|
Binding affinity of aminoglycoside to 16S ribosomal RNA A-site in Escherichia coli
|
Escherichia coli
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Which aminoglycoside ring is most important for binding? A hydropathic analysis of gentamicin, paromomycin, and analogues.
Year : 2001
Volume : 11
Issue : 2
First Page : 119
Last Page : 122
Authors : Cashman DJ, Rife JP, Kellogg GE.
Abstract : The NMR structures of gentamicin and paromomycin in complex with the A-site of Escherichia coli 16S ribosomal RNA were modified with molecular modeling to 12 analogues. The intermolecular interactions between these molecules and RNA were examined using the HINT (Hydropathic INTeractions) computational model to obtain interaction scores that have been shown previously to be related to free energy. The calculations correlated well with experimental binding data, and the interaction scores were used to analyze the specific structural features of each aminoglycoside that contribute to the overall binding with the 16S rRNA. Our calculations indicate that, while ring I binds to the main binding pocket of the rRNA A-site, ring IV of paromomycin-based aminoglycosides contributes significantly to the overall binding.
|
Dissociation constant for binding to mitochondrial 12S rRNA construct M3 was determined
|
Homo sapiens
|
440.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Decoding region bubble size and aminoglycoside antibiotic binding.
Year : 2002
Volume : 12
Issue : 16
First Page : 2241
Last Page : 2244
Authors : Ryu DH, Rando RR.
Abstract : Aminoglycoside antibiotics promiscuously bind to structurally diverse RNA molecules containing internal bubbles and bulges with affinities in the microM range. An interesting exception is found in the human 12S mitochondrial decoding region where aminoglycoside binding, unlike in the case of its bacterial and human cytoplasmic counterparts, is absent. Mutations that reduce the size of the bubble in the 12S decoding region immediately restore aminoglycoside binding, giving the system chemical switch like behavior.
|
Tested for binding affinity against RNA construct E
|
None
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Binding of aminoglycoside antibiotics with modified A-site 16S rRNA construct containing non-nucleotide linkers.
Year : 2002
Volume : 12
Issue : 3
First Page : 365
Last Page : 370
Authors : Tok JB, Wong W, Baboolal N.
Abstract : The design and synthesis of synthetically modified cyclic A-site 16S rRNA construct is reported. The binding characteristics of several members of the aminoglycoside antibiotics with this novel class of synthetically modified A-site 16S rRNA constructs were subsequently investigated.
|
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 after assembly using recombinant hTR and hTERT at 50 uM
|
Homo sapiens
|
29.0
%
|
|
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
|
60.0
%
|
|
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.
|
Dissociation constant of the compound
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Validation of automated docking programs for docking and database screening against RNA drug targets.
Year : 2004
Volume : 47
Issue : 17
First Page : 4188
Last Page : 4201
Authors : Detering C, Varani G.
Abstract : The increasing awareness of the essential role of RNA in controlling viral replication and in bacterial protein synthesis emphasizes the potential of ribonucleoproteins as targets for developing new antibacterial and antiviral drugs. RNA forms well defined three-dimensional structures with clefts and binding pockets reminiscent of the active sites of proteins. Furthermore, it precedes proteins in the translation pathway; inhibiting the function of a single RNA molecule would result in inhibition of multiple proteins. Thus, small molecules that bind RNA specifically would combine the advantages of antisense and RNAi strategies with the much more favorable medicinal chemistry of small-molecule therapeutics. The discovery of small-molecule inhibitors of RNA with attractive pharmacological potential would be facilitated if we had available effective computational tools of structure-based drug design. Here, we systematically test automated docking tools developed for proteins using existing three-dimensional structures of RNA-small molecule complexes. The results show that the native structures can generally be reproduced to within 2.5 angstroms more than 50-60% of the time. For more than half of the test complexes, the native ligand ranked among the top 10% compounds in a database-scoring test. Through this work, we provide parameters for the validated application of automated docking tools to the discovery of new inhibitors of RNA function.
|
Dissociation constant against 16S rRNA A-site
|
None
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and 16S A-site rRNA recognition of carbohydrate-free aminoglycosides.
Year : 2005
Volume : 15
Issue : 22
First Page : 4919
Last Page : 4922
Authors : Wang X, Migawa MT, Sannes-Lowery KA, Swayze EE.
