Repurposing 9-Aminoacridine as an Adjuvant Enhances the Antimicrobial Effects of Rifampin against Multidrug-Resistant Klebsiella pneumoniae.

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 in vivo 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. IMPORTANCE 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 in vitro and with low resistance occurrence. The combination of 9-AA or 9-AA liposomes with RIF possesses effective antimicrobial activity in vivo 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.

High-content, arrayed compound screens with rhinovirus, influenza A virus and herpes simplex virus infections.

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.

Molecular docking, synthesis and biological evaluation of phenacyl derivatives of 9-aminoacridine as anti-Alzheimer's agent.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder mainly characterized by progressive deterioration of memory and impaired cognitive function. The most promising approach for symptomatic relief of AD is to inhibit acetylcholinesterase (AChE). On the basis of this approach in-house library of 9-aminoacridine derivatives were constructed and allowed to docked against human acetylcholinesterase (hAChE) (PDB ID: 4EY7), using MOE 2018.01 and PyRx 0.9.2 (AutoDock Vina). Top ranked and best fitted molecules were synthesized by targeting the 9-amino group of aminoacridine with substituted phenacyl halides. Anti-Alzheimer's potential was checked by in vitro AChE inhibition, antioxidant activity (DPPH scavenging ability) and fibril disaggregation. Subjected ligands suggested as promising multitargeted candidate with pronounced results in term of IC50 values (AChE inhibition 2.400-26.138µM), however, none of them showed potential towards fibril inhibition.

Interactions of newly synthesized platinum nanoparticles with ICR-191 and their potential application.

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.

9-Amino acridine pharmacokinetics, brain distribution, and in vitro/in vivo efficacy against malignant glioma.

PURPOSE: The delivery of drugs to the brain is a major obstacle in the design and development of useful treatments for malignant glioma. Previous studies by our laboratory have identified a series of 9-amino acridine compounds that block the catalytic cycle of topoisomerase II resulting in apoptosis and cell death in a variety of cancer cell lines. METHODS: This study reports the in vitro and in vivo activity of two promising lead compounds, [{9-[2-(1H-Indol-3-yl)-ethylamino]-acridin-4-yl}-(4-methyl-piperazin-1-yl)-methanone (1) and [9-(1-Benzyl-piperidin-4-ylamino)-acridin-3-yl]-(4-methyl-piperazin-1-yl)-methanone] (2), using an orthotopic glioblastoma mouse model. In addition, the absorption, distribution, and metabolism properties are characterized by determining metabolic stability, MDCK accumulation, Pgp efflux transport, plasma protein binding, and brain distribution in mouse pharmacokinetic studies. RESULTS: The efficacy results indicate low micromolar ED(50) values against glioma cells and a significant increase in the survival of glioma-bearing mice dosed with (2) (p < 0.05). Pharmacokinetic data collected at time intervals following a 60 mg/kg oral dose of acridine 1 and 2 showed both compounds penetrate the blood-brain barrier yielding peak concentrations of 0.25 µM and 0.6 µM, respectively. Peak plasma concentrations were determined to be 2.25 µM (1) and 20.38 µM (2). The results were further compared with data collected using a 15 mg/kg intravenous dose of 2 which yielded a peak concentration in the brain of 1.7 µM at 2.0 h relative to a 2.04 µM peak plasma concentration. The bioavailability was calculated to be 83.8%. CONCLUSION: Taken overall, the results suggest compounds in this series may offer new strategies for the design of chemotherapeutics for treating brain cancers with high oral bioavailability and improved efficacy.

Binding of TCA to the prion protein: mechanism, implication for therapy, and application as probe for complex formation of bio-macromolecules.

Tricyclic aromatic compounds (TCA) are promising candidates for treatment of transmissible spongiform encephalopathies. Direct binding to the cellular prion protein (PrP(C)) has been proposed as anti-prion active mechanism. We here show by means of NMR-spectroscopy that binding of TCA occurs with millimolar affinity to motifs consisting of two neighboring aromatic residues (Ar-Ar motif). It is independent of the secondary structure of this motif and of the side chain attached to the TCA and it is not specific to PrP(C). Because biologically inactive 9-aminoacridine (9-aa) binds with similar K(D) as anti-prion active quinacrine, direct interaction with PrP(C) as mechanism of action appears highly unlikely. However, binding of 9-aa to Ar-Ar-motifs in proteins can be used as reporter for biological macromolecule interactions, by measuring changes in T(1)-NMR relaxation times of 9-aa.

Effectiveness of a honey dressing for healing pressure ulcers.

