|
Growth inhibition of Escherichia coli CC104 expressing rdxA gene after 16 hrs
|
Escherichia coli
|
35.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori, selected anaerobic bacteria and parasites, and Campylobacter jejuni.
Year : 2007
Volume : 51
Issue : 3
First Page : 868
Last Page : 876
Authors : Hoffman PS, Sisson G, Croxen MA, Welch K, Harman WD, Cremades N, Morash MG.
Abstract : Nitazoxanide (NTZ) exhibits broad-spectrum activity against anaerobic bacteria and parasites and the ulcer-causing pathogen Helicobacter pylori. Here we show that NTZ is a noncompetitive inhibitor (K(i), 2 to 10 microM) of the pyruvate:ferredoxin/flavodoxin oxidoreductases (PFORs) of Trichomonas vaginalis, Entamoeba histolytica, Giardia intestinalis, Clostridium difficile, Clostridium perfringens, H. pylori, and Campylobacter jejuni and is weakly active against the pyruvate dehydrogenase of Escherichia coli. To further mechanistic studies, the PFOR operon of H. pylori was cloned and overexpressed in E. coli, and the multisubunit complex was purified by ion-exchange chromatography. Pyruvate-dependent PFOR activity with NTZ, as measured by a decrease in absorbance at 418 nm (spectral shift from 418 to 351 nm), unlike the reduction of viologen dyes, did not result in the accumulation of products (acetyl coenzyme A and CO(2)) and pyruvate was not consumed in the reaction. NTZ did not displace the thiamine pyrophosphate (TPP) cofactor of PFOR, and the 351-nm absorbing form of NTZ was inactive. Optical scans and (1)H nuclear magnetic resonance analyses determined that the spectral shift (A(418) to A(351)) of NTZ was due to protonation of the anion (NTZ(-)) of the 2-amino group of the thiazole ring which could be generated with the pure compound under acidic solutions (pK(a) = 6.18). We propose that NTZ(-) intercepts PFOR at an early step in the formation of the lactyl-TPP transition intermediate, resulting in the reversal of pyruvate binding prior to decarboxylation and in coordination with proton transfer to NTZ. Thus, NTZ might be the first example of an antimicrobial that targets the "activated cofactor" of an enzymatic reaction rather than its substrate or catalytic sites, a novel mechanism that may escape mutation-based drug resistance.
|
Growth inhibition of Escherichia coli pBSK after 16 hrs
|
Escherichia coli
|
35.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori, selected anaerobic bacteria and parasites, and Campylobacter jejuni.
Year : 2007
Volume : 51
Issue : 3
First Page : 868
Last Page : 876
Authors : Hoffman PS, Sisson G, Croxen MA, Welch K, Harman WD, Cremades N, Morash MG.
Abstract : Nitazoxanide (NTZ) exhibits broad-spectrum activity against anaerobic bacteria and parasites and the ulcer-causing pathogen Helicobacter pylori. Here we show that NTZ is a noncompetitive inhibitor (K(i), 2 to 10 microM) of the pyruvate:ferredoxin/flavodoxin oxidoreductases (PFORs) of Trichomonas vaginalis, Entamoeba histolytica, Giardia intestinalis, Clostridium difficile, Clostridium perfringens, H. pylori, and Campylobacter jejuni and is weakly active against the pyruvate dehydrogenase of Escherichia coli. To further mechanistic studies, the PFOR operon of H. pylori was cloned and overexpressed in E. coli, and the multisubunit complex was purified by ion-exchange chromatography. Pyruvate-dependent PFOR activity with NTZ, as measured by a decrease in absorbance at 418 nm (spectral shift from 418 to 351 nm), unlike the reduction of viologen dyes, did not result in the accumulation of products (acetyl coenzyme A and CO(2)) and pyruvate was not consumed in the reaction. NTZ did not displace the thiamine pyrophosphate (TPP) cofactor of PFOR, and the 351-nm absorbing form of NTZ was inactive. Optical scans and (1)H nuclear magnetic resonance analyses determined that the spectral shift (A(418) to A(351)) of NTZ was due to protonation of the anion (NTZ(-)) of the 2-amino group of the thiazole ring which could be generated with the pure compound under acidic solutions (pK(a) = 6.18). We propose that NTZ(-) intercepts PFOR at an early step in the formation of the lactyl-TPP transition intermediate, resulting in the reversal of pyruvate binding prior to decarboxylation and in coordination with proton transfer to NTZ. Thus, NTZ might be the first example of an antimicrobial that targets the "activated cofactor" of an enzymatic reaction rather than its substrate or catalytic sites, a novel mechanism that may escape mutation-based drug resistance.
|
Inhibition of Escherichia coli JVQ2 PDH at 20 uM
|
Escherichia coli
|
22.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori, selected anaerobic bacteria and parasites, and Campylobacter jejuni.
Year : 2007
Volume : 51
Issue : 3
First Page : 868
Last Page : 876
Authors : Hoffman PS, Sisson G, Croxen MA, Welch K, Harman WD, Cremades N, Morash MG.
Abstract : Nitazoxanide (NTZ) exhibits broad-spectrum activity against anaerobic bacteria and parasites and the ulcer-causing pathogen Helicobacter pylori. Here we show that NTZ is a noncompetitive inhibitor (K(i), 2 to 10 microM) of the pyruvate:ferredoxin/flavodoxin oxidoreductases (PFORs) of Trichomonas vaginalis, Entamoeba histolytica, Giardia intestinalis, Clostridium difficile, Clostridium perfringens, H. pylori, and Campylobacter jejuni and is weakly active against the pyruvate dehydrogenase of Escherichia coli. To further mechanistic studies, the PFOR operon of H. pylori was cloned and overexpressed in E. coli, and the multisubunit complex was purified by ion-exchange chromatography. Pyruvate-dependent PFOR activity with NTZ, as measured by a decrease in absorbance at 418 nm (spectral shift from 418 to 351 nm), unlike the reduction of viologen dyes, did not result in the accumulation of products (acetyl coenzyme A and CO(2)) and pyruvate was not consumed in the reaction. NTZ did not displace the thiamine pyrophosphate (TPP) cofactor of PFOR, and the 351-nm absorbing form of NTZ was inactive. Optical scans and (1)H nuclear magnetic resonance analyses determined that the spectral shift (A(418) to A(351)) of NTZ was due to protonation of the anion (NTZ(-)) of the 2-amino group of the thiazole ring which could be generated with the pure compound under acidic solutions (pK(a) = 6.18). We propose that NTZ(-) intercepts PFOR at an early step in the formation of the lactyl-TPP transition intermediate, resulting in the reversal of pyruvate binding prior to decarboxylation and in coordination with proton transfer to NTZ. Thus, NTZ might be the first example of an antimicrobial that targets the "activated cofactor" of an enzymatic reaction rather than its substrate or catalytic sites, a novel mechanism that may escape mutation-based drug resistance.
|
Inhibition of Giardia lamblia recombinant nitroreductase 1 (EAA43030.1) expressed in Escherichia coli
|
Giardia intestinalis
|
300.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel Giardia lamblia nitroreductase, GlNR1, interacts with nitazoxanide and other thiazolides.