Abstract : The first carbohydrate-free aminoglycoside analogs bearing the 2-deoxystreptamine moiety were synthesized from asymmetrically protected 2-deoxystrepamine and subsequently demonstrated to have significant binding to the 16S A-site rRNA target and moderate functional activity.
|
Inhibitory concentration against cell-free bacterial transcription / translation (T/T) assay
|
None
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and 16S A-site rRNA recognition of carbohydrate-free aminoglycosides.
Year : 2005
Volume : 15
Issue : 22
First Page : 4919
Last Page : 4922
Authors : Wang X, Migawa MT, Sannes-Lowery KA, Swayze EE.
Abstract : The first carbohydrate-free aminoglycoside analogs bearing the 2-deoxystreptamine moiety were synthesized from asymmetrically protected 2-deoxystrepamine and subsequently demonstrated to have significant binding to the 16S A-site rRNA target and moderate functional activity.
|
Binding affinity to bacterial ribosomal A site RNA oligonucleotide
|
None
|
390.0
nM
|
|
Journal : J. Med. Chem.
Title : Binding of aminoglycosidic antibiotics to the oligonucleotide A-site model and 30S ribosomal subunit: Poisson-Boltzmann model, thermal denaturation, and fluorescence studies.
Year : 2006
Volume : 49
Issue : 18
First Page : 5478
Last Page : 5490
Authors : Yang G, Trylska J, Tor Y, McCammon JA.
Abstract : The binding of paromomycin and similar antibiotics to the oligonucleotide A-site model and the small (30S) ribosomal subunit has been studied using continuum electrostatics methods. Crystallographic information from complexes of paromomycin, tobramycin, and Geneticin bound to an A-site oligonucleotide, and paromomycin and streptomycin complexed to the 30S subunit was used as a foundation to develop structures of similar antibiotics in the same ribosomal binding site. Relative binding free energies were calculated by combining the electrostatic contribution, which was obtained by solving the Poisson-Boltzmann equation, with a surface-area-dependent apolar term and contributions from conformational changes. These computed results showed good correlation with the experimental data resulting from fluorescence binding assays and thermal denaturation studies, demonstrating the ability of the Poisson-Boltzmann model to provide insight into the electrostatic mechanisms for aminoglycoside binding and direction for designing more effective antibiotics.
|
Affinity to hairpin A-site 16S rRNA by Electrospray ionization mass spectrometry
|
None
|
370.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Monitoring aminoglycoside-induced conformational changes in 16S rRNA through acrylamide quenching.
Year : 2007
Volume : 15
Issue : 11
First Page : 3825
Last Page : 3831
Authors : Chao PW, Chow CS.
Abstract : Fluorescence of 2-aminopurine (2AP)-substituted A-site and acrylamide quenching were used to study the interactions of paromomycin and neamine with the decoding region of 16S rRNA. The results reveal that paromomycin binding to the A-site RNA leads to increased exposure of residue A1492. In contrast, neamine has little effect on the solvent accessibility of A1492. Electrospray ionization mass spectrometry was used to compare the affinity of paromomycin with the A-site and 2-AP-substituted A-site RNAs.
|
Affinity to 2-aminopurine labeled hairpin A-site 16S rRNA by Electrospray ionization mass spectrometry
|
None
|
980.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Monitoring aminoglycoside-induced conformational changes in 16S rRNA through acrylamide quenching.
Year : 2007
Volume : 15
Issue : 11
First Page : 3825
Last Page : 3831
Authors : Chao PW, Chow CS.
Abstract : Fluorescence of 2-aminopurine (2AP)-substituted A-site and acrylamide quenching were used to study the interactions of paromomycin and neamine with the decoding region of 16S rRNA. The results reveal that paromomycin binding to the A-site RNA leads to increased exposure of residue A1492. In contrast, neamine has little effect on the solvent accessibility of A1492. Electrospray ionization mass spectrometry was used to compare the affinity of paromomycin with the A-site and 2-AP-substituted A-site RNAs.
|
Inhibition of protein translation in Escherichia coli by coupled transcription/translation assay
|
Escherichia coli
|
56.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease-causing premature stop mutations.
Year : 2009
Volume : 52
Issue : 9
First Page : 2836
Last Page : 2845
Authors : Nudelman I, Rebibo-Sabbah A, Cherniavsky M, Belakhov V, Hainrichson M, Chen F, Schacht J, Pilch DS, Ben-Yosef T, Baasov T.
