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1.
Eur J Med Chem ; 45(11): 5022-30, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20805012

ABSTRACT

Adamantanamines 16, 18, 21, 24, 27, 28, 30, 32, 35, 36, 37, 40, 46 and 48 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. The effect of introducing a hydroxyl group close to the amino group on this class of compounds was examined for the first time. Aminoalcohol 24 proved to be the most active of the compounds tested against influenza A virus, being 6-fold more active than amantadine, equipotent to rimantadine and 26-fold more potent than ribavirin. Aminoalcohols 36 and 37 were found to have considerable activity against bloodstream forms of the African trypanosome, Trypanosoma brucei, being almost 10 times more potent than rimantadine.


Subject(s)
Adamantane/chemistry , Alcohols/chemistry , Amines/chemistry , Drug Design , Adamantane/chemical synthesis , Adamantane/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Influenza A virus/drug effects , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Spectrophotometry, Infrared , Trypanosoma brucei brucei/drug effects
3.
ChemMedChem ; 4(7): 1059-62, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19422003

ABSTRACT

Treating African trypanosomiasis: The synthesis and biological evaluation of novel 1-alkyloxy and 1-benzyloxyadamantano 2-guanylhydrazones, their 1-dioxa congeners and two 1-benzyladamantano 2-guanylhydrazones is reported. Preliminary structure-activity relationship data were elucidated and lead compounds suitable for further optimization were discovered.


Subject(s)
Hydrazones/chemical synthesis , Trypanocidal Agents/chemical synthesis , Trypanosoma brucei brucei/drug effects , Animals , Drug Design , Hydrazones/chemistry , Hydrazones/pharmacology , Parasitic Sensitivity Tests , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology
4.
Bioorg Med Chem ; 17(8): 3198-206, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19251424

ABSTRACT

The synthesis of several (2-oxaadamant-1-yl)amines is reported. They were evaluated as NMDA receptor antagonists and several of them were more active than amantadine, but none was more potent than memantine. None of the tested compounds displayed antiviral activity. Two of the derivatives showed a significant level of trypanocidal activity.


Subject(s)
Adamantane/analogs & derivatives , Adamantane/pharmacology , Amines/chemical synthesis , Amines/pharmacology , Adamantane/chemical synthesis , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cell Culture Techniques , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/pharmacology
5.
Bioorg Med Chem ; 16(23): 9925-36, 2008 Dec 01.
Article in English | MEDLINE | ID: mdl-18954995

ABSTRACT

The synthesis of several (3-noradamantyl)amines, [(3-noradamantyl)methyl]amines, (3,7-dimethyl-1-bisnoradamantyl)amines, and [(3,7-dimethyl-1-bisnoradamantyl)methyl]amines is reported. They were evaluated against a wide range of viruses and one of them inhibited the cytopathicity of influenza A virus at a concentration similar to that of amantadine. Several of the new polycyclic amines show an interesting activity as NMDA receptor antagonists. A rimantadine analogue displayed significant trypanocidal activity. Moreover, to further characterize the pharmacology of these compounds, their effects on dopamine uptake were also assessed.


Subject(s)
Amantadine/analogs & derivatives , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Amantadine/chemical synthesis , Amantadine/pharmacology , Animals , Cells, Cultured , Dogs , Dopamine/metabolism , Influenza A virus/drug effects , Inhibitory Concentration 50 , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism
6.
Org Biomol Chem ; 6(17): 3177-85, 2008 Sep 07.
Article in English | MEDLINE | ID: mdl-18698478

ABSTRACT

Adamantanopyrrolidines 8, 9 and 10, adamantanopyrrolidines 16 and 18, adamantanoxazolone 20, adamantanopyrazolone 23, adamantanopyrazolothione 24 and adamantanocyclopentanamine 32 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. Pyrrolidine 16 proved to be the most active of the compounds tested against influenza A virus, being 4-fold more active than amantadine, equipotent to rimantadine and 19-fold more potent than ribavirin. Oxazolone 20 showed significant trypanocidal activity against bloodstream forms of the African trypanosome, Trypanosoma brucei, being approximately 3 times more potent than rimantadine and almost 50-fold more active than amantadine.