Year : 2007
Volume : 51
Issue : 6
First Page : 1979
Last Page : 1986
Authors : Müller J, Wastling J, Sanderson S, Müller N, Hemphill A.
Abstract : The nitrothiazole analogue nitazoxanide [NTZ; 2-acetolyloxy-N-(5-nitro-2-thiazolyl)benzamide] represents the parent compound of a class of drugs referred to as thiazolides and exhibits a broad spectrum of activities against a wide variety of helminths, protozoa, and enteric bacteria infecting animals and humans. NTZ and other thiazolides are active against a wide range of other intracellular and extracellular protozoan parasites in vitro and in vivo, but their mode of action and respective subcellular target(s) have only recently been investigated. In order to identify potential targets of NTZ and other thiazolides in Giardia lamblia trophozoites, we have developed an affinity chromatography system using the deacetylated derivative of NTZ, tizoxanide (TIZ), as a ligand. Affinity chromatography on TIZ-agarose using cell extracts of G. lamblia trophozoites resulted in the isolation of an approximately 35-kDa polypeptide, which was identified by mass spectrometry as a nitroreductase (NR) homologue (EAA43030.1). NR was overexpressed as a six-histidine-tagged recombinant protein in Escherichia coli, purified, and then characterized using an assay for oxygen-insensitive NRs with dinitrotoluene as a substrate. This demonstrated that the NR was functionally active, and the protein was designated GlNR1. In this assay system, NR activity was severely inhibited by NTZ and other thiazolides, demonstrating that the antigiardial activity of these drugs could be, at least partially, mediated through inhibition of GlNR1.
|
Inhibition of Giardia lamblia recombinant nitroreductase 1 (EAA43030.1) expressed in Escherichia coli at 5 uM
|
Giardia intestinalis
|
75.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel Giardia lamblia nitroreductase, GlNR1, interacts with nitazoxanide and other thiazolides.
Year : 2007
Volume : 51
Issue : 6
First Page : 1979
Last Page : 1986
Authors : Müller J, Wastling J, Sanderson S, Müller N, Hemphill A.
Abstract : The nitrothiazole analogue nitazoxanide [NTZ; 2-acetolyloxy-N-(5-nitro-2-thiazolyl)benzamide] represents the parent compound of a class of drugs referred to as thiazolides and exhibits a broad spectrum of activities against a wide variety of helminths, protozoa, and enteric bacteria infecting animals and humans. NTZ and other thiazolides are active against a wide range of other intracellular and extracellular protozoan parasites in vitro and in vivo, but their mode of action and respective subcellular target(s) have only recently been investigated. In order to identify potential targets of NTZ and other thiazolides in Giardia lamblia trophozoites, we have developed an affinity chromatography system using the deacetylated derivative of NTZ, tizoxanide (TIZ), as a ligand. Affinity chromatography on TIZ-agarose using cell extracts of G. lamblia trophozoites resulted in the isolation of an approximately 35-kDa polypeptide, which was identified by mass spectrometry as a nitroreductase (NR) homologue (EAA43030.1). NR was overexpressed as a six-histidine-tagged recombinant protein in Escherichia coli, purified, and then characterized using an assay for oxygen-insensitive NRs with dinitrotoluene as a substrate. This demonstrated that the NR was functionally active, and the protein was designated GlNR1. In this assay system, NR activity was severely inhibited by NTZ and other thiazolides, demonstrating that the antigiardial activity of these drugs could be, at least partially, mediated through inhibition of GlNR1.
|
Antimicrobial activity against Giardia
|
Giardia
|
2.5
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Nitazoxanide kills replicating and nonreplicating Mycobacterium tuberculosis and evades resistance.
Year : 2009
Volume : 52
Issue : 19
First Page : 5789
Last Page : 5792
Authors : de Carvalho LP, Lin G, Jiang X, Nathan C.
Abstract : We report here that nitazoxanide (NTZ) and its active metabolite kill replicating and nonreplicating M. tuberculosis at low microg/mL levels. NTZ appears to evade resistance, as we were unable to recover resistant colonies, using up to 10(12) colony forming units. Therefore, NTZ is a novel lead compound that kills replicating and nonreplicating M. tuberculosis by a novel mechanism of action, which appears to bypass the development of resistance.
|
Inhibition of Helicobacter pyroli PFOR expressed in Escherichia coli at 40 uM
|
Helicobacter pylori
|
54.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biological activity of modified and exchanged 2-amino-5-nitrothiazole amide analogues of nitazoxanide.
Year : 2010
Volume : 20
Issue : 12
First Page : 3537
Last Page : 3539
Authors : Ballard TE, Wang X, Olekhnovich I, Koerner T, Seymour C, Hoffman PS, Macdonald TL.
Abstract : Head group analogues of the antibacterial and antiparasitic drug nitazoxanide (NTZ) are presented. A library of 39 analogues was synthesized and assayed for their ability to suppress growth of Helicobacter pylori, Campylobacter jejuni, Clostridium difficile and inhibit NTZ target pyruvate:ferredoxin oxidoreductase (PFOR). Two head groups assayed recapitulated NTZ activity and possessed improved activity over their 2-amino-5-nitrothiazole counterparts, demonstrating that head group modification is a viable route for the synthesis of NTZ-related antibacterial analogues.
|
Antiparasitic activity against Cryptosporidium parvum infected in human HTC8 cells after 46 hrs by immunofluorescence method
|
Cryptosporidium parvum
|
1.2
ug.mL-1
|
|
Antiparasitic activity against Cryptosporidium parvum infected in human HTC8 cells after 46 hrs by immunofluorescence method
|
Cryptosporidium parvum
|
10.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Evaluation of new thiazolide/thiadiazolide derivatives reveals nitro group-independent efficacy against in vitro development of Cryptosporidium parvum.