Abstract : Nonsense mutations promote premature translational termination and represent the underlying cause of a large number of human genetic diseases. The aminoglycoside antibiotic gentamicin has the ability to allow the mammalian ribosome to read past a false-stop signal and generate full-length functional proteins. However, severe toxic side effects along with the reduced suppression efficiency at subtoxic doses limit the use of gentamicin for suppression therapy. We describe here the first systematic development of the novel aminoglycoside 2 (NB54) exhibiting superior in vitro readthrough efficiency to that of gentamicin in seven different DNA fragments derived from mutant genes carrying nonsense mutations representing the genetic diseases Usher syndrome, cystic fibrosis, Duchenne muscular dystrophy, and Hurler syndrome. Comparative acute lethal toxicity in mice, cell toxicity, and the assessment of hair cell toxicity in cochlear explants further indicated that 2 exhibits far lower toxicity than that of gentamicin.
|
Binding affinity to Streptomyces coelicolor 1147 30S ribosomal protein S12 assessed as inhibition of protein synthesis at 0.2 ug/ml by fluorescence assay
|
Streptomyces coelicolor
|
80.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel insertion mutation in Streptomyces coelicolor ribosomal S12 protein results in paromomycin resistance and antibiotic overproduction.
Year : 2009
Volume : 53
Issue : 3
First Page : 1019
Last Page : 1026
Authors : Wang G, Inaoka T, Okamoto S, Ochi K.
Abstract : We identified a novel paromomycin resistance-associated mutation in rpsL, caused by the insertion of a glycine residue at position 92, in Streptomyces coelicolor ribosomal protein S12. This insertion mutation (GI92) resulted in a 20-fold increase in the paromomycin resistance level. In combination with another S12 mutation, K88E, the GI92 mutation markedly enhanced the production of the blue-colored polyketide antibiotic actinorhodin and the red-colored antibiotic undecylprodigiosin. The gene replacement experiments demonstrated that the K88E-GI92 double mutation in the rpsL gene was responsible for the marked enhancement of antibiotic production observed. Ribosomes with the K88E-GI92 double mutation were characterized by error restrictiveness (i.e., hyperaccuracy). Using a cell-free translation system, we found that mutant ribosomes harboring the K88E-GI92 double mutation but not ribosomes harboring the GI92 mutation alone displayed sixfold greater translation activity relative to that of the wild-type ribosomes at late growth phase. This resulted in the overproduction of actinorhodin, caused by the transcriptional activation of the pathway-specific regulatory gene actII-orf4, possibly due to the increased translation of transcripts encoding activators of actII-orf4. The mutant with the K88E-GI92 double mutation accumulated a high level of ribosome recycling factor at late stationary phase, underlying the high level of protein synthesis activity observed.
|
Binding affinity to Streptomyces coelicolor KO-178 30S ribosomal protein S12 K88E mutant assessed as inhibition of protein synthesis at 0.2 ug/ml by fluorescence assay
|
Streptomyces coelicolor
|
80.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel insertion mutation in Streptomyces coelicolor ribosomal S12 protein results in paromomycin resistance and antibiotic overproduction.
Year : 2009
Volume : 53
Issue : 3
First Page : 1019
Last Page : 1026
Authors : Wang G, Inaoka T, Okamoto S, Ochi K.
Abstract : We identified a novel paromomycin resistance-associated mutation in rpsL, caused by the insertion of a glycine residue at position 92, in Streptomyces coelicolor ribosomal protein S12. This insertion mutation (GI92) resulted in a 20-fold increase in the paromomycin resistance level. In combination with another S12 mutation, K88E, the GI92 mutation markedly enhanced the production of the blue-colored polyketide antibiotic actinorhodin and the red-colored antibiotic undecylprodigiosin. The gene replacement experiments demonstrated that the K88E-GI92 double mutation in the rpsL gene was responsible for the marked enhancement of antibiotic production observed. Ribosomes with the K88E-GI92 double mutation were characterized by error restrictiveness (i.e., hyperaccuracy). Using a cell-free translation system, we found that mutant ribosomes harboring the K88E-GI92 double mutation but not ribosomes harboring the GI92 mutation alone displayed sixfold greater translation activity relative to that of the wild-type ribosomes at late growth phase. This resulted in the overproduction of actinorhodin, caused by the transcriptional activation of the pathway-specific regulatory gene actII-orf4, possibly due to the increased translation of transcripts encoding activators of actII-orf4. The mutant with the K88E-GI92 double mutation accumulated a high level of ribosome recycling factor at late stationary phase, underlying the high level of protein synthesis activity observed.
|
Antimicrobial activity against Cryptosporidium parvum infected in human HCT-8 cells after 48 hrs by ELISA
|
Cryptosporidium parvum
|
711.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Efficacy of pyrvinium pamoate against Cryptosporidium parvum infection in vitro and in a neonatal mouse model.