Subject(s)
Amantadine/chemical synthesis , Antiviral Agents/chemical synthesis , Drug Design , Rimantadine/chemical synthesis , Trypanocidal Agents/chemical synthesis , Amantadine/chemistry , Amantadine/therapeutic use , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Influenza A Virus, H3N2 Subtype/pathogenicity , Orthomyxoviridae Infections/drug therapy , Ribavirin/therapeutic use , Rimantadine/chemistry , Rimantadine/therapeutic use , Swine , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosomiasis, African/drug therapy , Viral Matrix Proteins/metabolism
7.
J Med Chem ; 51(5): 1496-500, 2008 Mar 13.
Article in English | MEDLINE | ID: mdl-18281929

ABSTRACT

To develop functionalized adamantanes for treating African trypanosomiasis, we report on the synthesis of new 1-alkyl-2-aminoadamantanes 1a- i, 1-alkyltricyclo[3.3.1.1 (3,7)]decan-2-guanylhydrazones 2a- g, and their congeneric thiosemicarbazones 3a, b. The potency of these compounds against Trypanosoma brucei was compared to that of amantadine and rimantadine and found to be substantially higher. The most active analogues, 1c, 1d, 2c, 2g, and 3b, illustrate the synergistic effect of the lipophilic character of the C1 side chain and the C2 functionality on trypanocidal activity.


Subject(s)
Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Trypanocidal Agents/chemical synthesis , Trypanosoma brucei brucei/drug effects , Adamantane/pharmacology , Amantadine/pharmacology , Animals , Parasitic Sensitivity Tests , Rimantadine/pharmacology , Structure-Activity Relationship , Trypanocidal Agents/pharmacology
8.
Free Radic Biol Med ; 40(2): 198-209, 2006 Jan 15.
Article in English | MEDLINE | ID: mdl-16413403

ABSTRACT

Superoxide dismutases (SOD) are a family of antioxidant enzymes that function by removing superoxide anions from the cellular environment. Here, we show that the African trypanosome, Trypanosoma brucei, expresses four SOD isoforms, three of which we have validated biochemically as iron dependent, a feature normally associated with prokaryotic SODs. Localisation studies reveal that two of the enzymes are found predominantly in a parasite-specific organelle, the glycosome (TbSODB1 and TbSODB2), while the other two are targeted to the mitochondrion (TbSODA and TbSODC). Functional analysis of the SOD repertoire in bloodstream form parasites was performed using an inducible RNA interference (RNAi) approach. Down-regulation of the glycosomal SOD transcripts corresponded with a significant reduction in the corresponding proteins and a dramatic level of cell death within the population. The importance of one of the mitochondrial enzymes (TbSODA) only became apparent when parasites were exposed to the superoxide-generating agent paraquat following induction of RNAi. These experiments therefore identify essential components of the superoxide metabolising arm of the T. brucei oxidative defence system and validate these enzymes as parasite-specific targets for drug design.


Subject(s)
Iron/metabolism , Superoxide Dismutase/genetics , Trypanosoma brucei brucei/enzymology , Amino Acid Sequence , Animals , Chromosome Mapping , Gene Expression Regulation, Enzymologic/genetics , Isoenzymes/genetics , Isoenzymes/metabolism , Isoenzymes/physiology , Molecular Sequence Data , RNA Interference/physiology , Sequence Homology, Amino Acid , Superoxide Dismutase/metabolism , Superoxide Dismutase/physiology , Time Factors , Trypanosoma brucei brucei/metabolism , Trypanosoma brucei brucei/parasitology
9.
Proc Natl Acad Sci U S A ; 102(33): 11645-50, 2005 Aug 16.
Article in English | MEDLINE | ID: mdl-16087875

ABSTRACT

The capacity to synthesize vitamin C (ascorbate) is widespread in eukaryotes but is absent from humans. The last step in the biosynthetic pathway involves the conversion of an aldonolactone substrate to ascorbate, a reaction catalyzed by members of an FAD-dependent family of oxidoreductases. Here we demonstrate that both the African trypanosome, Trypanosoma brucei, and the American trypanosome, Trypanosoma cruzi, have the capacity to synthesize vitamin C and show that this reaction occurs in a unique single-membrane organelle, the glycosome. The corresponding T. brucei flavoprotein (TbALO) obeys Michaelis-Menten kinetics and can utilize both L-galactono-gamma-lactone and D-arabinono-gamma-lactone as substrate, properties characteristic of plant and fungal enzymes. We could detect no activity toward the mammalian enzyme substrate L-gulono-gamma-lactone. TbALO null mutants (bloodstream form) were found to display a transient growth defect, a trait that was enhanced when they were cultured in medium in which the essential serum component had been pretreated with ascorbate oxidase to deplete vitamin C. It is implicit, therefore, that bloodstream-form trypanosomes also possess a capacity for ascorbate transport.


