|
Inhibitory activity against the displacement of Picogreen from fMet-tRNA(fMet) by the aminoglycoside
|
Staphylococcus aureus
|
160.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of bacterial IF2 binding to fMet-tRNA((fMet)) by aminoglycosides.
Year : 2003
Volume : 13
Issue : 6
First Page : 993
Last Page : 996
Authors : Evans JM, Turner BA, Bowen S, Ho AM, Sarver RW, Benson E, Parker CN.
Abstract : Screening for inhibitors of bacterial protein synthesis Initiation Factor 2 (IF2) binding to N-formyl-Methionyl-transfer RNA (fMet-tRNA((fMet))) identified a series of aminoglycosides, that included amikacin and kanamycin A1, as inhibitors of this interaction. Subsequent testing revealed that aminoglycosides displayed a wide range of inhibitory activity. However, the failure of these compounds to completely inhibit binding of IF2 to fMet-tRNA((fMet)), the known ability of aminoglycosides to bind RNA, and the ability of the aminoglycosides to displace PicoGreen bound to fMet-tRNA((fMet)) suggest these compounds act by binding fMet-tRNA((fMet)). This hypothesis is further supported by isothermal denaturation experiments that failed to show any interaction between the IF2 protein and the aminoglycosides.
|
Maximal inhibition against the displacement of Picogreen from fMet-tRNA(fMet) by the aminoglycoside
|
Staphylococcus aureus
|
85.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of bacterial IF2 binding to fMet-tRNA((fMet)) by aminoglycosides.
Year : 2003
Volume : 13
Issue : 6
First Page : 993
Last Page : 996
Authors : Evans JM, Turner BA, Bowen S, Ho AM, Sarver RW, Benson E, Parker CN.
Abstract : Screening for inhibitors of bacterial protein synthesis Initiation Factor 2 (IF2) binding to N-formyl-Methionyl-transfer RNA (fMet-tRNA((fMet))) identified a series of aminoglycosides, that included amikacin and kanamycin A1, as inhibitors of this interaction. Subsequent testing revealed that aminoglycosides displayed a wide range of inhibitory activity. However, the failure of these compounds to completely inhibit binding of IF2 to fMet-tRNA((fMet)), the known ability of aminoglycosides to bind RNA, and the ability of the aminoglycosides to displace PicoGreen bound to fMet-tRNA((fMet)) suggest these compounds act by binding fMet-tRNA((fMet)). This hypothesis is further supported by isothermal denaturation experiments that failed to show any interaction between the IF2 protein and the aminoglycosides.
|
Maximal inhibition of the aminoglycoside on Staphylococcus aureus IF-2 binding to fMet-tRNA(fMet)
|
Staphylococcus aureus
|
43.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of bacterial IF2 binding to fMet-tRNA((fMet)) by aminoglycosides.
Year : 2003
Volume : 13
Issue : 6
First Page : 993
Last Page : 996
Authors : Evans JM, Turner BA, Bowen S, Ho AM, Sarver RW, Benson E, Parker CN.
Abstract : Screening for inhibitors of bacterial protein synthesis Initiation Factor 2 (IF2) binding to N-formyl-Methionyl-transfer RNA (fMet-tRNA((fMet))) identified a series of aminoglycosides, that included amikacin and kanamycin A1, as inhibitors of this interaction. Subsequent testing revealed that aminoglycosides displayed a wide range of inhibitory activity. However, the failure of these compounds to completely inhibit binding of IF2 to fMet-tRNA((fMet)), the known ability of aminoglycosides to bind RNA, and the ability of the aminoglycosides to displace PicoGreen bound to fMet-tRNA((fMet)) suggest these compounds act by binding fMet-tRNA((fMet)). This hypothesis is further supported by isothermal denaturation experiments that failed to show any interaction between the IF2 protein and the aminoglycosides.
|
Inhibition of purified telomerase of Euplotes aediculatus at 50 uM
|
Euplotes aediculatus
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
Year : 2004
Volume : 14
Issue : 13
First Page : 3467
Last Page : 3471
Authors : Dominick PK, Keppler BR, Legassie JD, Moon IK, Jarstfer MB.
Abstract : We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors.
|
Inhibition of telomerase after assembly using recombinant Tetraymena thermophilia TR and TERT at 50 uM
|
Tetrahymena thermophila
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
Year : 2004
Volume : 14
Issue : 13
First Page : 3467
Last Page : 3471
Authors : Dominick PK, Keppler BR, Legassie JD, Moon IK, Jarstfer MB.
Abstract : We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors.
|
Inhibition of telomerase before assembly using recombinant Tetraymena thermophilia TR and TERT at 50 uM
|
Tetrahymena thermophila
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
Year : 2004
Volume : 14
Issue : 13
First Page : 3467
Last Page : 3471
Authors : Dominick PK, Keppler BR, Legassie JD, Moon IK, Jarstfer MB.