Year : 2010
Volume : 54
Issue : 3
First Page : 1315
Last Page : 1318
Authors : Gargala G, Le Goff L, Ballet JJ, Favennec L, Stachulski AV, Rossignol JF.
Abstract : Thirty-nine new thiazolide/thiadiazolide compounds were compared with the nitrothiazole nitazoxanide for activity against Cryptosporidium parvum development in HCT-8 cells. Twenty-seven agents exerted > or =90% inhibition. Agents with a lower 50% inhibitory concentration (IC(50)) than nitazoxanide were either NO(2) or halogen 5 substituted on the thiazole moiety. Other 5 substitutions such as methyl, C(3)H(7), C(6)H(11), H, SO(2)CH(3), and SCH(3) negatively impacted activity. Five-substituted deacetylated analogues exhibited higher IC(50)s than their acetylated counterparts. Halogeno-thiazolide/thiadiazolides may provide valuable nitro-free alternatives to nitazoxanide.
|
Antiviral activity against HCV genotype 1a in replicon system
|
Hepatitis C virus subtype 1a
|
130.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potential for hepatitis C virus resistance to nitazoxanide or tizoxanide.
Year : 2008
Volume : 52
Issue : 11
First Page : 4069
Last Page : 4071
Authors : Korba BE, Elazar M, Lui P, Rossignol JF, Glenn JS.
Abstract : Nitazoxanide and its primary metabolite, tizoxanide, inhibit hepatitis C virus (HCV) replication in HCV replicon systems. To study the potential for resistance, we subjected Huh7 cells harboring HCV replicons to serial passage in 250 muM G418 and increasing concentrations of nitazoxanide or tizoxanide. Passage of the replicon-containing cell lines in either compound resulted in increases in the 50% effective concentrations (EC(50)s) (7- to 13-fold), EC(90)s (14- to 36-fold), and 50% cytotoxic concentrations (2- to 4-fold) of both compounds. Serial passage in either compound did not alter the susceptibility of HCV replicons to ribavirin or 2'-C-methylcytidine. Interestingly, serial passage in nitazoxanide or tizoxanide resulted in increased sensitivity to alpha interferon 2b: EC(50)s and EC(90)s were reduced three- and eightfold, respectively. Replicons isolated from these cell lines had no greater ability to confer tizoxanide resistance, or increased susceptibility to alpha interferon, than replicons isolated from the parental cell line that had not previously been exposed to nitazoxanide or tizoxanide. These findings are indicative of a cell-mediated activity differing from that of other anti-HCV drugs but complementary with interferon and are consistent with the enhanced response rates observed clinically when nitazoxanide is combined with pegylated interferon therapy. Finally, unlike data for other compounds in advanced clinical development for HCV, these data are consistent with resistance in HCV replicon-containing cell lines conferred by changes in the host and not by mutations in the virus.
|
Antiviral activity against HCV genotype 1b in RP7 replicon cell after 4 days by blot hybridization analysis
|
Hepatitis C virus subtype 1b
|
160.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potential for hepatitis C virus resistance to nitazoxanide or tizoxanide.
Year : 2008
Volume : 52
Issue : 11
First Page : 4069
Last Page : 4071
Authors : Korba BE, Elazar M, Lui P, Rossignol JF, Glenn JS.
Abstract : Nitazoxanide and its primary metabolite, tizoxanide, inhibit hepatitis C virus (HCV) replication in HCV replicon systems. To study the potential for resistance, we subjected Huh7 cells harboring HCV replicons to serial passage in 250 muM G418 and increasing concentrations of nitazoxanide or tizoxanide. Passage of the replicon-containing cell lines in either compound resulted in increases in the 50% effective concentrations (EC(50)s) (7- to 13-fold), EC(90)s (14- to 36-fold), and 50% cytotoxic concentrations (2- to 4-fold) of both compounds. Serial passage in either compound did not alter the susceptibility of HCV replicons to ribavirin or 2'-C-methylcytidine. Interestingly, serial passage in nitazoxanide or tizoxanide resulted in increased sensitivity to alpha interferon 2b: EC(50)s and EC(90)s were reduced three- and eightfold, respectively. Replicons isolated from these cell lines had no greater ability to confer tizoxanide resistance, or increased susceptibility to alpha interferon, than replicons isolated from the parental cell line that had not previously been exposed to nitazoxanide or tizoxanide. These findings are indicative of a cell-mediated activity differing from that of other anti-HCV drugs but complementary with interferon and are consistent with the enhanced response rates observed clinically when nitazoxanide is combined with pegylated interferon therapy. Finally, unlike data for other compounds in advanced clinical development for HCV, these data are consistent with resistance in HCV replicon-containing cell lines conferred by changes in the host and not by mutations in the virus.
|
Antimicrobial activity against biofilm-positive Staphylococcus epidermidis clinical isolate ICS1 by microdilution method
|
Staphylococcus epidermidis
|
1.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.
Year : 2010
Volume : 54
Issue : 7
First Page : 2767
Last Page : 2774
Authors : Tchouaffi-Nana F, Ballard TE, Cary CH, Macdonald TL, Sifri CD, Hoffman PS.
Abstract : Coagulase-negative species of Staphylococcus are often associated with opportunistic hospital-acquired infections that arise from the colonization of indwelling catheters. Here we show that the antiparasitic drug nitazoxanide (NTZ) and its active metabolite, tizoxanide (TIZ), are inhibitory to the growth of Staphylococcus epidermidis and other staphylococci, including methicillin-resistant Staphylococcus aureus strains, under aerobic and microaerobic conditions (MICs, 8 to 16 microg/ml). At sub-MIC levels, NTZ and TIZ also inhibited biofilm production under static conditions by strains of S. epidermidis and Staphylococcus haemolyticus with a 50% inhibitory concentration of approximately 2.5 microg/ml (8 microM). The 5-nitro group was required for biological activity, and a hydrophilic derivative of NTZ (AMIX) also inhibited biofilm formation. NTZ did not disperse the existing biofilm but did block further accumulation. Sub-MICs of NTZ had no effect on primary attachment to surfaces at either 4 or 37 degrees C. The inhibitory action of NTZ and TIZ, but not vancomycin, on biofilm production could be reversed by the addition of zinc salts (2.5 to 40 microM) but not other metals, suggesting that NTZ might target the zinc-dependent accumulation-associated protein (Aap) that mediates accumulation on surfaces. However, neither NTZ nor TIZ formed chelation complexes with zinc salts, based on spectrophotometric and nuclear magnetic resonance analyses, and addition of excess zinc to NTZ-grown bacteria (apo-Aap) did not restore the accumulation phenotype. Our studies suggest that sub-MIC levels of NTZ may affect the assembly or function of cell structures associated with the biofilm phenotype.
|
Antimicrobial activity against biofilm-positive Staphylococcus epidermidis clinical isolate ICS2 by microdilution method
|
Staphylococcus epidermidis
|
1.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.
