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Scientific Data Oct 2022Viruses are genetically and structurally diverse, and outnumber cells by orders of magnitude. They can cause acute and chronic infections, suppress, or exacerbate...
Viruses are genetically and structurally diverse, and outnumber cells by orders of magnitude. They can cause acute and chronic infections, suppress, or exacerbate immunity, or dysregulate survival and growth of cells. To identify chemical agents with pro- or antiviral effects we conducted arrayed high-content image-based multi-cycle infection screens of 1,280 mainly FDA-approved compounds with three human viruses, rhinovirus (RV), influenza A virus (IAV), and herpes simplex virus (HSV) differing in genome organization, composition, presence of an envelope, and tropism. Based on Z'-factors assessing screening quality and Z-scores ranking individual compounds, we identified potent inhibitors and enhancers of infection: the RNA mutagen 5-Azacytidine against RV-A16; the broad-spectrum antimycotic drug Clotrimazole inhibiting IAV-WSN; the chemotherapeutic agent Raltitrexed blocking HSV-1; and Clobetasol enhancing HSV-1. Remarkably, the topical antiseptic compound Aminacrine, which is clinically used against bacterial and fungal agents, inhibited all three viruses. Our data underscore the versatility and potency of image-based, full cycle virus propagation assays in cell-based screenings for antiviral agents.
Topics: Aminacrine; Anti-Infective Agents, Local; Antiviral Agents; Azacitidine; Clobetasol; Clotrimazole; Herpes Simplex; Humans; Influenza A virus; Mutagens; Rhinovirus
PubMed: 36209289
DOI: 10.1038/s41597-022-01733-4 -
European Journal of Medicinal Chemistry Oct 2023A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines...
A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines obtained exhibited in vitro activity in the low- or sub-micromolar range against (i) hepatic stages of Plasmodium berghei, (ii) erythrocytic forms of Plasmodium falciparum, and (iii) early and mature gametocytes of Plasmodium falciparum. The most active compound, having a meta-fluorocinnamoyl group linked to the acridine core, was 20- and 120-fold more potent, respectively, against the hepatic and gametocyte stages of Plasmodium infection than the reference drug, primaquine. Moreover, no cytotoxicity towards mammalian and red blood cells at the concentrations tested was observed for any of the compounds under investigation. These novel conjugates represent promising leads for the development of new multi-target antiplasmodials.
Topics: Animals; Aminacrine; Aminoacridines; Antimalarials; Mammals; Plasmodium berghei; Plasmodium falciparum; Primaquine
PubMed: 37390511
DOI: 10.1016/j.ejmech.2023.115575 -
Nucleic Acids Research Apr 2023
Topics: Humans; Aminacrine; Peptide Nucleic Acids; Tumor Suppressor Protein p53; Down-Regulation; HeLa Cells; Neoplasms; Proto-Oncogene Proteins c-mdm2
PubMed: 36864743
DOI: 10.1093/nar/gkad166 -
International Journal of Molecular... Jan 2022Aminoacridines, used for decades as antiseptic and antiparasitic agents, are prospective candidates for therapeutic repurposing and new drug development. Although the...
Aminoacridines, used for decades as antiseptic and antiparasitic agents, are prospective candidates for therapeutic repurposing and new drug development. Although the mechanisms behind their biological effects are not fully elucidated, they are most often attributed to the acridines' ability to intercalate into DNA. Here, we characterized the effects of 9-aminoacridine (9AA) on pre-rRNA metabolism in cultured mammalian cells. Our results demonstrate that 9AA inhibits both transcription of the ribosomal RNA precursors (pre-rRNA) and processing of the already synthesized pre-rRNAs, thereby rapidly abolishing ribosome biogenesis. Using a fluorescent intercalator displacement assay, we further show that 9AA can bind to RNA in vitro, which likely contributes to its ability to inhibit post-transcriptional steps in pre-rRNA maturation. These findings extend the arsenal of small-molecule compounds that can be used to block ribosome biogenesis in mammalian cells and have implications for the pharmacological development of new ribosome biogenesis inhibitors.
Topics: Aminacrine; Animals; Cell Culture Techniques; Cell Line; Cell Nucleolus; Humans; Mice; NIH 3T3 Cells; RNA Precursors; RNA Processing, Post-Transcriptional; RNA, Ribosomal; Ribosomal Proteins; Ribosomes; Transcription, Genetic
PubMed: 35163183
DOI: 10.3390/ijms23031260 -
American Journal of Alzheimer's Disease... May 2016In the present study, some 9-aminoacridine derivatives have been synthesized by condensation of 9-aminoacridine with substituted phenacyl, benzoyl, and benzyl halides...