Abstract : We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors.
|
Inhibition of human telomerase before assembly using recombinant hTR and hTERT at 50 uM
|
Homo sapiens
|
25.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
Year : 2004
Volume : 14
Issue : 13
First Page : 3467
Last Page : 3471
Authors : Dominick PK, Keppler BR, Legassie JD, Moon IK, Jarstfer MB.
Abstract : We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors.
|
Binding affinity to A-site RNA
|
None
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and implementation of an ribonucleic acid (RNA) directed fragment library.
Year : 2009
Volume : 52
Issue : 12
First Page : 3753
Last Page : 3761
Authors : Bodoor K, Boyapati V, Gopu V, Boisdore M, Allam K, Miller J, Treleaven WD, Weldeghiorghis T, Aboul-ela F.
Abstract : The design of RNA binding ligands is complicated by issues of specificity, target flexibility, and the tractability of known RNA inhibitors toward chemical derivitization. To address these difficulties, an RNA-directed fragment compound library is presented. We began with an analysis of 120 small molecules with reported RNA-binding activity. Calculated physical and chemical properties for the RNA ligands are comparable to those of ligands for established protein drug targets. To ensure that our library contained RNA-binding functionalities that might not be detected by the above comparisons, 114 fragment compounds were purchased on the basis of similarity to substructures of RNA ligands. Five "hits" were identified for the decoding site from the bacterial ribosome by NMR. These included fragments derived from A-site binding ligands but also compounds not previously identified as A-site binders. Hits generated in this manner can be used to probe the interaction surface of RNA and its conformational plasticity, facilitating structure-based optimization.
|
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.
|
Antitubercular activity against Mycobacterium tuberculosis H37Rv by BacTiter-Gl Microbial Cell Viability assay
|
Mycobacterium tuberculosis H37Rv
|
70.0
nM
|
|
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.
|
Antitubercular activity against Mycobacterium tuberculosis H37Rv by microdilution alamar Blue broth assay
|
Mycobacterium tuberculosis H37Rv
|
120.0
nM
|
|
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.
|
Antimicrobial activity against Mycobacterium tuberculosis H37Rv after 7 days by BacTiter-Glo assay
|
Mycobacterium tuberculosis H37Rv
|
70.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and evaluation of acridine and fused-quinoline derivatives as potential anti-tuberculosis agents.
Year : 2014
Volume : 73
First Page : 243
Last Page : 249
Authors : Muscia GC, Buldain GY, Asís SE.
Abstract : The synthesis of twelve acridine and polycyclic acridine derivatives prepared via the Friedländer reaction is described. The one-pot reactions of 2-amino-5-chloro or 5-nitro-benzophenones and a variety of cyclanones and indanones were carried out in a MW oven under TFA catalysis in good yields. The products were designed according natural antituberculosis products and were evaluated for growth inhibitory activity towards Mycobacterium tuberculosis H37Rv (Mtb) through the National Institute of Allergy and Infectious Diseases (NIAID, USA). Three of them underwent additional testings. The cyclopenta[b]quinoline derivative 9 and the acridine derivative 13 showed remarkable MIC values against the rifampin resistant strain. The former exhibited bactericidal activity at 50 μg/mL, its intracellular activity is similar to rifampin and it was not cytotoxic at low concentrations so it can be considered a new lead compound.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Rv assessed as growth inhibition by Alamar Blue staining-based broth microdilution assay
|
Mycobacterium tuberculosis H37Rv
|
70.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antimycobacterial evaluation of novel hybrid arylidene thiazolidine-2,4-diones.
Year : 2014
Volume : 24
Issue : 4
First Page : 1089
Last Page : 1093
Authors : Ponnuchamy S, Kanchithalaivan S, Ranjith Kumar R, Ali MA, Choon TS.
Abstract : A series of novel hybrid heterocycles comprising arylidene thiazolidine-2,4-dione and 1-cyclopropyl-2-(2-fluorophenyl)ethanone were synthesized. These compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv in High Throughput Screen. Most of the hybrid arylidene thiazolidine-2,4-diones displayed moderate to good activity with MIC of less than 50 μM. Compound 1m exhibited maximum potency being 5.87 fold more active at EC50 and 6.26 fold more active at EC90 than the standard drug pyrimethamine.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27294 after 7 days by microplate Alamar blue assay
|
Mycobacterium tuberculosis H37Rv
|
0.07
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 0.08 ug/ml after 7 days by microplate Alamar blue assay relative to control
|
Mycobacterium tuberculosis H37Rv
|
79.8
%
|
|
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 0.16 to 0.31 ug/ml after 7 days by microplate Alamar blue assay relative to control
|
Mycobacterium tuberculosis H37Rv
|
96.0
%
|
|
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 0.63 ug/ml after 7 days by microplate Alamar blue assay relative to control
|
Mycobacterium tuberculosis H37Rv
|
97.3
%
|
|
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 1.25 to 5 ug/ml after 7 days by microplate Alamar blue assay relative to control
|
Mycobacterium tuberculosis H37Rv
|
98.0
%
|
|
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 assessed as growth inhibition by microdilution AlamarBlue broth assay
|
Mycobacterium tuberculosis H37Rv
|
70.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Sequential synthesis of amino-1,4-naphthoquinone-appended triazoles and triazole-chromene hybrids and their antimycobacterial evaluation.