Year : 2008
Volume : 52
Issue : 9
First Page : 3106
Last Page : 3112
Authors : Downey AS, Chong CR, Graczyk TK, Sullivan DJ.
Abstract : No effective approved drug therapy exists for Cryptosporidium infection of immunocompromised patients. Here we investigated the nonabsorbed anthelmintic drug pyrvinium pamoate for inhibition of the growth of the intestinal protozoan parasite Cryptosporidium parvum. The concentration of pyrvinium that effected 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was 354 nM. For comparison, in the same assay, 50% growth inhibition was obtained with 711 microM paromomycin or 27 microM chloroquine. We used a neonatal mouse model to measure the anti-Cryptosporidium activity of pyrvinium pamoate in vivo. Beginning 3 days after infection, pyrvinium at 5 or 12.5 mg/kg of body weight/day was administered to the treatment group mice for 4 or 6 consecutive days. Nine days after infection, the mice were sacrificed, and drug efficacy was determined by comparing the numbers of oocysts in the fecal smears of treated versus untreated mice. The intensities of trophozoite infection in the ileocecal intestinal regions were also compared using hematoxylin-and-eosin-stained histological slides. We observed a >90% reduction in infection intensity in pyrvinium-treated mice relative to that in untreated controls, along with a substantial reduction in tissue pathology. Based on these results, pyrvinium pamoate is a potential drug candidate for the treatment of cryptosporidiosis in both immunocompetent and immunocompromised individuals.
|
Antimicrobial activity against Cryptosporidium parvum infected in human HCT-8 cells assessed as growth inhibition after 48 hrs by ELISA
|
Cryptosporidium parvum
|
40.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Efficacy of pyrvinium pamoate against Cryptosporidium parvum infection in vitro and in a neonatal mouse model.
Year : 2008
Volume : 52
Issue : 9
First Page : 3106
Last Page : 3112
Authors : Downey AS, Chong CR, Graczyk TK, Sullivan DJ.
Abstract : No effective approved drug therapy exists for Cryptosporidium infection of immunocompromised patients. Here we investigated the nonabsorbed anthelmintic drug pyrvinium pamoate for inhibition of the growth of the intestinal protozoan parasite Cryptosporidium parvum. The concentration of pyrvinium that effected 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was 354 nM. For comparison, in the same assay, 50% growth inhibition was obtained with 711 microM paromomycin or 27 microM chloroquine. We used a neonatal mouse model to measure the anti-Cryptosporidium activity of pyrvinium pamoate in vivo. Beginning 3 days after infection, pyrvinium at 5 or 12.5 mg/kg of body weight/day was administered to the treatment group mice for 4 or 6 consecutive days. Nine days after infection, the mice were sacrificed, and drug efficacy was determined by comparing the numbers of oocysts in the fecal smears of treated versus untreated mice. The intensities of trophozoite infection in the ileocecal intestinal regions were also compared using hematoxylin-and-eosin-stained histological slides. We observed a >90% reduction in infection intensity in pyrvinium-treated mice relative to that in untreated controls, along with a substantial reduction in tissue pathology. Based on these results, pyrvinium pamoate is a potential drug candidate for the treatment of cryptosporidiosis in both immunocompetent and immunocompromised individuals.
|
Antileishmanial activity against promastigotes of Leishmania donovani at 10 ug/ml
|
Leishmania donovani
|
123.92
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel tetrahydronaphthyl azoles and related cyclohexyl azoles as antileishmanial agents.
Year : 2011
Volume : 21
Issue : 5
First Page : 1407
Last Page : 1410
Authors : Marrapu VK, Srinivas N, Mittal M, Shakya N, Gupta S, Bhandari K.
Abstract : A novel series of trans-2-aryloxy-1,2,3,4,-tetrahydronaphthyl azoles and related cyclohexyl azoles were synthesized and evaluated in vitro against Leishmania donovani. Compound 9 identified as most active analog with IC(50) value of 0.64 μg/mL and SI value of 34.78 against amastigotes, and is several folds more potent than the reference drugs sodium stilbogluconate and paromomycin. It also exhibited significant in vivo inhibition of 83.33%, and provided a new structural scaffold for antileishmanials.
|
Antileishmanial activity against amastigotes of Leishmania donovani
|
Leishmania donovani
|
24.79
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel tetrahydronaphthyl azoles and related cyclohexyl azoles as antileishmanial agents.
