displaying potency superior to the second-line antitubercular drugs Cycloserine and Pyrimethamine and, equal as the first line anti-TB Ethambutol. The data from Cycle-2 screening assay (MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation) confirm the promising anti-TB results from Cycle-1 for mono-indolizine mono-salts. These data indicate that mono-indolizine mono-salt 6d is a potent compound against both replicating and non-replicating Mycobacterium tuberculosis, is active against both extracellular and intracellular organisms, has a bacteriostatic mechanism of action and has basically no toxicity. We see no influence concerning the anti-TB activity of the fused-pyridine substituents.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27294 at 100 ug/ml after 7 days by microplate Alamar blue assay relative to control
|
Mycobacterium tuberculosis H37Rv
|
97.7
%
|
|
Journal : Eur. J. Med. Chem.
Title : Antimycobacterial activity of nitrogen heterocycles derivatives: bipyridine derivatives. Part III.
Year : 2014
Volume : 74
First Page : 664
Last Page : 670
Authors : Danac R, Mangalagiu II.
Abstract : Three classes of fused bipyridine heterocycles were designed, synthesized and evaluated for their antimycobacterial activities. The method for preparation of fused bipyridine derivatives is straight and efficient. The primary antimycobacterial screening reveals that mono-indolizine mono-salts are displaying potency superior to the second-line antitubercular drugs Cycloserine and Pyrimethamine and, equal as the first line anti-TB Ethambutol. The data from Cycle-2 screening assay (MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation) confirm the promising anti-TB results from Cycle-1 for mono-indolizine mono-salts. These data indicate that mono-indolizine mono-salt 6d is a potent compound against both replicating and non-replicating Mycobacterium tuberculosis, is active against both extracellular and intracellular organisms, has a bacteriostatic mechanism of action and has basically no toxicity. We see no influence concerning the anti-TB activity of the fused-pyridine substituents.
|
Inhibition of alanine racemase in Mycobacterium tuberculosis H37Rv assessed as remaining activity at MIC preincubated for 16 hrs followed by L-Ala-[13C]-[3H] addition measured over 8 hrs by LC-MS/MS analysis
|
Mycobacterium tuberculosis H37Rv
|
10.0
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Metabolomics Reveal d-Alanine:d-Alanine Ligase As the Target of d-Cycloserine in Mycobacterium tuberculosis.
Year : 2013
Volume : 4
Issue : 12
First Page : 1233
Last Page : 1237
Authors : Prosser GA, de Carvalho LP.
Abstract : Stable isotope-mass spectrometry (MS)-based metabolomic profiling is a powerful technique for following changes in specific metabolite pool sizes and metabolic flux under various experimental conditions in a test organism or cell type. Here, we use a metabolomics approach to interrogate the mechanism of antibiotic action of d-cycloserine (DCS), a second line antibiotic used in the treatment of multidrug resistant Mycobacterium tuberculosis infections. We use doubly labeled (13)C α-carbon-(2)H l-alanine to allow tracking of both alanine racemase and d-alanine:d-alanine ligase activity in M. tuberculosis challenged with DCS and reveal that d-alanine:d-alanine ligase is more strongly inhibited than alanine racemase at equivalent DCS concentrations. We also shed light on mechanisms surrounding d-Ala-mediated antagonism of DCS growth inhibition and provide evidence for a postantibiotic effect for this drug. Our results illustrate the potential of metabolomics in cellular drug-target engagement studies and consequently have broad implications in future drug development and target validation ventures.
|
Cytotoxicity against monkey Vero cells assessed as decrease in cell viability after 72 hrs by MTT assay
|
Chlorocebus sabaeus
|
6.25
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : One-pot microwave assisted stereoselective synthesis of novel dihydro-2'H-spiro[indene-2,1'-pyrrolo-[3,4-c]pyrrole]-tetraones and evaluation of their antimycobacterial activity and inhibition of AChE.
Year : 2017
Volume : 27
Issue : 14
First Page : 3071
Last Page : 3075
Authors : Bharkavi C, Vivek Kumar S, Ashraf Ali M, Osman H, Muthusubramanian S, Perumal S.
