ABSTRACT
Oxidative stress may be the major cause of induction of Shiga toxin-converting (Stx) prophages from chromosomes of Shiga toxin-producing Escherichia coli (STEC) in human intestine. Thus, we aimed to test a series of novel antioxidant compounds for their activities against prophage induction, thus, preventing pathogenicity of STEC. Forty-six compounds (derivatives of carbazole, indazole, triazole, quinolone, ninhydrine, and indenoindole) were tested. Fifteen of them gave promising results and were further characterized. Eleven compounds had acceptable profiles in cytotoxicity tests with human HEK-293 and HDFa cell lines. Three of them (selected for molecular studies) prevent the prophage induction at the level of expression of specific phage genes. In bacterial cells treated with hydrogen peroxide, expression of genes involved in the oxidative stress response was significantly less efficient in the presence of the tested compounds. Therefore, they apparently reduce the oxidative stress, which prevents induction of Stx prophage in E. coli.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antioxidants/pharmacology , Shiga Toxin/antagonists & inhibitors , Shiga-Toxigenic Escherichia coli/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antioxidants/chemical synthesis , Antioxidants/chemistry , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Structure , Oxidative Stress/drug effects , Shiga Toxin/genetics , Shiga Toxin/metabolism , Shiga-Toxigenic Escherichia coli/cytology , Shiga-Toxigenic Escherichia coli/metabolism , Structure-Activity RelationshipABSTRACT
Casein Kinase 2 (CK2) is a ubiquitous kinase protein currently targeted for the treatment of some cancers. Recently, the series of indeno[1,2-b]indoles has revealed great interest as potent and selective CK(2) ATP-competitive inhibitors. Among them, 1-amino-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (CM1) was selected for an encapsulation study in order to improve its biodisponibility. Its complexation was evaluated at the molecular scale, with a series of fluorinated or hydrocarbonated amphiphilic cyclodextrins (CDs). Then the encapsulation of CM1 within CD nanoparticles at the supramolecular level was achieved. Nanoparticles formed between CM1 and hexakis[6-deoxy-6-(3-perfluorohexylpropanethio)-2,3-di-O-methyl]-α-cyclodextrin, a fluorinated amphiphilic α-cyclodextrin, gave the best results in terms of encapsulation rate, stability and drug release. These nanospheres showed an encapsulation efficiency of 65% and a sustained release of the entrapped drug over 3h. Based on these results, encapsulation within fluorinated amphiphilic CD nanoparticles could be considered as a potential drug delivery system for indenoindole-type CK2 inhibitors, allowing better biodisponibility and offering perspectives for tumor targeting development.
Subject(s)
Casein Kinase II/antagonists & inhibitors , Drug Delivery Systems , Indenes/administration & dosage , Indoles/administration & dosage , alpha-Cyclodextrins/chemistry , Delayed-Action Preparations , Drug Stability , Nanoparticles , Time FactorsABSTRACT
The syntheses of new N-polysubstituted imidazo[4,5-b]pyridine-7-one (IP, 5 and 8a-8f) and indazole-4,7-dione (ID, 9 and 10) derivatives are described. The binding affinity of IP and ID towards the recombinant Nucleotide Binding Domain NBD1 of Cryptosporidium parvum CpABC3 was evaluated by intrinsic fluorescence quenching. IP induced a moderate quenching of the intrinsic fluorescence of H6-NBD1 whereas IDs 9 and 10 showed a binding affinity comparable to the ATP analogue TNP-ATP. In addition, 8d, 8e and 10 were shown to be competitive inhibitors of the ATPase activity, but with low affinity. These compounds could thus act like some flavonoid derivatives, which can partly overlap both the nucleotide-binding site and the adjacent hydrophobic steroid-binding region of mammalian P-glycoproteins.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , Cryptosporidium parvum , Imidazoles/chemical synthesis , Imidazoles/metabolism , Indazoles/chemical synthesis , Indazoles/metabolism , Protozoan Proteins/metabolism , Pyridines/chemical synthesis , Pyridines/metabolism , Pyridones/chemical synthesis , Pyridones/metabolism , ATP-Binding Cassette Transporters/chemistry , Imidazoles/chemistry , Indazoles/chemistry , Ligands , Nucleotides/metabolism , Protein Binding , Protozoan Proteins/chemistry , Pyridines/chemistry , Pyridones/chemistry , Spectrometry, FluorescenceABSTRACT
Quinonic derivatives were tested against a virulent RH strain of Toxoplasma gondii maintained in cell culture in THP-1, a human myelomonocytic cell line. The derivatives were tested at various doses (0.5-4 microg/ml) and compared with the reference molecules clindamycine, sulfadiazine, pyrimethamine and atovaquone. The percentage of parasite growth inhibition was observed after 72 h of incubation. The tested derivatives are bicyclic, tricyclic or tetracyclic quinones. Eight of these compounds exhibit over 70% inhibition of parasite growth; and two were nearly equipotent to pyrimethamine. These data indicate that the most active compounds against the RH strain of T. gondii are bis-heterocyclic quinones.
Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Quinones/chemistry , Quinones/pharmacology , Toxoplasma/drug effects , Animals , Cell Line , Humans , Inhibitory Concentration 50 , Parasitic Sensitivity Tests/methods , Structure-Activity Relationship , Toxoplasma/growth & developmentABSTRACT
Benzimidazole-4,7-diones derivatives substituted at 1- and/or 2-position have been synthetized and tested as inhibitors of purine nucleoside phosphorylase (PNP), isolated from two strains of Toxoplasma gondii (RH and ME 49). They were identified as inhibitors of both enzymes.