Year : 2011
Volume : 21
Issue : 5
First Page : 1407
Last Page : 1410
Authors : Marrapu VK, Srinivas N, Mittal M, Shakya N, Gupta S, Bhandari K.
Abstract : A novel series of trans-2-aryloxy-1,2,3,4,-tetrahydronaphthyl azoles and related cyclohexyl azoles were synthesized and evaluated in vitro against Leishmania donovani. Compound 9 identified as most active analog with IC(50) value of 0.64 μg/mL and SI value of 34.78 against amastigotes, and is several folds more potent than the reference drugs sodium stilbogluconate and paromomycin. It also exhibited significant in vivo inhibition of 83.33%, and provided a new structural scaffold for antileishmanials.
|
Antileishmanial activity against Leishmania donovani infected in Hamster assessed as inhibition of parasites growth at 50 mg/kg, ip for 5 times
|
Leishmania donovani
|
46.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel tetrahydronaphthyl azoles and related cyclohexyl azoles as antileishmanial agents.
Year : 2011
Volume : 21
Issue : 5
First Page : 1407
Last Page : 1410
Authors : Marrapu VK, Srinivas N, Mittal M, Shakya N, Gupta S, Bhandari K.
Abstract : A novel series of trans-2-aryloxy-1,2,3,4,-tetrahydronaphthyl azoles and related cyclohexyl azoles were synthesized and evaluated in vitro against Leishmania donovani. Compound 9 identified as most active analog with IC(50) value of 0.64 μg/mL and SI value of 34.78 against amastigotes, and is several folds more potent than the reference drugs sodium stilbogluconate and paromomycin. It also exhibited significant in vivo inhibition of 83.33%, and provided a new structural scaffold for antileishmanials.
|
Antileishmanial activity against amastigote stage of Leishmania donovani infected in golden hamster assessed as inhibition of parasite multiplication at 50 mg/kg, ip administered 5 days measured on day 7 by Giemsa staining assay relative to control
|
Leishmania donovani
|
46.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents.
Year : 2013
Volume : 23
Issue : 13
First Page : 3979
Last Page : 3982
Authors : Suryawanshi SN, Kumar S, Tiwari A, Shivahare R, Chhonker YS, Pandey S, Shakya N, Bhatta RS, Gupta S.
Abstract : A series of aryl S,N-ketene acetals 7(a-f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values ranging from 1.2 to 3.5 μM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromomycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Clint) of compound 7b in hamster liver microsomes.
|
Inhibition of Mycobacterium smegmatis ribosome containing wild type ribosomal RNA A-site in rabbit reticulocyte lysates assessed as reduction in ribosome-mediated protein synthesis in presence of S-30 extracts by fire fly luciferase synthesis based cell-free translation assay
|
Mycobacterium smegmatis
|
0.03
ug.mL-1
|
|
Journal : MedChemComm
Title : Synthesis, antiribosomal and antibacterial activity of 4-O-glycopyranosyl paromomycin aminoglycoside antibiotics
Year : 2014
Volume : 5
Issue : 8
First Page : 1179
Last Page : 1187
Authors : Chen W, Matsushita T, Shcherbakov D, Boukari H, Vasella A, Bottger EC, Crich D
|
Inhibition of Mycobacterium smegmatis ribosome containing ribosomal RNA A-site G1491C mutant in rabbit reticulocyte lysates assessed as reduction in ribosome-mediated protein synthesis in presence of S-30 extracts by fire fly luciferase synthesis based cell-free translation assay
|
Mycobacterium smegmatis
|
10.42
ug.mL-1
|
|
Journal : MedChemComm
Title : Synthesis, antiribosomal and antibacterial activity of 4-O-glycopyranosyl paromomycin aminoglycoside antibiotics
Year : 2014
Volume : 5
Issue : 8
First Page : 1179
Last Page : 1187
Authors : Chen W, Matsushita T, Shcherbakov D, Boukari H, Vasella A, Bottger EC, Crich D
|
Inhibition of Mycobacterium smegmatis ribosome containing ribosomal RNA A-site G1491A mutant in rabbit reticulocyte lysates assessed as reduction in ribosome-mediated protein synthesis in presence of S-30 extracts by fire fly luciferase synthesis based cell-free translation assay
