DEVELOPMENT OF EFFECTIVE ANTIVIRAL AGENTS OF A NEW TYPE

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DEVELOPMENT OF EFFECTIVE ANTIVIRAL AGENTS OF A
NEW TYPE

• Professor
• Oleg Shadyro
• Belarusian State University
• Department of Chemistry, Minsk, Belarus
• shadyro_at_open.by

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The main goal of the study was the development
of antivital agents based on the substances
capable of regulating various types of free
radical reactions.





3
Some time ago, we have developed an antiviral
product Butaminophen? that has proven to be
effective against herpetic injuries of various
types.

• Advantages of the product / technology
• The Product
• is an effective anti-herpetic agent,
• particularly against strains resistant to
  acyclovir,
• it possesses also wound-healing,
  anti-inflammatory and antipyrotic action.
• The Technology
• is simple and easy to put into practice,
• is a low-cost manufacturing process,
• the starting raw material is readily available.

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A general scheme depicting synthetic pathways to
obtain some sterically hindered aminophenol
derivatives
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Membrane structure
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Lipid peroxidation process
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Free-radical fragmentation of cardiolipin

• Shadyro O.I., Yurkova I.L., Kisel M.A., Brede O.,
  Arnhold J. Radiation-induced fragmentation of
  cardiolipin in a model membrane. International
  Journal of Radiation Biology, 2004, 80, 239-245.
• Shadyro O.I., Yurkova I.L., Kisel M.A., Brede O.,
  Arnhold J. Radiation-induced free-radical
  transformations of Phospholipids MALDI-TOF MS
  study. Chemistry and Physics of Lipids, 2004,
  132, 235-246.

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Free-radical fragmentation of cerebrosides

• Shadyro O.I., Yurkova I.L., Kisel M.A., Brede O.,
  Arnhold J. Formation of phosphatidic acid,
  ceramide and diglyceride on radiolysis of lipids
  identification by MALDI-TOF mass spectrometry.
  Free Radical Biology Medicine, 2004, 36,
  1612-1624.
• Shadyro O.I., Yurkova I.L., Kisel M.A., Arnhold
  J. Free-radical fragmentation of
  galactocerebrosides a MALDI-TOF mass
  spectrometry study. Chemistry and Physics of
  Lipids, 2005, 134, 41-49.
• Shadyro O.I., Yurkova I.L., Kisel M.A., Arnhold
  J. Iron-mediated free-radical formation of
  signaling lipids in a model system. Chemistry and
  Physics of Lipids, 2005, 137, 29-37.

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A new approach to the regulation of free-radical
processes in biosystems has been proposed
Diphenol and aminophenol derivatives were found
to be capable of regulating free-radical
transformations occurring in bioorganic compounds
with participation of both oxygen-centered
(oxidation) and carbon-centered (fragmentation)
radicals.
Shadyro O.I. et al. Quinones as free-radical
fragmentation inhibitors in biologically
important molecules. Free Rad. Res., 2002, 36,
859-867. Shadyro O.I., Murase H., Kagiya T. et
al. Effects of phenolic compounds on reactions
involving various organic radicals. Free Rad.
Res., 2003, 37, 1087-1097. Shadyro O.I. et al.
Reactions of arylamine and aminophenol
derivatives, and riboflavin with organic
radicals. Free Rad. Res., 2004, 38, 1183-1190.
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Percent inhibition produced by aminophenols in
reactions involving various radicals
Test compounds Structure gtCHOO? gt?CH gt?CHOH
N-1 28 81 92
N-2 48 44 45
N-3 48 44 34
N-4 49 34 41
N-5 33 77 78
N-6 17 81 76
N-7 58 83 80
N-8 1,2 4,6 0,8
N-9 9,1 8,3 2,3
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Effective concentrations of aminophenols
inhibiting the zymosan-stimulated production of
ROS by macrophages
Test compounds Structure Concentration range, ?M EC50, ?M EC90, ?M
N-1 0.001-10 0.06 0.65
N-2 0.001-10 No inhibition No inhibition
N-3 0.001-10 No inhibition No inhibition
N-4 0.001-10 No inhibition No inhibition
N-5 0.001-10 9.8 gt 10
N-6 0.001-10 No inhibition No inhibition
N-7 0.001-10 No inhibition No inhibition
N-9 0.001-10 No inhibition No inhibition
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Antiviral properties of the test compounds in a
cell culture infected with HSV
Test compounds Structure MNTC, ?M EC50 (I95), ?M EC90 (I95), ?M
N-1 113.2 87.3 (214.9?35.3) 288.2 (709.9?117.2)
N-2 379.7 8.5 (10.5?6.9) 14.8 (18.2?12.1)
N-3 720.9 38.2 (41.3?35.3) 64.5 (69.6?59.5)
N-4 686.2 8.6 (10.3?7.2) 14.1 (17.2?11.7)
N-5 336.7 23.0 (56.4?9.4) 169.4 (316.2?90.9)
N-6 643.1 30.9 (37.0?25.7) 83.0 (99.4?69.1)
N-7 611.6 18.0 (22.4?14.5) 41.9 (52.3?33.6)
N-8 1444.0 798.0 (1053.8?604.3) 1960.5 (2588.8?1484.8)
N-9 722.0 255.2 (569.2?114.4) 623.8 (1373.9?283.3)
I95 is confidence interval at 95 probability.
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Antiviral properties of the test compounds in
mice infected with skin herpes
Wounds in places of vesicle formation
Erythema and vesicles
Normal ear
Erythema
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Chemico-pharmacological advantages of compound
N-2 as compared to Butaminophen

• Lower toxicity
• Higher antiviral activity against herpes viruses
• Higher chemical stability

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Antiviral activity of compound N-2 against
influenza A/FPV/Rostok (H7N1) virus in chicken
embryo cell culture
Compound code Concentration, ?M Titer of virus, lg PFU/ml EC50, ?M MNTC/ EC50
N-2 759 380 190 48 24 12 0 4.2 4.5 4.6 4.7 5.4 5.5 5.5 43.6 17.4
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Antiviral activity of compound N-12 against HIV-1
in a cell culture
Compound code Concentration, ?M Percent of infected cells EC50, ?M MNTC/ EC50
N-12 876 221 55 14 0 12 27 32 41 96 7.9 111
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Conclusions

• The obtained data indicate that sterically
  hindered aminophenol derivatives possess
  antiviral properties and hence may be regarded as
  a novel class of antiviral agents.
• Among the compounds tested, the most pronounced
  antiviral properties were found for N-acyl and
  N-aryl dertivatives of sterically hindered
  o-aminophenol which were able to interact with
  various organic radicals while displaying low
  reactivity towards reactive oxygen species.