Year : 2014
Volume : 85
First Page : 737
Last Page : 746
Authors : Devi Bala B, Muthusaravanan S, Choon TS, Ashraf Ali M, Perumal S.
Abstract : A general method for the synthesis of a library of hitherto unreported amino-1,4-naphthoquinone-appended triazoles was accomplished via a sequential three-component reaction of substituted N-propargylaminonaphthoquinones with variously substituted alkyl bromides/2-bromonaphthalene-1,4-dione and sodium azide in the presence of Et3N/CuI in water. Aminonaphthoquinone-appended iminochromene-triazole hybrid heterocycles were also synthesized from the amino-1,4-naphthoquinone-appended-1,2,3-triazolylacetonitriles. All the triazole hybrids were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB). Among the triazoles, 2-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)(4-(trifluoromethyl)phenyl)amino)naphthalene-1,4-dione (7d) emerged as the most active one with IC50 = 1.87 μM, being more potent than the anti-TB drugs, cycloserine (6 times), pyrimethamine (20 times) and equipotent as the drug ethambutol (IC50 < 1.56 μM).
|
Antimicrobial activity against Mycobacterium tuberculosis H37Rv ATCC 27294 incubated for 7 days by BacTiter-Glo cell viability assay
|
Mycobacterium tuberculosis H37Rv
|
102.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel quinoxaline derivatives as potential candidates for treatment of multidrug-resistant and latent tuberculosis.
Year : 2016
Volume : 26
Issue : 9
First Page : 2188
Last Page : 2193
Authors : Santivañez-Veliz M, Pérez-Silanes S, Torres E, Moreno-Viguri E.
Abstract : Twenty-four quinoxaline derivatives were evaluated for their antimycobacterial activity using BacTiter-Glo microbial cell viability assay. Five compounds showed MIC values <3.1 μM and IC50 values<1.5 μM in primary screening and therefore, they were moved on for further evaluation. Compounds 21 and 18 stand out, showing MIC values of 1.6 μM and IC50 values of 0.5 and 1.0 μM, respectively. Both compounds were the most potent against three evaluated drug-resistant strains. Moreover, they exhibited intracellular activity in infected macrophages, considering log-reduction and cellular viability. In addition, compounds 16 and 21 were potent against non-replicating Mycobacterium tuberculosis and compound 21 was bactericidal. Therefore, quinoxaline derivatives could be considered for making further advances in the future development of antimycobacterial agents.
|
Antibacterial activity against Pseudomonas aeruginosa PA7 DSM 24068 after 18 hrs
|
Pseudomonas aeruginosa PA7
|
3.8
ug.mL-1
|
|
Journal : Bioorg Med Chem
Title : New nitrofurans amenable by isocyanide multicomponent chemistry are active against multidrug-resistant and poly-resistant Mycobacterium tuberculosis.
Year : 2017
Volume : 25
Issue : 6
First Page : 1867
Last Page : 1874
Authors : Krasavin M, Parchinsky V, Kantin G, Manicheva O, Dogonadze M, Vinogradova T, Karge B, Brönstrup M.
Abstract : A set of structurally diverse N-amino δ-lactams decorated with a 5-nitro-2-furyl moiety was synthesized using isocyanide-based multicomponent chemistry and evaluated for antibacterial activity. Three compounds displayed a selective and potent (MIC 22-33μM) inhibition of M. tuberculosis H37Rv strain growth, while other Gram-positive (MRSA and E. faecium) or Gram-negative (E. coli, P. aeruginosa, A. baumannii, K. pneumoniae) pathogens were not affected. The compounds also displayed moderate-low cytotoxicity, as demonstrated in cell line viability assays. Several multidrug- and poly-resistant patient-derived M. tuberculosis strains were found to be susceptible to treatment with these compounds. The three most potent compounds share a significant structural similarity which provides a basis for further scaffold-hopping analog design.
|
Antimicrobial activity against Mycobacterium tuberculosis H37Rv by Alamar blue assay
|
Mycobacterium tuberculosis H37Rv
|
70.0
nM
|
|
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.
|
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.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Rv
|
Mycobacterium tuberculosis H37Rv
|
80.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and antimycobacterial activity of triterpeni≿ A-ring azepanes.