|
Mycobacterium smegmatis
|
0.57
ug.mL-1
|
|
Journal : MedChemComm
Title : Synthesis, antiribosomal and antibacterial activity of 4-O-glycopyranosyl paromomycin aminoglycoside antibiotics
Year : 2014
Volume : 5
Issue : 8
First Page : 1179
Last Page : 1187
Authors : Chen W, Matsushita T, Shcherbakov D, Boukari H, Vasella A, Bottger EC, Crich D
|
Inhibition of Mycobacterium smegmatis ribosome containing ribosomal RNA A-site A1408G mutant in rabbit reticulocyte lysates assessed as reduction in ribosome-mediated protein synthesis in presence of S-30 extracts by fire fly luciferase synthesis based cell-free translation assay
|
Mycobacterium smegmatis
|
0.26
ug.mL-1
|
|
Journal : MedChemComm
Title : Synthesis, antiribosomal and antibacterial activity of 4-O-glycopyranosyl paromomycin aminoglycoside antibiotics
Year : 2014
Volume : 5
Issue : 8
First Page : 1179
Last Page : 1187
Authors : Chen W, Matsushita T, Shcherbakov D, Boukari H, Vasella A, Bottger EC, Crich D
|
Inhibition of human ribosome containing eukaryotic wild type ribosomal RNA A-site in rabbit reticulocyte lysates assessed as reduction in ribosome-mediated protein synthesis in presence of S-30 extracts by fire fly luciferase synthesis based cell-free translation assay
|
Homo sapiens
|
50.54
ug.mL-1
|
|
Journal : MedChemComm
Title : Synthesis, antiribosomal and antibacterial activity of 4-O-glycopyranosyl paromomycin aminoglycoside antibiotics
Year : 2014
Volume : 5
Issue : 8
First Page : 1179
Last Page : 1187
Authors : Chen W, Matsushita T, Shcherbakov D, Boukari H, Vasella A, Bottger EC, Crich D
|
Inhibition of human ribosome containing eukaryotic ribosomal RNA A-site A1555G mutant in rabbit reticulocyte lysates assessed as reduction in ribosome-mediated protein synthesis in presence of S-30 extracts by fire fly luciferase synthesis based cell-free translation assay
|
Homo sapiens
|
5.83
ug.mL-1
|
|
Journal : MedChemComm
Title : Synthesis, antiribosomal and antibacterial activity of 4-O-glycopyranosyl paromomycin aminoglycoside antibiotics
Year : 2014
Volume : 5
Issue : 8
First Page : 1179
Last Page : 1187
Authors : Chen W, Matsushita T, Shcherbakov D, Boukari H, Vasella A, Bottger EC, Crich D
|
Inhibition of human ribosome containing eukaryotic ribosomal RNA A-site Cyt14 allele in rabbit reticulocyte lysates assessed as reduction in ribosome-mediated protein synthesis in presence of S-30 extracts by fire fly luciferase synthesis based cell-free translation assay
|
Homo sapiens
|
10.39
ug.mL-1
|
|
Journal : MedChemComm
Title : Synthesis, antiribosomal and antibacterial activity of 4-O-glycopyranosyl paromomycin aminoglycoside antibiotics
Year : 2014
Volume : 5
Issue : 8
First Page : 1179
Last Page : 1187
Authors : Chen W, Matsushita T, Shcherbakov D, Boukari H, Vasella A, Bottger EC, Crich D
|
Inhibition of ribosome-mediated protein synthesis in in rabbit reticulocyte lysates in presence of S-30 extracts by fire fly luciferase synthesis based cell-free translation assay
|
Oryctolagus cuniculus
|
9.78
ug.mL-1
|
|
Journal : MedChemComm
Title : Synthesis, antiribosomal and antibacterial activity of 4-O-glycopyranosyl paromomycin aminoglycoside antibiotics
Year : 2014
Volume : 5
Issue : 8
First Page : 1179
Last Page : 1187
Authors : Chen W, Matsushita T, Shcherbakov D, Boukari H, Vasella A, Bottger EC, Crich D
|
Inhibition of pre-miR-372 (unknown origin) cleavage assessed as reduction of oncogenic microRNAs biogenesis at 200 uM by measuring fluorescence every minute for 5 hrs using 5'-FAM,3'-dabcyl-pre-miRNA beacons by FRET assay in presence of recombinant Dicer
|
Not specified
|
10.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting.
Year : 2015
Volume : 23
Issue : 17
First Page : 5334
Last Page : 5344
Authors : Tran TP, Vo DD, Di Giorgio A, Duca M.