In the present study, some 9-aminoacridine derivatives have been synthesized by condensation of 9-aminoacridine with substituted phenacyl, benzoyl, and benzyl halides (RM1-RM6). Compounds were investigated for acetylcholinesterase and butyrylcholinesterase inhibition potential, considering these enzymes playing a key role in Alzheimer's disease. All derivatives showed better inhibition of enzymes than the standard galantamine, whereas except RM4, all exhibit better results than tacrine, a well-known acridine derivative used for the treatment of Alzheimer's disease.
Topics: Alzheimer Disease; Aminacrine; Cholinesterase Inhibitors; Humans; In Vitro Techniques
PubMed: 26385945
DOI: 10.1177/1533317515603115 -
Scientific Reports Mar 2019One of the greatest challenges of modern medicine is to find cheaper and easier ways to produce transporters for biologically active substances, which will provide...
One of the greatest challenges of modern medicine is to find cheaper and easier ways to produce transporters for biologically active substances, which will provide selective and efficient drug delivery to the target cells, while causing low toxicity towards healthy cells. Currently, metal-based nanoparticles are considered a successful and viable solution to this problem. In this work, we propose the use of novel synthesis method of platinum nanoparticles (PtNPs) connected with their precise biophysical characterization and assessment of their potential toxicity. To work as an efficient nanodelivery platform, nanoparticles should interact with the desired active compounds spontaneously and non-covalently. We investigated possible direct interactions of PtNPs with ICR-191, a model acridine mutagen with well-established biophysical properties and mutagenic activity, by Dynamic Light Scattering, fluorescence spectroscopy, and Isothermal Titration Calorimetry. Moreover, to determine the biological activity of ICR-191-PtNPs aggregates, we employed Ames mutagenicity test, eukaryotic cell line analysis and toxicity test against the model organism Caenorhabditis elegans. PtNPs' interesting physicochemical properties associated to the lack of toxicity in a tested range of concentrations, as well as their ability to modulate ICR-191 biological activity, suggest that these particles successfully work as potential delivery platforms for different biologically active substances.
Topics: Aminacrine; Biophysical Phenomena; Drug Delivery Systems; Humans; Metal Nanoparticles; Mutagens; Nitrogen Mustard Compounds; Platinum
PubMed: 30899037
DOI: 10.1038/s41598-019-41092-6 -
Journal of Neurochemistry Dec 2010Polyamine-containing toxins and synthetic dicationic derivatives of adamantane and phenylcyclohexyl selectively antagonize Ca(2+)-permeable... (Comparative Study)
Comparative Study
Polyamine-containing toxins and synthetic dicationic derivatives of adamantane and phenylcyclohexyl selectively antagonize Ca(2+)-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor channels. These compounds demonstrate voltage-dependent open-channel block and are trapped by closed channels. In this study, we describe an alternative mechanism of non-competitive AMPA receptor inhibition caused by 9-aminoacridine and some of its derivatives. These compounds exhibit similar potency against Ca(2+)-permeable and Ca(2+)-impermeable AMPA receptors. The inhibition is largely voltage-independent, binding and unbinding do not require presence of agonist. We conclude that 9-aminoacridine binds to a shallow site in the AMPA receptor, which is located above the activation gate. A comparison of three-dimensional structures of the antagonists suggests that the 'V-like' shape of the hydrophobic headgroup favors voltage-dependent binding to the deep site in the channel pore, whereas the compounds possessing flat aromatic headgroups preferably bind to the shallow site. The characterization of the novel mechanism of AMPA receptor channel antagonism opens a way to develop a new family of pharmacological agents, which can be of scientific and practical importance.
Topics: Aminacrine; Animals; Animals, Newborn; Binding Sites; Rats; Rats, Wistar; Receptors, AMPA
PubMed: 20969571
DOI: 10.1111/j.1471-4159.2010.07068.x -
Microbiology Spectrum Jun 2023The increasing occurrence of extensively drug-resistant and pan-drug-resistant K. pneumoniae has posed a serious threat to global public health. Therefore, new...
The increasing occurrence of extensively drug-resistant and pan-drug-resistant K. pneumoniae has posed a serious threat to global public health. Therefore, new antimicrobial strategies are urgently needed to combat these resistant K. pneumoniae-related infections. Drug repurposing and combination are two effective strategies to solve this problem. By a high-throughput screening assay of FDA-approved drugs, we found that the potential small molecule 9-aminoacridine (9-AA) could be used as an antimicrobial alone or synergistically with rifampin (RIF) against extensively/pan-drug-resistant K. pneumoniae. In addition, 9-AA could overcome the shortcomings of RIF by reducing the occurrence of resistance. Mechanistic studies revealed that 9-AA interacted with bacterial DNA and disrupted the proton motive force in K. pneumoniae. Through liposomeization and combination with RIF, the cytotoxicity of 9-AA was significantly reduced without affecting its antimicrobial activity. In addition, we demonstrated the antimicrobial activity of 9-AA combined with RIF without detectable toxicity. In summary, 9-AA has the potential to be an antimicrobial agent or a RIF adjuvant for the treatment of multidrug-resistant K. pneumoniae infections. Klebsiella pneumoniae is a leading cause of clinically acquired infections. The increasing occurrence of drug-resistant K. pneumoniae has posed a serious threat to global public health. We found that the potential small molecule 9-AA could be used as an antimicrobial alone or synergistically with RIF against drug-resistant K. pneumoniae and with low resistance occurrence. The combination of 9-AA or 9-AA liposomes with RIF possesses effective antimicrobial activity without detected toxicity. 9-AA exerted its antimicrobial activity by interacting with specific bacterial DNA and disrupting the proton motive force in K. pneumoniae. In summary, we found that 9-AA has the potential to be developed as a new antibacterial agent and adjuvant for RIF. Therefore, our study can reduce the risk of antimicrobial resistance and provide an option for the exploitation of new clinical drugs and a theoretical basis for the research on a new antimicrobial agent.