Year : 2010
Volume : 54
Issue : 7
First Page : 2767
Last Page : 2774
Authors : Tchouaffi-Nana F, Ballard TE, Cary CH, Macdonald TL, Sifri CD, Hoffman PS.
Abstract : Coagulase-negative species of Staphylococcus are often associated with opportunistic hospital-acquired infections that arise from the colonization of indwelling catheters. Here we show that the antiparasitic drug nitazoxanide (NTZ) and its active metabolite, tizoxanide (TIZ), are inhibitory to the growth of Staphylococcus epidermidis and other staphylococci, including methicillin-resistant Staphylococcus aureus strains, under aerobic and microaerobic conditions (MICs, 8 to 16 microg/ml). At sub-MIC levels, NTZ and TIZ also inhibited biofilm production under static conditions by strains of S. epidermidis and Staphylococcus haemolyticus with a 50% inhibitory concentration of approximately 2.5 microg/ml (8 microM). The 5-nitro group was required for biological activity, and a hydrophilic derivative of NTZ (AMIX) also inhibited biofilm formation. NTZ did not disperse the existing biofilm but did block further accumulation. Sub-MICs of NTZ had no effect on primary attachment to surfaces at either 4 or 37 degrees C. The inhibitory action of NTZ and TIZ, but not vancomycin, on biofilm production could be reversed by the addition of zinc salts (2.5 to 40 microM) but not other metals, suggesting that NTZ might target the zinc-dependent accumulation-associated protein (Aap) that mediates accumulation on surfaces. However, neither NTZ nor TIZ formed chelation complexes with zinc salts, based on spectrophotometric and nuclear magnetic resonance analyses, and addition of excess zinc to NTZ-grown bacteria (apo-Aap) did not restore the accumulation phenotype. Our studies suggest that sub-MIC levels of NTZ may affect the assembly or function of cell structures associated with the biofilm phenotype.
|
Antimicrobial activity against biofilm-positive Staphylococcus epidermidis clinical isolate ICS3 by microdilution method
|
Staphylococcus epidermidis
|
1.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.
Year : 2010
Volume : 54
Issue : 7
First Page : 2767
Last Page : 2774
Authors : Tchouaffi-Nana F, Ballard TE, Cary CH, Macdonald TL, Sifri CD, Hoffman PS.
Abstract : Coagulase-negative species of Staphylococcus are often associated with opportunistic hospital-acquired infections that arise from the colonization of indwelling catheters. Here we show that the antiparasitic drug nitazoxanide (NTZ) and its active metabolite, tizoxanide (TIZ), are inhibitory to the growth of Staphylococcus epidermidis and other staphylococci, including methicillin-resistant Staphylococcus aureus strains, under aerobic and microaerobic conditions (MICs, 8 to 16 microg/ml). At sub-MIC levels, NTZ and TIZ also inhibited biofilm production under static conditions by strains of S. epidermidis and Staphylococcus haemolyticus with a 50% inhibitory concentration of approximately 2.5 microg/ml (8 microM). The 5-nitro group was required for biological activity, and a hydrophilic derivative of NTZ (AMIX) also inhibited biofilm formation. NTZ did not disperse the existing biofilm but did block further accumulation. Sub-MICs of NTZ had no effect on primary attachment to surfaces at either 4 or 37 degrees C. The inhibitory action of NTZ and TIZ, but not vancomycin, on biofilm production could be reversed by the addition of zinc salts (2.5 to 40 microM) but not other metals, suggesting that NTZ might target the zinc-dependent accumulation-associated protein (Aap) that mediates accumulation on surfaces. However, neither NTZ nor TIZ formed chelation complexes with zinc salts, based on spectrophotometric and nuclear magnetic resonance analyses, and addition of excess zinc to NTZ-grown bacteria (apo-Aap) did not restore the accumulation phenotype. Our studies suggest that sub-MIC levels of NTZ may affect the assembly or function of cell structures associated with the biofilm phenotype.
|
Antimicrobial activity against biofilm-positive Staphylococcus epidermidis clinical isolate ICS4 by microdilution method
|
Staphylococcus epidermidis
|
1.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.
Year : 2010
Volume : 54
Issue : 7
First Page : 2767
Last Page : 2774
Authors : Tchouaffi-Nana F, Ballard TE, Cary CH, Macdonald TL, Sifri CD, Hoffman PS.
Abstract : Coagulase-negative species of Staphylococcus are often associated with opportunistic hospital-acquired infections that arise from the colonization of indwelling catheters. Here we show that the antiparasitic drug nitazoxanide (NTZ) and its active metabolite, tizoxanide (TIZ), are inhibitory to the growth of Staphylococcus epidermidis and other staphylococci, including methicillin-resistant Staphylococcus aureus strains, under aerobic and microaerobic conditions (MICs, 8 to 16 microg/ml). At sub-MIC levels, NTZ and TIZ also inhibited biofilm production under static conditions by strains of S. epidermidis and Staphylococcus haemolyticus with a 50% inhibitory concentration of approximately 2.5 microg/ml (8 microM). The 5-nitro group was required for biological activity, and a hydrophilic derivative of NTZ (AMIX) also inhibited biofilm formation. NTZ did not disperse the existing biofilm but did block further accumulation. Sub-MICs of NTZ had no effect on primary attachment to surfaces at either 4 or 37 degrees C. The inhibitory action of NTZ and TIZ, but not vancomycin, on biofilm production could be reversed by the addition of zinc salts (2.5 to 40 microM) but not other metals, suggesting that NTZ might target the zinc-dependent accumulation-associated protein (Aap) that mediates accumulation on surfaces. However, neither NTZ nor TIZ formed chelation complexes with zinc salts, based on spectrophotometric and nuclear magnetic resonance analyses, and addition of excess zinc to NTZ-grown bacteria (apo-Aap) did not restore the accumulation phenotype. Our studies suggest that sub-MIC levels of NTZ may affect the assembly or function of cell structures associated with the biofilm phenotype.
|
Antimicrobial activity against biofilm-positive Staphylococcus epidermidis clinical isolate ICS5 by microdilution method
|
Staphylococcus epidermidis
|
1.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.