Abstract : MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing.
|
Inhibition of pre-miR-373 (unknown origin) cleavage assessed as reduction of oncogenic microRNAs biogenesis at 200 uM by measuring fluorescence every minute for 5 hrs using 5'-FAM,3'-dabcyl-pre-miRNA beacons by FRET assay in presence of recombinant Dicer
|
Not specified
|
10.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting.
Year : 2015
Volume : 23
Issue : 17
First Page : 5334
Last Page : 5344
Authors : Tran TP, Vo DD, Di Giorgio A, Duca M.
Abstract : MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing.
|
Inhibition of pre-miR-17 (unknown origin) cleavage assessed as reduction of oncogenic microRNAs biogenesis at 200 uM by measuring fluorescence every minute for 5 hrs using 5'-FAM,3'-dabcyl-pre-miRNA beacons by FRET assay in presence of recombinant Dicer
|
Not specified
|
10.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting.
Year : 2015
Volume : 23
Issue : 17
First Page : 5334
Last Page : 5344
Authors : Tran TP, Vo DD, Di Giorgio A, Duca M.
Abstract : MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing.
|
Inhibition of pre-miR-21 (unknown origin) cleavage assessed as reduction of oncogenic microRNAs biogenesis at 200 uM by measuring fluorescence every minute for 5 hrs using 5'-FAM,3'-dabcyl-pre-miRNA beacons by FRET assay in presence of recombinant Dicer
|
Not specified
|
10.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting.
Year : 2015
Volume : 23
Issue : 17
First Page : 5334
Last Page : 5344
Authors : Tran TP, Vo DD, Di Giorgio A, Duca M.
Abstract : MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing.
|
Binding affinity to 5'-fluorescein-tagged Escherichia coli ribosomal A site wt-bac duplex RNA incubated for 2 mins by fluorescence spectrophotometric analysis
|
Escherichia coli
|
5.0
nM
|
|
Journal : Bioorg Med Chem
Title : Use of a fluorescence assay to determine relative affinities of semisynthetic aminoglycosides to small RNAs representing bacterial and mitochondrial A sites.
Year : 2019
Volume : 27
Issue : 22
First Page : 115121
Last Page : 115121
Authors : Waduge P, Sati GC, Crich D, Chow CS.
Abstract : The off-target binding of aminoglycosides (AGs) to the A site of human mitochondrial ribosomes in addition to bacterial ribosomes causes ototoxicity and limits their potential as antibiotics. A fluorescence assay was employed to determine relative binding affinities of classical and improved AG compounds to synthetic RNA constructs representing the bacterial and mitochondrial A sites. Results compared well with previously reported in vitro translation assays with engineered ribosomes. Therefore, the minimal RNA motifs and fluorescence assay are shown here to be useful for assessing the selectivity of new compounds.
|
Anti-ribosomal activity against bacterial 70S hybrid ribosomes assessed as inhibition of cell-free translation incubated for 35 mins by dual luciferase reporter assay
|
Bacteria
|
0.03
ug.mL-1
|
|
Journal : Bioorg Med Chem
Title : Use of a fluorescence assay to determine relative affinities of semisynthetic aminoglycosides to small RNAs representing bacterial and mitochondrial A sites.
Year : 2019
Volume : 27
Issue : 22
First Page : 115121
Last Page : 115121
Authors : Waduge P, Sati GC, Crich D, Chow CS.
Abstract : The off-target binding of aminoglycosides (AGs) to the A site of human mitochondrial ribosomes in addition to bacterial ribosomes causes ototoxicity and limits their potential as antibiotics. A fluorescence assay was employed to determine relative binding affinities of classical and improved AG compounds to synthetic RNA constructs representing the bacterial and mitochondrial A sites. Results compared well with previously reported in vitro translation assays with engineered ribosomes. Therefore, the minimal RNA motifs and fluorescence assay are shown here to be useful for assessing the selectivity of new compounds.
|
Anti-ribosomal activity against human-bacterial hybrid ribosome containing human mitochondrial ribosome A site harboring A1555G mutant 12s rRNA assessed as inhibition of cell-free translation by dual luciferase reporter assay
|
Homo sapiens
|
6.0
ug.mL-1
|
|
Journal : Bioorg Med Chem
Title : Use of a fluorescence assay to determine relative affinities of semisynthetic aminoglycosides to small RNAs representing bacterial and mitochondrial A sites.