Abstract : An efficient one-pot microwave assisted stereoselective synthesis of novel dihydro-2'H-spiro[indene-2,1'-pyrrolo[3,4-c]pyrrole]-tetraone derivatives through three-component 1,3-dipolar cycloaddition of azomethine ylides generated in situ from ninhydrin and sarcosine with a series of 1-aryl-1H-pyrrole-2,5-diones is described. The synthesised compounds were screened for their antimycobacterial and AChE inhibition activities. Compound 4b (IC50 1.30µM) has been found to display twelve fold antimycobacterial activity compared to cycloserine and it is thirty seven times more active than pyrimethamine. Compound 4h displays maximum AchE inhibitory activity with IC50 value of 0.78±0.01µmol/L.
|
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
|
14.71
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
1.47
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
12.0
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
60.23
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
25.21
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
1.72
%
|
|
|
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
|
-5.65
%
|
|
|
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
|
-2.21
%
|
|
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.
|
Inhibition of Enterococcus faecalis JH2-2 C-terminal 6His-tagged DdlB expressed in Escherichia coli LMG194 at 10 uM preincubated for 30 mins followed by substrate addition and measured after 20 mins by Biomol Green reagent assay relative to control
|
Enterococcus faecalis
|
30.0
%
|
|
Journal : Eur J Med Chem
Title : 1-(2-Hydroxybenzoyl)-thiosemicarbazides are promising antimicrobial agents targeting d-alanine-d-alanine ligase in bacterio.
Year : 2018
Volume : 159
First Page : 324
Last Page : 338
Authors : Ameryckx A, Thabault L, Pochet L, Leimanis S, Poupaert JH, Wouters J, Joris B, Van Bambeke F, Frédérick R.
Abstract : The bacterial cell wall and the enzymes involved in peptidoglycan synthesis are privileged targets for the development of novel antibacterial agents. In this work, a series of 1-(2-hydroxybenzoyl)-thiosemicarbazides inhibitors of D-Ala-D-Ala ligase (Ddl) were designed and synthesized in order to target resistant strains of bacteria. Among these, the 4-(3,4-dichlorophenyl)-1-(2-hydroxybenzoyl)-3-thiosemicarbazide 29 was identified as a potent Ddl inhibitor with activity in the micromolar range. This compound, possessing strong antimicrobial activity including against multidrug resistant strains, was proven to act through a bactericidal mechanism and demonstrated very low cytotoxicity on THP-1 human monocytic cell line. Inhibition of Ddl activity by 29 was confirmed in bacterio using UPLC-MS/MS by demonstrating an increase in D-Ala intracellular pools accompanied by a commensurate decrease in D-Ala-D-Ala. Further structure-activity relationships (SARs) studies provided evidence that the hydroxyl substituent in the 2-position (R<sub>1</sub>) of the benzoylthiosemicarbazide scaffold is essential for the enzymatic inhibition. This work thus highlights the 1-(2-hydroxybenzoyl)-thiosemicarbazide motif as a very promising tool for the development of novel antibacterial compounds acting through an interesting mechanism of action and low cytotoxicity.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
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Severe acute respiratory syndrome coronavirus 2
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23.75
%
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
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Severe acute respiratory syndrome coronavirus 2
|
29.49
%
|
|
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.
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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
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Chlorocebus sabaeus
|
0.17
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.17
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.09
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
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Antimycobacterial activity against Mycobacterium bovis BCG assessed as inhibition of bacterial growth at 10 ug/ml measured by microplate alamar blue assay
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Mycobacterium tuberculosis variant bovis BCG
|
71.0
%
|
|
|
Antimycobacterial activity against Mycobacterium bovis BCG assessed as inhibition of bacterial growth at 5 ug/ml measured by microplate alamar blue assay
|
Mycobacterium tuberculosis variant bovis BCG
|
50.0
%
|
|
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Ra assessed as inhibition of bacterial growth at 10 ug/ml measured by microplate alamar blue assay
|
Mycobacterium tuberculosis
|
67.0
%
|
|
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Antimycobacterial activity against Mycobacterium tuberculosis H37Ra assessed as inhibition of bacterial growth at 5 ug/ml measured by microplate alamar blue assay
|
Mycobacterium tuberculosis
|
50.0
%
|
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