Year : 2010
Volume : 54
Issue : 7
First Page : 2767
Last Page : 2774
Authors : Tchouaffi-Nana F, Ballard TE, Cary CH, Macdonald TL, Sifri CD, Hoffman PS.
Abstract : Coagulase-negative species of Staphylococcus are often associated with opportunistic hospital-acquired infections that arise from the colonization of indwelling catheters. Here we show that the antiparasitic drug nitazoxanide (NTZ) and its active metabolite, tizoxanide (TIZ), are inhibitory to the growth of Staphylococcus epidermidis and other staphylococci, including methicillin-resistant Staphylococcus aureus strains, under aerobic and microaerobic conditions (MICs, 8 to 16 microg/ml). At sub-MIC levels, NTZ and TIZ also inhibited biofilm production under static conditions by strains of S. epidermidis and Staphylococcus haemolyticus with a 50% inhibitory concentration of approximately 2.5 microg/ml (8 microM). The 5-nitro group was required for biological activity, and a hydrophilic derivative of NTZ (AMIX) also inhibited biofilm formation. NTZ did not disperse the existing biofilm but did block further accumulation. Sub-MICs of NTZ had no effect on primary attachment to surfaces at either 4 or 37 degrees C. The inhibitory action of NTZ and TIZ, but not vancomycin, on biofilm production could be reversed by the addition of zinc salts (2.5 to 40 microM) but not other metals, suggesting that NTZ might target the zinc-dependent accumulation-associated protein (Aap) that mediates accumulation on surfaces. However, neither NTZ nor TIZ formed chelation complexes with zinc salts, based on spectrophotometric and nuclear magnetic resonance analyses, and addition of excess zinc to NTZ-grown bacteria (apo-Aap) did not restore the accumulation phenotype. Our studies suggest that sub-MIC levels of NTZ may affect the assembly or function of cell structures associated with the biofilm phenotype.
|
Antimicrobial activity against Staphylococcus epidermidis clinical isolate 5179-R1 derived from PNAG negative, icaA::IS257 mutant 5179 strain produces a proteinaceous biofilm dependent on a truncated 140-kDa isoform of Aap by microdilution method
|
Staphylococcus epidermidis
|
1.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.
Year : 2010
Volume : 54
Issue : 7
First Page : 2767
Last Page : 2774
Authors : Tchouaffi-Nana F, Ballard TE, Cary CH, Macdonald TL, Sifri CD, Hoffman PS.
Abstract : Coagulase-negative species of Staphylococcus are often associated with opportunistic hospital-acquired infections that arise from the colonization of indwelling catheters. Here we show that the antiparasitic drug nitazoxanide (NTZ) and its active metabolite, tizoxanide (TIZ), are inhibitory to the growth of Staphylococcus epidermidis and other staphylococci, including methicillin-resistant Staphylococcus aureus strains, under aerobic and microaerobic conditions (MICs, 8 to 16 microg/ml). At sub-MIC levels, NTZ and TIZ also inhibited biofilm production under static conditions by strains of S. epidermidis and Staphylococcus haemolyticus with a 50% inhibitory concentration of approximately 2.5 microg/ml (8 microM). The 5-nitro group was required for biological activity, and a hydrophilic derivative of NTZ (AMIX) also inhibited biofilm formation. NTZ did not disperse the existing biofilm but did block further accumulation. Sub-MICs of NTZ had no effect on primary attachment to surfaces at either 4 or 37 degrees C. The inhibitory action of NTZ and TIZ, but not vancomycin, on biofilm production could be reversed by the addition of zinc salts (2.5 to 40 microM) but not other metals, suggesting that NTZ might target the zinc-dependent accumulation-associated protein (Aap) that mediates accumulation on surfaces. However, neither NTZ nor TIZ formed chelation complexes with zinc salts, based on spectrophotometric and nuclear magnetic resonance analyses, and addition of excess zinc to NTZ-grown bacteria (apo-Aap) did not restore the accumulation phenotype. Our studies suggest that sub-MIC levels of NTZ may affect the assembly or function of cell structures associated with the biofilm phenotype.
|
Antiprotozoan activity against Trichomonas vaginalis GT3 trophozoites after 48 hrs
|
Trichomonas vaginalis
|
68.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of benzologues of Nitazoxanide and Tizoxanide: a comparative study of their in vitro broad-spectrum antiprotozoal activity.
Year : 2011
Volume : 21
Issue : 10
First Page : 3168
Last Page : 3171
Authors : Navarrete-Vazquez G, Chávez-Silva F, Argotte-Ramos R, Rodríguez-Gutiérrez Mdel C, Chan-Bacab MJ, Cedillo-Rivera R, Moo-Puc R, Hernández-Nuñez E.
Abstract : We have synthesized two new benzologues of Nitazoxanide (NIT) and Tizoxanide (TIZ), using a short synthetic route. Both compounds were tested in vitro against six protozoa (Giardia intestinalis, Trichomonas vaginalis, Entamoeba histolytica, Plasmodium berghei, Leishmania mexicana and Trypanosoma cruzi). Compound 1 (benzologue of NIT) showed broad antiprotozoal effect against all parasites tested, showing IC(50)'s<5 μM. This compound was five-times more active than NIT, and 18-times more potent than metronidazole against G. intestinalis. It was 10-times more active than pentamidine against L. mexicana, and it was sevenfold more potent than benznidazole versus T. cruzi. This compound could be considered as a new broad spectrum antiprotozoal agent.
|
Antiprotozoan activity against Entamoeba histolytica HM1-IMSS trophozoites after 48 hrs
|
Entamoeba histolytica
|
504.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of benzologues of Nitazoxanide and Tizoxanide: a comparative study of their in vitro broad-spectrum antiprotozoal activity.
Year : 2011
Volume : 21
Issue : 10
First Page : 3168
Last Page : 3171
Authors : Navarrete-Vazquez G, Chávez-Silva F, Argotte-Ramos R, Rodríguez-Gutiérrez Mdel C, Chan-Bacab MJ, Cedillo-Rivera R, Moo-Puc R, Hernández-Nuñez E.
