An Effective Synthesis Method for Tilorone Dihydrochloride with Obvious IFN-α Inducing Activity

Abstract

Tilorone dihydrochloride (1) has great potential for inducing interferon against pathogenic infection. In this paper, we describe a convenient preparation method for 2,7-dihydroxyfluoren-9-one (2), which is a usual pharmaceutical intermediate for preparing tilorone dihydrochloride (1). In the novel method, methyl esterification of 4,4 1 -dihydroxy-[1,1 1 -biphenyl]-2-carboxylic acid (4) was carried out under milder conditions with higher yield and played an important role in the preparation of compound 2. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS, and 1 H-NMR. Furthermore, the synthesized tilorone dihydrochloride exhibited an obvious effect on induction of interferon-α (IFN-α) in mice within 12 h, and the peak level was observed until 24 h. This fruitful work has resulted in tilorone dihydrochloride becoming available in large-scale and wide application in clinics, which has a good pharmaceutical development prospects.

Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond

“…Tilorone was originally synthesized and developed at the pharmaceutical company Merrell Dow which is now part of Sanofi (8). The synthesis has been improved upon in recent years (9). Tilorone is currently used clinically as an antiviral in several countries outside the USA and is sold under the trade names Amixin® or Lavomax®.…”

Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection

“…Tilorone has been known for decades to be an immunomodulator both in vivo [75, 76] and in vitro [77], but this modulation had been previously understood to be through the stimulation of type I IFN expression. Our data suggests that tilorone may also have a more complex action by activating many different pathways associated with the immune system, with a statistically significant increase in observed protein concentrations in tilorone-treated unchallenged mice over both vehicle-treated and naïve mice in 9 of the 23 chemokines/cytokines tested (S5 Fig).…”

“…It is noted that there is a statistically significant difference between the pyronaridine 75 mg/kg and 50 mg/kg groups in the plaque assay, with respective geometric means of 9.13 x 10 2 and 3.49 x 10 4 PFU/ml (Tukey’s HSD test). Since there is strong evidence from previous studies that showed tilorone is an immunomodulator [75–77], this indicates that the mechanism of action against maEBOV is likely to be at least partly due to the host immune response. We now show for the first time an increase in nearly all of the cytokine and chemokines tested in the tilorone-treated, unchallenged group (S5 Fig).…”

Interferon‑α and its effects on cancer cell apoptosis (Review)

“…It was previously demonstrated that in vivo treatment of wild-type mice with TAK-981 upregulates the gene expression of IFN-α and -β in blood cells and splenocytes ( 31 ). Tilorone dihydrochloride is the first synthetic, orally active, low-molecular weight compound that can significantly induce IFN-α in vivo within 24 h of administration ( 32 , 33 ). It was previously reported that in patients with Sézary syndrome, TLR7/8 agonists induce inflammatory cytokines.…”