Year : 2019
Volume : 27
Issue : 22
First Page : 115121
Last Page : 115121
Authors : Waduge P, Sati GC, Crich D, Chow CS.
Abstract : The off-target binding of aminoglycosides (AGs) to the A site of human mitochondrial ribosomes in addition to bacterial ribosomes causes ototoxicity and limits their potential as antibiotics. A fluorescence assay was employed to determine relative binding affinities of classical and improved AG compounds to synthetic RNA constructs representing the bacterial and mitochondrial A sites. Results compared well with previously reported in vitro translation assays with engineered ribosomes. Therefore, the minimal RNA motifs and fluorescence assay are shown here to be useful for assessing the selectivity of new compounds.
|
Anti-ribosomal activity against human-bacterial hybrid ribosome containing human mitochondrial ribosome A site harboring wild type 12s rRNA assessed as inhibition of cell-free translation by dual luciferase reporter assay
|
Homo sapiens
|
51.0
ug.mL-1
|
|
Journal : Bioorg Med Chem
Title : Use of a fluorescence assay to determine relative affinities of semisynthetic aminoglycosides to small RNAs representing bacterial and mitochondrial A sites.
Year : 2019
Volume : 27
Issue : 22
First Page : 115121
Last Page : 115121
Authors : Waduge P, Sati GC, Crich D, Chow CS.
Abstract : The off-target binding of aminoglycosides (AGs) to the A site of human mitochondrial ribosomes in addition to bacterial ribosomes causes ototoxicity and limits their potential as antibiotics. A fluorescence assay was employed to determine relative binding affinities of classical and improved AG compounds to synthetic RNA constructs representing the bacterial and mitochondrial A sites. Results compared well with previously reported in vitro translation assays with engineered ribosomes. Therefore, the minimal RNA motifs and fluorescence assay are shown here to be useful for assessing the selectivity of new compounds.
|
Inhibition of Mycobacterium smegmatis wild type ribosomes assessed as inhibition of translation activity using Firefly luciferase mRNA reporter based luminescence analysis
|
Mycobacterium smegmatis
|
38.0
nM
|
|
Journal : MedChemComm
Title : Synthesis, ribosomal selectivity, and antibacterial activity of netilmicin 4'-derivatives.
Year : 2019
Volume : 10
Issue : 6
First Page : 946
Last Page : 950
Authors : Sonousi A, Shcherbakov D, Vasella A, Böttger EC, Crich D.
Abstract : Halogenation of a suitably protected netilmicin derivative enables preparation of 4'-chloro-, bromo-, and iodo derivatives of netilmicin after deprotection. Suzuki coupling of a protected 4'-bromo derivative with phenylboronic acid or butyltrifluoroborate affords the corresponding 4'-phenyl and 4'-butyl derivatives of netilmicin. Sulfenylation of suitably protected netilmicin derivative with ethanesulfenyl chloride followed by deprotection affords 4'-ethylsulfanylnetilmicin. All netilmicin 4'-derivatives displayed reduced levels of inhibition for prokaryotic ribosomes and reduced antibacterial activity against typical Gram-positive and Gram-negative strains. None of the derivatives displayed enhanced target selectivity.
|
Ototoxicity against C57BL/6 mouse cochlea hair cells assessed as reduction in cell viability at 0.1 mM incubated for 23 hrs by FITC-phalloidin staining-based assay
|
Mus musculus
|
4.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : The relationship between the structure and toxicity of aminoglycoside antibiotics.
Year : 2020
Volume : 30
Issue : 13
First Page : 127218
Last Page : 127218
Authors : Jospe-Kaufman M, Siomin L, Fridman M.
Abstract : Aminoglycoside antibiotics, used to treat persistent gram-negative infections, tuberculosis, and life-threatening infections in neonates and patients with cystic fibrosis, can infer acute kidney injury and irreversible hearing loss. The full repertoire of cellular targets and processes leading to the toxicity of aminoglycosides is not fully resolved, making it challenging to devise rational directions to circumvent their adverse effects. As a result, there has been very limited effort to rationally address the issue of aminoglycoside-induced toxicity. Here we provide an overview of the reported effects of aminoglycosides on cells of the inner ear and on kidney tubular epithelial cells. We describe selected examples for structure-toxicity relationships established by evaluation of both natural and semisynthetic aminoglycosides. The various assays and models used to evaluate these antibiotics and recent progress in development of safer aminoglycoside antibiotics are discussed.