Abstract : We have synthesized two new benzologues of Nitazoxanide (NIT) and Tizoxanide (TIZ), using a short synthetic route. Both compounds were tested in vitro against six protozoa (Giardia intestinalis, Trichomonas vaginalis, Entamoeba histolytica, Plasmodium berghei, Leishmania mexicana and Trypanosoma cruzi). Compound 1 (benzologue of NIT) showed broad antiprotozoal effect against all parasites tested, showing IC(50)'s<5 μM. This compound was five-times more active than NIT, and 18-times more potent than metronidazole against G. intestinalis. It was 10-times more active than pentamidine against L. mexicana, and it was sevenfold more potent than benznidazole versus T. cruzi. This compound could be considered as a new broad spectrum antiprotozoal agent.
|
Antiviral activity against Hepatitis B virus infected in human HepG2(2.2.15) cells assessed as decrease in extracellular viral DNA measured 24 hrs after last dose
|
Hepatitis B virus
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication.
Year : 2011
Volume : 54
Issue : 12
First Page : 4119
Last Page : 4132
Authors : Stachulski AV, Pidathala C, Row EC, Sharma R, Berry NG, Iqbal M, Bentley J, Allman SA, Edwards G, Helm A, Hellier J, Korba BE, Semple JE, Rossignol JF.
Abstract : We report the syntheses and activities of a wide range of thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 μm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.
|
Antiviral activity against Hepatitis B virus infected in human HepG2(2.2.15) cells assessed as decrease in intracellular viral DNA measured 24 hrs after last dose
|
Hepatitis B virus
|
590.0
nM
|
|
Journal : J. Med. Chem.
Title : Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication.
Year : 2011
Volume : 54
Issue : 12
First Page : 4119
Last Page : 4132
Authors : Stachulski AV, Pidathala C, Row EC, Sharma R, Berry NG, Iqbal M, Bentley J, Allman SA, Edwards G, Helm A, Hellier J, Korba BE, Semple JE, Rossignol JF.
Abstract : We report the syntheses and activities of a wide range of thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 μm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.
|
Antiviral activity against HCV genotype 1b infected in Ava5 cells assessed as inhibition of viral replication after 3 days by blot hybridization analysis
|
Hepatitis C virus subtype 1b
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication.
Year : 2011
Volume : 54
Issue : 24
First Page : 8670
Last Page : 8680
Authors : Stachulski AV, Pidathala C, Row EC, Sharma R, Berry NG, Lawrenson AS, Moores SL, Iqbal M, Bentley J, Allman SA, Edwards G, Helm A, Hellier J, Korba BE, Semple JE, Rossignol JF.
Abstract : We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.
|
Antiviral activity against HCV genotype 1a infected in Huh7.5 cells assessed as inhibition of viral replication after 3 days by blot hybridization analysis
|
Hepatitis C virus subtype 1a
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication.
Year : 2011
Volume : 54
Issue : 24
First Page : 8670
Last Page : 8680
Authors : Stachulski AV, Pidathala C, Row EC, Sharma R, Berry NG, Lawrenson AS, Moores SL, Iqbal M, Bentley J, Allman SA, Edwards G, Helm A, Hellier J, Korba BE, Semple JE, Rossignol JF.
Abstract : We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.
|
Antimicrobial activity against Trichomonas vaginalis GT3 incubated for 48 hrs followed by compound washout measured after 48 hrs
|
Trichomonas vaginalis
|
79.43
nM
|
|
Antimicrobial activity against Trichomonas vaginalis GT3 incubated for 48 hrs followed by compound washout measured after 48 hrs
|
Trichomonas vaginalis
|
68.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 2-acylamino-5-nitro-1,3-thiazoles: preparation and in vitro bioevaluation against four neglected protozoan parasites.
Year : 2014
Volume : 22
Issue : 5
First Page : 1626
Last Page : 1633
Authors : Nava-Zuazo C, Chávez-Silva F, Moo-Puc R, Chan-Bacab MJ, Ortega-Morales BO, Moreno-Díaz H, Díaz-Coutiño D, Hernández-Núñez E, Navarrete-Vázquez G.
Abstract : The 2-acylamino-5-nitro-1,3-thiazole derivatives (1-14) were prepared using a one step reaction. All compounds were tested in vitro against four neglected protozoan parasites (Giardia intestinalis, Trichomonas vaginalis, Leishmania amazonensis and Trypanosoma cruzi). Acetamide (9), valeroylamide (10), benzamide (12), methylcarbamate (13) and ethyloxamate (14) derivatives were the most active compounds against G. intestinalis and T. vaginalis, showing nanomolar inhibition. Compound 13 (IC50=10nM), was 536-times more active than metronidazole, and 121-fold more effective than nitazoxanide against G. intestinalis. Compound 14 was 29-times more active than metronidazole and 6.5-fold more potent than nitazoxanide against T. vaginalis. Ureic derivatives 2, 3 and 5 showed moderate activity against L. amazonensis. None of them were active against T. cruzi. Ligand efficiency indexes analysis revealed higher intrinsic quality of the most active 2-acylamino derivatives than nitazoxanide and metronidazole. In silico toxicity profile was also computed for the most active compounds. A very low in vitro mammalian cytotoxicity was obtained for 13 and 14, showing selectivity indexes (SI) of 246,300 and 141,500, respectively. Nitazoxanide showed an excellent leishmanicidal and trypanocidal effect, repurposing this drug as potential new antikinetoplastid parasite compound.
|
Antiviral activity against Hepatitis B virus
|
Hepatitis B virus
|
120.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : A review of non-nucleoside anti-hepatitis B virus agents.
Year : 2014
Volume : 75
First Page : 267
Last Page : 281
Authors : Zhang F, Wang G.
Abstract : Hepatitis B Virus is the most common cause of chronic liver disease worldwide. Currently approved agents of chronic HBV infection treatment include interferon and nucleoside analogues. However, the side effects of interferon and the viral resistance of nucleoside analogues make the current treatment far from satisfactory. Therefore, new drugs with novel structures and mechanisms are needed. Recently, a number of non-nucleoside HBV inhibitors have been obtained from natural sources or prepared by synthesis/semi-synthesis. Some of them exhibited potent anti-HBV activity with novel mechanisms. These compounds provide useful information for the medicinal chemist to develop novel non-nucleoside compounds as anti-HBV agents.
|
Trichomonicidal activity against Trichomonas vaginalis GT3 compound treated for 48 hrs followed by incubation for 48 hrs in compound-free medium by cell counting
|
Trichomonas vaginalis
|
68.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of nitro(benzo)thiazole acetamides and in vitro antiprotozoal effect against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis.
