Kisteniuk N.S., Skrotska O.I.

National University of Food Technologies, Ukrainian

Tyloronu analogs as antiviral agents

 

Years of experience in the clinical use of interferon (IFN) preparations revealed their effectiveness for prevention and treatment. However, in clinical use of these drugs was found deficiencies of their application.

Ø                Formation of anti-interferon antibodies that neutralize exogenous IFN.

Ø                With an overdose of exogenous IFN may have side effects.

Ø                Rates of treatment by preparations IFN are extremely expensive [1, 2].

The main method to eliminate such shortcomings is the use of interferon inducers (IIFN). The most known representative of inducers IFN is synthetic tilorone. (2,7-bis[2-(diethylamino)ethoxy]-9H-fluoren-9-one) Figure 1. In Ukraine first tiloron was synthesized O. Bogatsky and staff by technology [3]. And implemented by into medical practice as the drug Amixin IS (JSC "InterChem").

C:\Natali\2 семестр\СТЕНД\TiloroneHCl.png

Figure 1. 2,7-bis[2-(diethylamino)ethoxy]-9H-fluoren-9-one

Predecessor of tilorone is fluorene Figure 2 and fluorenon Figure 3, which is not able to of inducing the synthesis of IFN. However, derivatives of fluorene and fluorenon turned biologically active substances that suppress the development of many virus infections [1].

 

C:\Natali\2 семестр\СТЕНД\флуоренон.png 

Figure 2

C:\Natali\2 семестр\СТЕНД\флуорен.png

Figure 3

Were carried out numerical studies of new derivatives tilorone. As a result, the study of derivatives 28 tilorone antiviral activity detected in dihydrochloride bis [dybutylaminopropil] -9 oksofluoren--2,7-dicarboxylate Figure 4.

Y = СОО

X = -(СН2)2

R' = n-С4Н9

Q = О
 
C:\Natali\5 курс Я магістр\Статті\media\image3.png

Figure 4. dihydrochloride bis [dybutylaminopropil] -9 oksofluoren--2,7-dicarboxylate

Also is described is shown interferonindukuyucha synthesis and active in of 2,7-bis-2 (4-aza-tricyclo [4,3,1,13'8] -undets-4-yl)-9H-ethoxy fluo- ren-9-one Figure 5. Same time is not fixed interferonindukuyucha activity in vitro separate from the nucleus or side chain fluorenonovoyi system. Recently shown erferonogenie activity glycoside derivative fluorenolu-9, and the authors associate it with intercalation ability of the drug [4].

C:\Natali\5 курс Я магістр\Статті\media\image3.png

Figure 4. 2,7-bis-2(4-aza-tricyclo [4,3,1,13'8] -undets-4-yl)-9H-ethoxy fluoren-9-one

So, for the manifestation interferonindukuyuchoyi and antiviral activity of these compounds necessary condition is the presence of side chain molecules of the two groups with basic properties (eg. amines) and the presence of a central system lipophilic aromatic nature. But, later found compound 2,7-dietoksyfluorenonu who had high interferonindukuyuchu activity Figure 6 and compound - 2,7-di (adaman- tan-1 oyiloksy) fluorenonu Figure 7, which had high antiviral activity. Therefore the precondition is reduced to nothing regarding of basicity of side chains [1].


C:\Natali\5 курс Я магістр\Статті\media\image3.png

C:\Natali\5 курс Я магістр\Статті\media\image3.png

Figure 6. 2,7-dietoksyfluorenonu

Figure 7. 2,7-di (adaman- tan-1 oyiloksy) fluorenonu

In particular, the conditions shown in vitro antiviral and immune-modulating activity for 9 fluorenon-4-carboxamides Figure 8 [6], β-O-glucosides 9 fluorenon-2-karbohidrokyeesteriv [7], 2/4-substituted-9 -fluorenoniv and their O-glucosides [8].

глюкозидів [8].

Тable 1. 9 fluorenon-4-carboxamides

Сотр.

К

Сотр.

К

1

(СН2)2ОН

6

(СН2)2N(СНз)2

2

(СН2)3ОН

7

(СН2)зN(СНз)2

3

СН2СНОНСН3

8

(СН2)2N(СН2СН3)2

4

(СН2)4ОН

9

(СН2)2N      O

5

(СН2)2О(СН2)2ОН

10

(СН2)3N      O

C:\Natali\5 курс Я магістр\Статті\media\image2.jpeg

 

Figure 8. 9 fluorenon-4-carboxamides

 

In a study conducted in the Department interferon problems and immunomodulators Institute of Microbiology and Virology. DK Zabolotnogo NAS of Ukraine, was conducted a large-scale screening of compounds which resulted in been selected most active and least toxic compounds Figure 9, 10.

C:\Natali\2 семестр\СТЕНД\TiloroneHCl11.png

Figure 9. 4,4-bis [2 (diatylamino) ethoxy] biphenyl dihydrochloride

C:\Natali\2 семестр\СТЕНД\тилорон 2.gif

Figure 10. 2-methoxycarbonyl-4-4 bis [2 (diatylamino) ethoxy] biphenyl dihydrochloride

Biphenyl derivatives relate up to amphiphilic compounds with clearly established polar and nonpolar domains. Their molecules include nonpolar hydrophobic domain, which includes aromatic rings, and two are symmetrical hydrophilic lateral chains are positively charged under physiological pH. This chemical structure allows the investigated compounds effective impact on cell surface. Currently IIFN have taken a worthy place in the therapy of virus infections as antiviral drugs and correctors immunity [9].

Were synthesized numerous series of heterocyclic analogues tilorone bis-base (Figure 11) carbazole, dibenzofurans, dybenzotiofeny; phenanthrene, fenantrydyny, dybenzopirany, xanten and acenaphthene [10].

 

 

Тable 2 bis-base  analogues tilorone

Сотр.

Назва

К

1

(1) karbozoly

X = NН

2

(1) dibenzofurans

X = O

3

(1) dibenzotiofeny

X = S

4

(2) fenanthrene

X = CH

5

(2) fenantrydyny

X = N

6

(3) dybenzopirany

X = O

7

(4) ksksanteny

X = O

8

(1) dimethylamino acetyldybenzotiofen

X = S

R = -СО-СН2-N(СН3)2

9

 

(1)dimethylamino acetyldybenzofurans

X = О

R = -СО-СН2-N(СН3)2

image5

1

image5

2

 image5

3

image5

4

image5

де Y = О; СН2; СО; СОО; S; СS; СS0; Z = (СН2)n; R1 - alkyl, або NR1R1- N – containing heterocycle

Figure 11. bis-base  analogues tilorone

Among them the most interferonindukuyuchu activity showed diethylaminopropilfluoranten (Figure 12), and dimethyl dimethylaminoatsetyldybenzot aminoatsetyldybenzofuran [11].

 

R = (СН2)3N(С2Н5)2

 
 
image5   

Figure 12. diethylaminopropilfluoranten

Thus, today a large number of have been synthesized derivatives tilorone which can be used as of inductors IFN, but only some of them were appropriate for clinical use. Most of inductors IFN through toxicity, lack scrutiny of and high cost in medical practice is not used. Therefore an urgent task today is the search and creation drugs interferon of inductors deprived of their mentioned deficiencies.

 

 

References:

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