Year : 2018
Volume : 143
First Page : 464
Last Page : 472
Authors : Medvedeva NI, Kazakova OB, Lopatina TV, Smirnova IE, Giniyatullina GV, Baikova IP, Kataev VE.
Abstract : A series of A-ring azepanones and azepanes derived from betulonic, oleanonic and ursonic acids was synthesized and evaluated for their in vitro antimycobacterial activities against M. tuberculosis (MTB) H37Rv and SDR-TB in the National Institute of Allergy and Infectious Diseases. Triterpenic A-azepano-28-hydroxy-derivatives were synthesized by the reduction with LiAlH4 of triterpenic azepanones available from the Beckmann rearrangement of the corresponding C3-oximes. Modification of azepanes at NH-group and atoms С12, C20, C28 and C29 of triterpenic core led to the derivatives with oxo, epoxy, aminopropyl, oximino and acyl substituents. The primary assay of tested triterpenoids against MTB H37Rv demonstrated their MIC values ranged from 3.125 to >200 μM. Ursane type A-azepano-28-cinnamoates were the most active being 2 and 4 times more efficient than the initial 28-hydroxy-derivative. The follow-up testing revealed A-azepano-28-cinnamoyloxybetulin as a leader compound with MIC 2 and MBC 4 μM against MTB H37Rv and MICs 4, 1 and 1 μM against INH, RIF and OFX resistant strains, respectively. Five oleanane and ursane azepanes pronounced better activity than isoniazid against INH-R1 and rifampicin against INH-R2 strains. This work opens a new direction in the design and synthesis of new antitubercular agents basing on azepanotriterpenoids.
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Binding affinity to 16S rRNA A-site in Escherichia coli S30 extract assessed as inhibition of translation measured after 30 mins by coupled transcription/translation-based luciferase reporter gene assay
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Escherichia coli
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70.0
nM
|
|
Journal : J Med Chem
Title : Effects of 5-O-Ribosylation of Aminoglycosides on Antimicrobial Activity and Selective Perturbation of Bacterial Translation.
Year : 2016
Volume : 59
Issue : 17
First Page : 8008
Last Page : 8018
Authors : Herzog IM, Louzoun Zada S, Fridman M.
Abstract : We studied six pairs of aminoglycosides and their corresponding ribosylated derivatives synthesized by attaching a β-O-linked ribofuranose to the 5-OH of the deoxystreptamine ring of the parent pseudo-oligosaccharide antibiotic. Ribosylation of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside kanamycin B led to improved selectivity for inhibition of prokaryotic relative to cytosolic eukaryotic in vitro translation. For the pseudodisaccharide aminoglycoside scaffolds neamine and nebramine, ribosylated derivatives were both more potent antimicrobials and more selective to inhibition of prokaryotic translation. On the basis of the results of this study, we suggest that modification of the 5-OH position of the streptamine ring of other natural or semisynthetic pseudodisaccharide aminoglycoside scaffolds containing an equatorial amine at the 2' sugar position with a β-O-linked ribofuranose is a promising avenue for the development of novel aminoglycoside antibiotics with improved efficacy and reduced toxicity.
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Antimycobacterial activity against Mycobacterium tuberculosis H37Rv assessed as inhibition of bacterial growth by microdilution alamar blue broth assay
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Mycobacterium tuberculosis
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70.0
nM
|
|
Journal : Bioorg Med Chem
Title : A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids and evaluation of their antimycobacterial, anticancer and AchE inhibitory activities.
Year : 2016
Volume : 24
Issue : 22.0
First Page : 5873
Last Page : 5883
Authors : Bharkavi C,Vivek Kumar S,Ashraf Ali M,Osman H,Muthusubramanian S,Perumal S
Abstract : A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC 1.07μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC <1.56μM) and 6l (IC=2.87μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC values of 1.10 and 1.16μmol/L respectively.
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Antimycobacterial activity against Mycobacterium tuberculosis H37Rv assessed as inhibition of bacterial growth at 0.17 mM by microdilution alamar blue broth assay relative to control
|
Mycobacterium tuberculosis
|
30.0
%
|
|
Journal : Bioorg Med Chem
Title : A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids and evaluation of their antimycobacterial, anticancer and AchE inhibitory activities.
Year : 2016
Volume : 24
Issue : 22.0
First Page : 5873
Last Page : 5883
Authors : Bharkavi C,Vivek Kumar S,Ashraf Ali M,Osman H,Muthusubramanian S,Perumal S
Abstract : A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC 1.07μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC <1.56μM) and 6l (IC=2.87μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC values of 1.10 and 1.16μmol/L respectively.