OBJECTIVE: To compare the effect of a honey dressing vs an ethoxy-diaminoacridine plus nitrofurazone dressing in patients with pressure ulcers. DESIGN: This 5-week randomized clinical trial evaluated the effect of a honey dressing on pressure ulcer healing. SETTING AND SUBJECTS: Thirty-six patients with a total of 68 stage II or III pressure ulcers referred from a university hospital in Izmir were enrolled in the study. Twenty-six subjects completed the trial. INSTRUMENTS: Ulcers were measured with acetate tracings and Pressure Ulcer Scale for Healing (PUSH) evaluations. METHODS: Fifteen patients with 25 pressure ulcers were treated with honey dressings, and 11 patients with 25 pressure ulcers were treated with ethoxy-diaminoacridine plus nitrofurazone dressings. Wound healing was assessed weekly using the PUSH tool, version 3.0. The primary outcome measure was the change in PUSH tool scores in each group at 5 weeks. RESULTS: The two groups were statistically similar with regard to baseline and wound characteristics. After 5 weeks of treatment, patients who were treated by honey dressing had significantly better PUSH tool scores than subjects treated with the ethoxy-diaminoacridine plus nitrofurazone dressing (6.55 +/- 2.14 vs 12.62 +/- 2.15, P < .001). CONCLUSION: By week 5, PUSH tool scores showed that healing among subjects using a honey dressing was approximately 4 times the rate of healing in the comparison group. The use of a honey dressing is effective and practical.

Could an aminoacridine interfere with the cellular mechanisms involved in the process of human immunodeficiency virus infection?

Immune activation and synthesis of nucleic acids participate in the course of infection by human immunodeficiency virus. Aminoacridines, formally used as antiparasitic drugs, but almost abandoned nowadays for therapeutic use, are strong deoxyribonucleic acid chemoprotectors and lysosome stabilizers. Theoretically, these actions within the cell and other peculiar pharmacological characteristics of aminoacridines, particularly quinacrine, could pose barriers to human immunodeficiency virus infection and replication.

Determination of basal acetylcholine release in vivo by rat brain dialysis with a U-shaped cannula: effect of SM-10888, a putative therapeutic drug for Alzheimer's disease.

A U-shaped dialysis cannula was implanted into rat frontal cortex, hippocampus and striatum, and after 1 day for surgical recovery the cannula was perfused with Ringer's solution without any acetylcholinesterase (AChE) inhibitor under freely moving conditions. With a highly sensitive assay method for acetylcholine (ACh), the basal ACh content in the dialysates were detectable in those brain regions for several hours. The basal levels in the frontal cortex, hippocampus and striatum were 82 +/- 9, 72 +/- 4, 70 +/- 8 fmol/20 microliters (mean +/- S.E.M.), respectively. When SM-10888, a novel AChE inhibitor and putative therapeutic drug for Alzheimer's disease, was injected intraperitoneally, ACh in the dialysate of the cortex increased in a dose-dependent manner. Changes in the levels of hippocampal and striatal ACh release evoked by SM-10888 were similar to, but smaller than, that in the cortex. These data suggest that since the present assay method is able to determine in vivo basal ACh release in the dialysate without any AChE inhibitor, it is possible to study the effect of a novel drug such as SM-10888 in the brain regions.

An evaluation of 9-aminoacridine/Gelfoam to reduce dry socket formation.

This clinical study was undertaken to evaluate the effectiveness of locally applied 9-aminoacridine in Gelfoam in reducing the incidence of dry socket formation after third molar extractions. Results indicated that this technique was not effective. The incidence of dry socket formation in smokers and nonsmokers was compared. Also, the influence of surgical trauma on dry socket formation was examined.

Phase I clinical and pharmacokinetic study of 4'-(9-acridinylamino)-methanesulfon-m-anisidide in children with cancer.

Forty-one pediatric patients with advanced cancer (24 with acute leukemia and 17 with diverse solid tumors) received 74 courses of therapy with a new chemotherapeutic agent, 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA: NSC 249992). Treatments were given by slow i.v. injection daily for five days every two to three weeks. In patients with leukemia: (a) dosages were escalated from 1.3 to 150 mg/sq m/day; (b) toxicity in the form of stomatitis, vomiting, and phlebitis occurred at dosage levels of 125 to 150 mg/sq m/day; and (c) oncolytic effects were observed in 13 of 24 patients. In patients with solid tumors: (a) dosages were escalated from 5 to 50 mg/sq m/day; (b) toxicity (stomatitis, myelosuppression, and phlebitis) occurred at the dosage level of 50 mg/sq m/day; and (c) no oncolytic responses were noted. Serum concentrations of total and free AMSA were assayed by a fluorescence technique and declined in a biphasic manner with free AMSA declining more rapidly than total AMSA. Dosages of greater than 100 mg/sq m/day were required to maintain serum concentrations of total and free AMSA greater than 0.2 microM for the entire five-day schedule. The results suggest that maximum tolerated dosages of AMSA may differ in children with leukemia and solid tumors; however, hematopoietic toxicity could not be fully evaluated in the patients with leukemia. AMSA has clear antileukemic activity that warrants future Phase II trials.

9-Aminoacridine--its present status and current recommendations for use as a surgical and endodontic irrigant in dentistry.

Evidence is presented to support the use of 9-aminoacridine as a safe and effective surgical irrigant in dentistry. The available literature confirms that 9-aminoacridine is a potent antimicrobial agent, effective against a wide range of microorganisms commonly found in septic wounds and causing minimal tissue irritation. The use of 9-aminoacridine for routine root canal irrigation and as an antiseptic in the management of maxillofacial abscesses is recommended.