Year : 2015
Volume : 23
Issue : 9
First Page : 2204
Last Page : 2210
Authors : Navarrete-Vázquez G, Chávez-Silva F, Colín-Lozano B, Estrada-Soto S, Hidalgo-Figueroa S, Guerrero-Álvarez J, Méndez ST, Reyes-Vivas H, Oria-Hernández J, Canul-Canché J, Ortiz-Andrade R, Moo-Puc R.
Abstract : We synthesized four 5-nitrothiazole (1-4) and four 6-nitrobenzothiazole acetamides (5-8) using an easy two step synthetic route. All compounds were tested in vitro against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis, showing excellent antiprotozoal effects. IC₅₀'s of the most potent compounds range from nanomolar to low micromolar order, being more active than their drugs of choice. Compound 1 (IC₅₀=122 nM), was 44-times more active than Metronidazole, and 10-fold more effective than Nitazoxanide against G. intestinalis and showed good trichomonicidal activity (IC₅₀=2.24 μM). This compound did not display in vitro cytotoxicity against VERO cells. The in vitro inhibitory effect of compounds 1-8 and Nitazoxanide against G. intestinalis fructose-1,6-biphosphate aldolase (GiFBPA) was evaluated as potential drug target, showing a clear inhibitory effect over the enzyme activity. Molecular docking of compounds 1, 4 and Nitazoxanide into the ligand binding pocket of GiFBPA, revealed contacts with the active site residues of the enzyme. Ligand efficiency metrics of 1 revealed optimal combinations of physicochemical and antiprotozoal properties, better than Nitazoxanide.
|
Inhibition of Giardia intestinalis fructose 1,6-bisphosphate aldolase at 400 nM after 2 hrs by spectrophotometry
|
Giardia intestinalis
|
31.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of nitro(benzo)thiazole acetamides and in vitro antiprotozoal effect against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis.
Year : 2015
Volume : 23
Issue : 9
First Page : 2204
Last Page : 2210
Authors : Navarrete-Vázquez G, Chávez-Silva F, Colín-Lozano B, Estrada-Soto S, Hidalgo-Figueroa S, Guerrero-Álvarez J, Méndez ST, Reyes-Vivas H, Oria-Hernández J, Canul-Canché J, Ortiz-Andrade R, Moo-Puc R.
Abstract : We synthesized four 5-nitrothiazole (1-4) and four 6-nitrobenzothiazole acetamides (5-8) using an easy two step synthetic route. All compounds were tested in vitro against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis, showing excellent antiprotozoal effects. IC₅₀'s of the most potent compounds range from nanomolar to low micromolar order, being more active than their drugs of choice. Compound 1 (IC₅₀=122 nM), was 44-times more active than Metronidazole, and 10-fold more effective than Nitazoxanide against G. intestinalis and showed good trichomonicidal activity (IC₅₀=2.24 μM). This compound did not display in vitro cytotoxicity against VERO cells. The in vitro inhibitory effect of compounds 1-8 and Nitazoxanide against G. intestinalis fructose-1,6-biphosphate aldolase (GiFBPA) was evaluated as potential drug target, showing a clear inhibitory effect over the enzyme activity. Molecular docking of compounds 1, 4 and Nitazoxanide into the ligand binding pocket of GiFBPA, revealed contacts with the active site residues of the enzyme. Ligand efficiency metrics of 1 revealed optimal combinations of physicochemical and antiprotozoal properties, better than Nitazoxanide.
|
Inhibition of HBV DNA replication
|
Hepatitis B virus
|
120.0
nM
|
|
Journal : MedChemComm
Title : Non-nucleoside anti-HBV agents: advances in structural optimization and mechanism of action investigations
Year : 2015
Volume : 6
Issue : 4
First Page : 521
Last Page : 535
Authors : Liu N, Zhao F, Jia H, Rai D, Zhan P, Jiang X, Liu X
|
Antiviral activity against HBV infected in human HepG2(2.2.15) cells assessed as inhibition of extracellular viral DNA level
|
Hepatitis B virus
|
120.0
nM
|
|
Journal : J Med Chem
Title : Past, Current, and Future Developments of Therapeutic Agents for Treatment of Chronic Hepatitis B Virus Infection.
Year : 2017
Volume : 60
Issue : 15
First Page : 6461
Last Page : 6479
Authors : Pei Y, Wang C, Yan SF, Liu G.
Abstract : For decades, treatment of hepatitis B virus (HBV) infection has been relying on interferon (IFN)-based therapies and nucleoside/nucleotide analogues (NAs) that selectively target the viral polymerase reverse transcriptase (RT) domain and thereby disrupt HBV viral DNA synthesis. We have summarized here the key steps in the HBV viral life cycle, which could potentially be targeted by novel anti-HBV therapeutics. A wide range of next-generation direct antiviral agents (DAAs) with distinct mechanisms of actions are discussed, including entry inhibitors, transcription inhibitors, nucleoside/nucleotide analogues, inhibitors of viral ribonuclease H (RNase H), modulators of viral capsid assembly, inhibitors of HBV surface antigen (HBsAg) secretion, RNA interference (RNAi) gene silencers, antisense oligonucleotides (ASOs), and natural products. Compounds that exert their antiviral activities mainly through host factors and immunomodulation, such as host targeting agents (HTAs), programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, and Toll-like receptor (TLR) agonists, are also discussed. In this Perspective, we hope to provide an overview, albeit by no means being comprehensive, for the recent development of novel therapeutic agents for the treatment of chronic HBV infection, which not only are able to sustainably suppress viral DNA but also aim to achieve functional cure warranted by HBsAg loss and ultimately lead to virus eradication and cure of hepatitis B.
|
Antiprolferative activity against human Caco2 cells assessed as inhibition of cell proliferation by measuring [3H]-thymidine incorporation at 1 mM incubated for 48 hrs by liquid scintillometry
|
Homo sapiens
|
80.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : In vitro studies on the inhibition of colon cancer by amino acid derivatives of bromothiazole.
Year : 2017
Volume : 27
Issue : 15
First Page : 3507
Last Page : 3510
Authors : Vale N, Correia-Branco A, Patrício B, Duarte D, Martel F.
