Tilorone Hydrochloride: An Orally Active Antiviral Agent

Krueger, R F; Mayer, Gerald D.

doi:10.1126/science.169.3951.1213

Cited by 184 publications

(77 citation statements)

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“…When tested in vitro the three compounds possessed EC 50 values 230–420 nM, much lower than the positive control chloroquine (EC 50 4.0 μM) used in this study and identified previously 3 . 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 .…”

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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“…Tilorone hydrochloride, the orange, watersoluble dihydrochloride salt of 2,7-bis[2-(diethylamino) ethoxy] fluoren-9-one, is a broadspectrum antiviral agent (5). In mice, it is effective against Semliki Forest virus by the oral, subcutaneous, and intraperitoneal treatment routes.…”

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confidence: 99%

Tilorone Hydrochloride: Lack of Correlation Between Interferon Induction and Viral Protection

Giron¹,

Schmidt²,

Pindak³

1972

Antimicrob Agents Chemother

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The protection of mice against MM virus infection and the induction of circulating interferon by tilorone hydrochloride were determined. Whereas protection was evident with doses of 0.15 and 1.5 mg/kg, interferon was not detected with doses lower than 150 mg/kg. Protection was apparently not dependent on interferon induction.Tilorone hydrochloride, the orange, watersoluble dihydrochloride salt of 2,7-bis[2-(diethylamino) ethoxy] fluoren-9-one, is a broadspectrum antiviral agent (5). In mice, it is effective against Semliki Forest virus by the oral, subcutaneous, and intraperitoneal treatment routes. It has also been shown to be effective against intranasal infection by vesicular stomatis virus (VSV; 2). Its mode of action is presumably interferon stimulation (2, 6). We have investigated the protection elicited by different doses of tilorone given intraperitoneally against MM virus infection in mice. At the same time, the amount of circulating interferon induced by each dose of tilorone was determined.Female Swiss Webster mice weighing about 14 g were treated intraperitoneally with different doses of tilorone diluted in Hanks balanced salt solution. Ten mice from each group were bled at 6, 12, and 24 hr after the administration of tilorone. The blood was pooled, and the plasma was collected and assayed for interferon activity. At 24 hr after the injection of tilorone, the mice remaining in each group were challenged intraperitoneatly with about 100 plaque-forming units of MM virus (2 LD50). Deaths were recorded daily for 20 days. The results (Table 1) show that, in terms of mortality and mean survival time, a tilorone dose of 7.5 mg/kg was sufficient to protect mice. They also suggest that doses as low as 0.15 and 1.5 mg/kg can have a protective effect, although at these doses the results were variable. Circulating interferon, however, was not detected with tilorone doses of less than 150 mg/kg. As these data show, in our system there was no correlation between the protection of mice against MM virus infection and the amount of circulating interferon induced by tilorone.These results are not in agreement with those of De Clercq and Merigan (2), who reported that the degree of protection of mice against intranasal infection with VSV was directly related to the titers of interferon induced by different doses of tilorone. Their interferon titers in response to tilorone were much higher than those in the present study. Since the 50% reduction in plaque count as a method for assay of interferon is more sensitive when MM virus is the challenge agent than when VSV is used (1), we must conclude that the differences in interferon titers in the two studies are real. This discrepancy could be due to a genotypic difference in the animals.

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“…Tilorone, (2,7-bis[2-(diethylamino)ethoxy]-9H-fluoren-9-one), was discovered in 1970 as the first low molecular-weight IFN-inducing agent, effective in vivo against several DNA and RNA viruses in connection with its DNA intercalating property. [3][4][5] In fact, the mechanism of action of tilorone is related to DNA-intercalation induced by the two main components of the drug: the chromophore and the side chains. 6 Intercalation alters DNA chemo-physical properties stimulating cytokines expression 7 .…”

Section: Introductionmentioning

confidence: 99%

9-Fluorenon-4-carboxamides: synthesis, conformational analysis, anti-HSV-2, and immunomodulatory evaluation. Note II

Alcaro¹,

Arena²,

Bella³

et al. 2004

Arkivoc

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Title 9-fluorenon-4-carboxamides has been prepared as asymmetrically-substituted analogues of the antiviral tilorone and their antiherpetic and cytokine-inducing properties have been explored. The best pharmacological profiles were shown by carboxamides 1, 4, 9, and 10 endowed with anti-HSV-2, IFNα, IFNγ and TNFα-inducing properties assayed on peripheral blood mononuclear cells (PBMC). The conformational analysis of compounds 1-10 has been performed by molecular modelling techniques and a geometrical descriptor was evaluated.

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Tilorone Hydrochloride: An Orally Active Antiviral Agent

Cited by 184 publications

References 0 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

Tilorone Hydrochloride: Lack of Correlation Between Interferon Induction and Viral Protection

9-Fluorenon-4-carboxamides: synthesis, conformational analysis, anti-HSV-2, and immunomodulatory evaluation. Note II

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