α7 nicotinic acetylcholine receptor agonist properties of tilorone and related tricyclic analogues

Briggs, Clark A.; Schrimpf, Michael R.; Anderson, David J.; Gubbins, Earl J.; Grønlien, Jens Halvard; Håkerud, Monika; Ween, Hilde; Thorin-Hagene, Kirsten; Malysz, John; Li, J; Bunnelle, William H.; Gopalakrishnan, Murali; Meyer, Michael D.

doi:10.1038/sj.bjp.0707649

Cited by 35 publications

(33 citation statements)

References 52 publications

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“…Tilorone is an investigational agent that has been known for over 40 years as an antiviral 56 and is an inducer of interferon in mice 57 . It has been shown to possess a broad array of biological activities including cell growth inhibition in PC3 CDK5dn prostate cancer cells (IC 50 8–12 μM) 58 , inhibition of Primase DnaG from Bacillus anthracis (IC 50 7.1 μM) 59 , in a mouse model of pulmonary fibrosis it decreased lung hydroxyproline content and the expression of collagen genes 60 , α7 nicotinic receptor (nAChR) agonist activity (K i 56 nM) 61 , activated human alpha7 nAChR with an EC 50 value of 2.5 μM 62 , radioprotective activity 63 , potent modulation of HIF-mediated gene expression in neurons with neuroprotective properties 64 and induction of the accumulation of glycosaminoglycans, delay infectious prion clearance, and prolong prion disease incubation time 65 . Quinacrine is an old antimalarial drug now more widely used as an antiprotozoal for the treatment of giardiasis 66 and as an anthelmintic.…”

Section: Discussionmentioning

confidence: 99%

Machine learning models identify molecules active against the Ebola virus in vitro

et al. 2016

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The search for small molecule inhibitors of Ebola virus (EBOV) has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs) with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC 50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in vitro.

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Section: Discussionmentioning

confidence: 99%

Machine learning models identify molecules active against the Ebola virus in vitro

et al. 2016

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“…Sold under the trade name Amixin or Lavomax, tilorone is approved for use in Russia, Ukraine, Kazakhstan, Belarus, Armenia, Georgia, Kyrgyzstan, Moldova, Turkmenistan, and Uzbekistan for multiple viral disease indications (i.e., influenza, acute respiratory viral infection, viral hepatitis, viral encephalitis, myelitis, and others) and is included in the list of vital and essential medicines of the Russian Federation. Tilorone has a broad array of biological activities (13)(14)(15)(16)(17)(18)(19)(20) and was first reported to be a small-molecule interferon (IFN) inducer with broad-spectrum antiviral activities (21)(22)(23). IFNs are pleiotropic cytokines with a long history of involvement in the development and treatment of viral infections and can inhibit viral replication by direct or indirect means such that combining IFNs with other antiviral drugs is a proven clinical strategy.…”

mentioning

confidence: 99%

Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection

Ekins

Lingerfelt

Comer

et al. 2018

Antimicrob Agents Chemother

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Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside the United States. A machinelearning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent in vitro EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate, and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9, and 1A2). Tilorone was shown to have 52% human plasma protein binding with excellent plasma stability and a mouse liver microsome half-life of 48 min. Dose range-finding studies in mice demonstrated a maximum tolerated single dose of 100 mg/kg of body weight. A pharmacokinetics study in mice at 2-and 10-mg/kg dose levels showed that the drug is rapidly absorbed, has dosedependent increases in maximum concentration of unbound drug in plasma and areas under the concentration-time curve, and has a half-life of approximately 18 h in both males and females, although the exposure was ϳ2.5-fold higher in male mice. Tilorone doses of 25 and 50 mg/kg proved efficacious in protecting 90% of mice from a lethal challenge with mouse-adapted with once-daily intraperitoneal (i.p.) dosing for 8 days. A subsequent study showed that 30 mg/kg/day of tilorone given i.p. starting 2 or 24 h postchallenge and continuing through day 7 postinfection was fully protective, indicating promising activity for the treatment of EVD.

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“…Одним з найефективніших противірусних за-собів широкого спектра дії є аміксин (1), якому притаманні: здатність індукувати інтерферон [1][2][3][4][5], імунотропна активність [6][7][8], інгібування репро-дукції вірусів в інтерфероннезалежний спосіб [9], протизапальна [10][11][12] та антиканцерогенна [13] дія, протипухлинна [14,15] та радіопротекторна активність [16][17][18], афінітет до a7нАХР [19], ан-тигіпоксична активність [20], здатність інгібува-ти перекисне окиснення ліпідів [21]. Якщо щодо деяких видів активності аміксину механізм їхньої реалізації можна вважати встановленим більш-менш точно, то стосовно механізму реалізації про-тивірусної та інтерфероніндукуючої активності досі немає загальноприйнятої точки зору.…”

Section: Issn 2308-8303 в смеси ксилола с водным раствором йодида натunclassified

“…Найменшу цитотоксичність проявили сполу-ки, які містять 4-заміщений піперидин як термі-нальну аміногрупу (19,20). Сполука 17, що мі-стить незаміщений піперидин майже на один по-рядок більш цитотоксична за її заміщені анало-ги.…”

Section: цитотоксичність похідних 44'-дигідрокси-біфенілуunclassified

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Synthesis and cytotoxicity of aminoethoxydiphenyls

Zanoza¹,

Maltzev²,

Lyakhov³

et al. 2014

J. org. pharm. chem.

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В ІЧ-спектрах наявні смуги поглинання, характерні для зв'язків C-H (аром.), C-H (аліф), C-O-C та NH протонованих термінальних аміногруп. У спектрах 1 H-ЯМР наявні сигнали від ароматич-них та аліфатичних протонів, мультиплетність та інтегральна інтенсивність яких відповідає припи-суваним структурам. На клітинах ПТП вивчена цитотоксичність низки 4,4'-біс-(2-аміноетокси)дифе-нілів, значення якої зіставні з токсичністю аміксину та знаходяться в діапазоні від низьких до помірних. SYNTHESIS AND CYTOTOXICITY OF AMINOETHOXYDIPHENYLS to induce IFI in biphenyl derivatives that are incapable to intercalate in NA indicates the possibility of implementing alternative mechanisms. This determined our interest to the study of aminoethoxydiphenyls (AED), which synthesis and investigation of cytotoxicity become the subject of this article. 4,4'-Bis-(2-chloroethoxy)diphenyl was obtained by alkylation of dihydroxydiphenyl with dichloroethane in its mixture with aqueous sodium hydroxide (20%) in the presence of tetrabutylammonium chloride (TBAC). Series of AED were synthesized by substitution of chlorine by iodine in the mixture of xylene with the aqueous solution of sodium iodide in the presence of TBAC with subsequent amination with primary and secondary amines. The protonated molecular ions (MI) intensive peaks of the compounds synthesized are observed in the mass spectra with FAB ionization. The most common way of MI fragmentation is

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α7 nicotinic acetylcholine receptor agonist properties of tilorone and related tricyclic analogues

Cited by 35 publications

References 52 publications

Machine learning models identify molecules active against the Ebola virus in vitro

Machine learning models identify molecules active against the Ebola virus in vitro

Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection

Synthesis and cytotoxicity of aminoethoxydiphenyls

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