Topics: Humans; Rifampin; Klebsiella pneumoniae; Aminacrine; DNA, Bacterial; Drug Repositioning; Klebsiella Infections; Anti-Bacterial Agents; Anti-Infective Agents; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial
PubMed: 37036368
DOI: 10.1128/spectrum.04474-22 -
Biophysical Journal Dec 2002Functional N-methyl-D-aspartate receptors (NMDARs) are heteromultimers formed by NR1 and NR2 subunits. The M3 segment, as contributed by NR1, forms the core of the...
Functional N-methyl-D-aspartate receptors (NMDARs) are heteromultimers formed by NR1 and NR2 subunits. The M3 segment, as contributed by NR1, forms the core of the extracellular vestibule, including binding sites for channel blockers, and represents a critical molecular link between ligand binding and channel opening. Taking advantage of the substituted cysteine accessibility method along with channel block and multivalent coordination, we studied the contribution of the M3 segment in NR2C to the extracellular vestibule. We find that the M3 segment in NR2C, like that in NR1, contributes to the core of the extracellular vestibule. However, the M3 segments from the two subunits are staggered relative to each other in the vertical axis of the channel. Compared to NR1, homologous positions in NR2C, including those in the highly conserved SYTANLAAF motif, are located about four amino acids more externally. The staggering of subunits may represent a key structural feature underlying the distinct functional properties of NMDARs.
Topics: Aminacrine; Amino Acid Sequence; Animals; Cations; Cell Membrane; Cells, Cultured; Cysteine; Extracellular Space; Female; Glutamic Acid; Ion Channel Gating; Ion Channels; Macromolecular Substances; Membrane Potentials; Mesylates; Molecular Sequence Data; Mutagenesis, Site-Directed; Oocytes; Protein Conformation; Protein Subunits; Receptors, N-Methyl-D-Aspartate; Sequence Homology, Amino Acid; Silver; Xenopus
PubMed: 12496098
DOI: 10.1016/S0006-3495(02)75331-9 -
The Journal of Neuroscience : the... Aug 1999NMDA receptor-mediated calcium transients play a critical role in synaptogenesis, synaptic plasticity, and excitotoxicity. NMDA receptors are heteromeric complexes of...
NMDA receptor-mediated calcium transients play a critical role in synaptogenesis, synaptic plasticity, and excitotoxicity. NMDA receptors are heteromeric complexes of NR1A combined with NR2A, NR2B, NR2C, and/or NR2D subunits. The NR2 subunits determine a variety of electrophysiological and pharmacological properties of the NMDA receptor complex. In this report, we provide evidence for the first time that there is also a significant difference in peak channel open probability (P(o)) between NMDA receptors composed of NR1A/NR2A and those of NR1A/NR2B subunits. First, whole-cell patch-clamp recordings from human embryonic kidney (HEK) 293 cells expressing NMDA receptors revealed that NR1A/NR2A-mediated peak current densities are approximately four times larger than those of NR1A/NR2B. We show that this fourfold difference is unlikely caused by differences in receptor surface expression, since these levels were similar for the two subtypes by Western blot analysis. To determine whether P(o) contributed to the difference in peak current densities, we used two different open channel antagonists, MK-801 and 9-aminoacridine, in a variety of experimental paradigms. Our results indicate that peak P(o) is significantly higher (twofold to fivefold) for NR1A/NR2A than NR1A/NR2B, with estimated values of approximately 0.35 and 0.07, respectively. These results suggest that a change in the relative expression levels of NR2A and NR2B can regulate peak amplitude of NMDA receptor-mediated excitatory postsynaptic potentials and therefore may play a role in mechanisms underlying synaptic plasticity.
Topics: Aminacrine; Cell Line; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Neuronal Plasticity; Patch-Clamp Techniques; Peptide Fragments; Probability; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Transfection
PubMed: 10436042
DOI: 10.1523/JNEUROSCI.19-16-06844.1999