Subject(s)
Ascorbic Acid/biosynthesis , Microbodies/metabolism , Trypanosoma brucei brucei/cytology , Trypanosoma brucei brucei/metabolism , Trypanosoma cruzi/cytology , Trypanosoma cruzi/metabolism , Amino Acid Sequence , Animals , Ascorbate Oxidase/metabolism , Ascorbic Acid/chemistry , Ascorbic Acid/metabolism , Biological Transport , Flavoproteins/genetics , Flavoproteins/metabolism , Genes, Protozoan/genetics , Kinetics , Lactones/metabolism , Molecular Sequence Data , Mutation/genetics , Protozoan Proteins/genetics , Protozoan Proteins/metabolism , Sequence Alignment , Trypanosoma brucei brucei/genetics , Trypanosoma cruzi/genetics
10.
J Biol Chem ; 278(34): 31640-6, 2003 Aug 22.
Article in English | MEDLINE | ID: mdl-12791697

ABSTRACT

Detoxification of hydroperoxides in trypanosomes is mediated by a series of linked redox pathways that are dependent on the parasite-specific thiol trypanothione for reducing equivalents. These pathways are characterized by differences in subcellular location, electron transport molecules, and substrate specificity. To determine the functional significance of the enzymes involved, we have used a tetracycline-inducible RNA interference system to down-regulate expression of each of the corresponding transcripts in bloodstream form Trypanosoma brucei. We have identified two peroxidases, a cytosolic peroxiredoxin (TbCPX) and a member of the non-selenium glutathione-dependent peroxidase family (TbGPXI), that appear to be essential for the viability of this clinically relevant stage of the parasite life cycle. The addition of tetracycline to the cultures resulted in a major reduction in mRNA levels and enzyme activity, a dramatic fall in growth rate, and significant cell death. Furthermore, within 20 h of adding tetracycline, cells in which the cytosolic peroxiredoxin transcript was targeted were found to be 16-fold more susceptible to killing by exogenous hydrogen peroxide. We also observed that knockdown of the tryparedoxin TbT-PNI, a thioredoxin-like protein that facilitates electron transport to both TbCPX and TbGPXI, resulted in a reduction in growth rate. These experiments therefore identify redox pathways that are essential for oxidative defense in T. brucei and validate the corresponding peroxidases as targets for drug design.


Subject(s)
Hydrogen Peroxide/metabolism , RNA Interference , Trypanosoma brucei brucei/enzymology , Amino Acid Sequence , Animals , Base Sequence , Cell Line , DNA Primers , Molecular Sequence Data , Sequence Homology, Amino Acid
11.
Infect Immun ; 70(1): 86-95, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11748167

ABSTRACT

Bromelain, a mixture of cysteine proteases from pineapple stems, blocks signaling by the mitogen-activated protein (MAP) kinases extracellular regulated kinase 1 (ERK-1) and ERK-2, inhibits inflammation, and protects against enterotoxigenic Escherichia coli infection. In this study, we examined the effect of bromelain on Salmonella enterica serovar Typhimurium infection, since an important feature of its pathogenesis is its ability to induce activation of ERK-1 and ERK-2, which leads to internalization of bacteria and induction of inflammatory responses. Our results show that bromelain dose dependently blocks serovar Typhimurium-induced ERK-1, ERK-2, and c-Jun NH(2)-terminal kinase (JNK) activation in Caco-2 cells. Bromelain also blocked signaling induced by carbachol and anisomycin, pharmacological MAP kinase agonists. Despite bromelain inhibition of serovar Typhimurium-induced MAP kinase signaling, it did not prevent subsequent invasion of the Caco-2 cells by serovar Typhimurium or alter serovar Typhimurium -induced decreases in resistance across Caco-2 monolayers. Surprisingly, bromelain also did not block serovar Typhimurium-induced interleukin-8 (IL-8) secretion but synergized with serovar Typhimurium to enhance IL-8 production. We also found that serovar Typhimurium does not induce ERK phosphorylation in Caco-2 cells in the absence of serum but that serovar Typhimurium-induced invasion and decreases in monolayer resistance are unaffected. Collectively, these data indicate that serovar Typhimurium-induced invasion of Caco-2 cells, changes in the resistance of epithelial cell monolayers, and IL-8 production can occur independently of the ERK and JNK signaling pathways. Data also confirm that bromelain is a novel inhibitor of MAP kinase signaling pathways and suggest a novel role for proteases as inhibitors of signal transduction pathways in intestinal epithelial cells.


Subject(s)
Bromelains/metabolism , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinases/metabolism , Salmonella typhimurium/metabolism , Signal Transduction , Animals , Anisomycin/metabolism , Anisomycin/pharmacology , Bromelains/pharmacology , Caco-2 Cells , Carbachol/metabolism , Carbachol/pharmacology , Enzyme Activation , Humans , Interleukin-8/metabolism , Intestines/cytology , JNK Mitogen-Activated Protein Kinases , Mice , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinase 9 , Salmonella typhimurium/pathogenicity
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