Abstract : The investment in cancer research is critical to find more and better treatments, but essentially to save lives. Here, we describe the synthesis and characterization on new bromothiazole derivatives with amino acids and with core of nitazoxanide, an FDA-approved antiprotozoal drug. Using a human adenocarcinoma-derived cell line (the Caco-2 cell line), we then investigated the antiproliferative (3H-thymidine incorporation) and cytotoxic (extracellular lactate dehydrogenase activity) effect of these derivatives. All the derivatives caused a concentration-dependent decrease in cell proliferation and viability. At their highest concentration, all compounds were able to reduce 3H-thymidine incorporation by more than 80%, corresponding to a more marked antiproliferative effect than butyrate. As to their cytotoxic effect, it was comparable to that of butyrate. The ability of bromo substituent in thiazole ring with new sequences of amino acids in inducing cell death and apoptosis in Caco-2 cells (and other cell lines) is now being studied.
|
Antiprotozoal activity against Trichomonas vaginalis GT3 trophozoites incubated for 48 hrs
|
Trichomonas vaginalis
|
68.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum.
Year : 2017
Volume : 27
Issue : 15
First Page : 3490
Last Page : 3494
Authors : Colín-Lozano B, León-Rivera I, Chan-Bacab MJ, Ortega-Morales BO, Moo-Puc R, López-Guerrero V, Hernández-Núñez E, Argüello-Garcia R, Scior T, Barbosa-Cabrera E, Navarrete-Vázquez G.
Abstract : We designed and synthesized five new 5-nitrothiazole-NSAID chimeras as analogues of nitazoxanide, using a DCC-activated amidation. Compounds 1-5 were tested in vitro against a panel of five protozoa: 2 amitochondriates (Giardia intestinalis, Trichomonas vaginalis) and 3 kinetoplastids (Leishmania mexicana, Leishmania amazonensis and Trypanosoma cruzi). All chimeras showed broad spectrum and potent antiprotozoal activities, with IC50 values ranging from the low micromolar to nanomolar order. Compounds 1-5 were even more active than metronidazole and nitazoxanide, two marketed first-line drugs against giardiasis. In particular, compound 4 (an indomethacin hybrid) was one of the most potent of the series, inhibiting G. intestinalis growth in vitro with an IC50 of 0.145μM. Compound 4 was 38-times more potent than metronidazole and 8-times more active than nitazoxanide. The in vivo giardicidal effect of 4 was evaluated in a CD-1 mouse model obtaining a median effective dose of 1.709μg/kg (3.53nmol/kg), a 321-fold and 1015-fold increase in effectiveness after intragastric administration over metronidazole and nitazoxanide, respectively. Compounds 1 and 3 (hybrids of ibuprofen and clofibric acid), showed potent giardicidal activities in the in vitro as well as in the in vivo assays after oral administration. Therefore, compounds 1-5 constitute promising drug candidates for further testing in experimental chemotherapy against giardiasis, trichomoniasis, leishmaniasis and even trypanosomiasis infections.
|
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
|
50.75
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-2.79
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
13.55
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
19.1
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
9.65
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
26.69
%
|
|
|
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
|
17.15
%
|
|
|
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
|
43.61
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
11.0
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
100.65
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
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
|
0.78
%
|
|
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
|
0.78
%
|
|
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
|
-0.07
%
|
|
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.
|
Growth inhibiting activity of Naegleria gruberi in vitro
|
Naegleria gruberi
|
62.7
%
|
|
Title : Naegleria gruberi Pathogen Box compounds screening
Authors : Sarink, M; Mykytyn, A; Tielens, A; van Hellemond, J
Abstract : 400 compounds from the Pathogen box were screened for inhibitory activity against Naegleria gruberi strain NEG-M. N. gruberi was grown in modified PYNFH medium in 96-wells plates. Compounds were added in 10 uM concentrations in triplicate wells. Optical density was measured daily, after 6 days area under the curve was calculated and compared to 0.1 % DMSO control.
|
Inhibition of IL-6 induced STAT3 transcriptional activity in human HEK-Blue IL-6 cells assessed as secreted embryonic alkaline phosphatase reporter gene expression at 10 uM by microplate reader
|
Homo sapiens
|
54.6
%
|
|
Journal : ACS Med Chem Lett
Title : Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors.
Year : 2021
Volume : 12
Issue : 5.0
First Page : 696
Last Page : 703
Authors : Lü Z,Li X,Li K,Wang C,Du T,Huang W,Ji M,Li C,Xu F,Xu P,Niu Y
Abstract : We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3.
|
Cytotoxicity against human HeLa cells assessed as inhibition of cell viability at 10 uM measured after 48 hrs by MTT assay
|
Homo sapiens
|
19.4
%
|
|
Journal : ACS Med Chem Lett
Title : Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors.
Year : 2021
Volume : 12
Issue : 5.0
First Page : 696
Last Page : 703
Authors : Lü Z,Li X,Li K,Wang C,Du T,Huang W,Ji M,Li C,Xu F,Xu P,Niu Y
Abstract : We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3.
|
Cytotoxicity against human HEK 293T cells assessed as cell growth inhibition at 50 uM measured after 48 hrs by MTT assay
|
Homo sapiens
|
24.4
%
|
|
Journal : ACS Med Chem Lett
Title : Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors.
Year : 2021
Volume : 12
Issue : 5.0
First Page : 696
Last Page : 703
Authors : Lü Z,Li X,Li K,Wang C,Du T,Huang W,Ji M,Li C,Xu F,Xu P,Niu Y
Abstract : We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3.
|
Cytotoxicity against human HEK 293T cells assessed as cell growth inhibition at 10 uM measured after 48 hrs by MTT assay
|
Homo sapiens
|
-3.3
%
|
|
Journal : ACS Med Chem Lett
Title : Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors.
Year : 2021
Volume : 12
Issue : 5.0
First Page : 696
Last Page : 703
Authors : Lü Z,Li X,Li K,Wang C,Du T,Huang W,Ji M,Li C,Xu F,Xu P,Niu Y
Abstract : We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3.
|
Giardicidal activity against Giardia intestinalis WB ATCC 30957 incubated for 48 hrs by hemocytometric counting method
|
Giardia intestinalis
|
18.0
nM
|
|
|
Giardicidal activity against metronidazole-resistant Giardia intestinalis incubated for 48 hrs by hemocytometric counting method
|
Giardia intestinalis
|
17.0
nM
|
|
|
Giardicidal activity against Giardia intestinalis IMSS isolate incubated for 48 hrs by hemocytometric counting method
|
Giardia intestinalis
|
15.0
nM
|
|
|
Giardicidal activity against albendazole-resistant Giardia intestinalis incubated for 48 hrs by hemocytometric counting method
|
Giardia intestinalis
|
21.0
nM
|
|
