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Вінницька Р.Б., Крвавич А.С., Конечна Р.Т., Литвин Б.Я., Стадницька Н.Є., Марінцова Н.Г., Новіков В.П. Синтез нових азотовмісних гідроксинаф
14.05.2014, 15:28

Резюме

Вінницька Р.Б., Крвавич А.С., Конечна Р.Т., Литвин Б.Я., Стадницька Н.Є., Марінцова Н.Г., Новіков В.П. Синтез нових азотовмісних гідроксинафтохінонів – синтетичних аналогів природнього шиконіну і юг лона та їх фунгіцидна активність.

Наведено результати дослідження одержання азотовмісних синтетичних аналогів природного шиконіну і юглону та їх скринінг на фунгіцидну активність.

Ключові слова: шиконін, юглон, синтетичні аналоги, фунгіцидна активність.

Резюме

Винницкая Р.Б., Крвавич А.С., Конечная Р.Т., Литвин Б.Я., Стадницкая Н.Е., Маринцова Н.Г., Новиков В.П.

Синтез новых азотосодержащих гидроксинафтохинонов - синтетических аналогов природного шиконина и юглона и их фунгицыдная активность

Приведены результаты исследования получения азотосодержащих синтетических аналогов природного шиконина и юглона и их скрининг на фунгицидную активность.

Ключевые слова: шиконин, юглон, синтетические аналоги, фунгицыдная активность.

Summary

Vynnytska R.B., Krvavych A.S., Konechna R.T., Litvin B.J., Stadnytska N.E., Marintsova N.G., Novikov V.P.

Synthesis of new nitrogen hydroxynaphthoquinones - synthetic analogues of natural shikonin and juglone and their fungicidal activity.

The results of studies of the production of nitrogen-containing synthetic analogues of natural shikonin and juglone and screening of their fungicidal activity were presented.

Key words: shikonin, juglone, synthetic analogues, fungicidal activity.

Література
1. Доброчаева Д.Н. Бурачниковоцветные (Boraginales Hutch.) Европейской части СССР: дисерт. на соиск. учен. степ. д.б.н. / Д.Н. Доброчаева. – Киев, 1977. - С. 269-290.
2. Растительные ресурсы СССР. Цветковые растения, их химический состав, использование / Под. ред. Соколова П.Д. – Л.: Наука, 1990. - С. 109-133.
3. Меденцев А.Г. Нафтохиноновые метаболиты грибов / А.Г. Меденцев, В.К. Акименко // Прикладная биохимия и микробиология. - 1996. - Т.32, № 1. - С. 10-33.
4. Vogel R. Buchner Neues Repert / R. Vogel, C. Reischauer. - FürPharm., 1856, Bd.5. – 106 р.
5. Доналдсон Н. Химия и технология соединений нафталинового ряда / Н. Доналдсон. - М: Госхимиздат, 1963. – 656 с.
6. Методические рекомендации по определению фунгицидной активности новых соединений. - Черкассы: ВНИИХСЗР, НИИТЭЗИМ, 1994. – С. 4-26.

УДК 547.655.6

SYNTHESIS OF NEW NITROGEN-CONTAINING HYDROXYNAPHTHOQUINONES SYNTHETIC ANALOGIES OF NATURAL SHIKONIN AND JUGLONE AND THEIR FUNGICIDAL ACTIVITY

R.B. Vinnytska, A.S. Krvavych, R.T. Konechna,
B.Y, Lytvyn, N.Y. Stadnytska,
N.G. Marintsova, V.P. Novikov

Lviv Polytechnic National University

Introduction

Shikonin (1) is strong antibiotic of naphthazarin series, which doesn’t cause allergic reactions, habituation and has antibacterial, wound healing, anticancer and anti-inflammatory properties. It is obtained from several rare plants of the family Boraginaceae, namely Lithospermum erythrorhizon and Armebia euchroma [1,3].

Juglone (2) has cytotoxic, antimicrobial, antiseptic and preservative actions and is contained in the green peel of walnut (Juglans regia) [4,5] in the form of 1, 4, 5-trihydroxynaphthalene.

 Aim of the work: Production of synthetic nitrogen-containing analogues of shikonin (1) and juglone (2) and the primary screening of their fungicidal activity.

Materials and methods

2,3-Dichlorojuglone (3a) and 2,3-dichloronaphthazarin (3b), purchased from Merck, were used as objects in the study. During the experiment, all nitrogen-containing synthetic analogues (5a-d) were prepared by the following procedure: 0,01 mol of allylamine or leucine in 100 ml ethanol solution was gradually supplemented to the suspension of 0,005 mol of dichloroquinones (3a, b) and 0,02 mol of K2CO3 in 100 ml ethanol solution for 30 min with vigorous stirring, the mixture was kept boiling for 2 h, then cooled. 2/3 of the solvent were evaporated in vacuum, mixture was cooled, the crystals, which have formed, were filtered, washed with water (3 × 100 mL) and dried in vacuum. The yield of red crystals – 85-95%. Physico-chemical properties were determined and 1H NMR and IR spectra were recorded for the new products (Table 1).

Screening of fungicidal activity was carried out by the standard method [6] using 5 species of fungi: Fusarium oxysporum, Helminthosporium sativum, Penicillium expansum, Botrytis cinerea, Aspergillus niger. shikonin (1), juglone (2), dichloronaphtoquinone (3) and TMTD (tetramethylthiuramdisulfid) were used as standards. Accuracy of the results on activity varied within ± 2 %.

Antifungal activity of the studied compounds was determined by evaluation of inhibition of growth of fungi mycelium colonies in vitro. For this purpose potato dextrose agar medium with pre-introduced ​​acetone solution of the studied substance to get 0,003% concentration in medium, was poured into a Petri dish. After 24 h after acetone evaporation the inoculation of spores of the test fungi cultures (105 spores/ml) was carried out. The inoculated dished were placed for incubation into a thermostat at 22-25°C. Counting was performed after 72 h by determining the growth rate of fungi colonies compared with controls.

 

Results and discussion

Use of dichlornaphthoquinones (3a, b) as initial products, in the reactions of nucleophilic substitution of one of the chlorine atoms on the amine residue ultimately leads to production of aminoderivatives (4a-d) - synthetic nitrogen-containing analogues of natural shikonin (1) and juglone (2). 3.3-Dimethylallylamine and amino acid leucine were used as the amine component in these interactions.

Composition and structure of the obtained compounds (4 a-d) has been confirmed by the results of elemental analysis, thin layer chromatography and spectral data (Table 1). In the IR spectra allylaminoderivatives (4a, b) there are characteristic absorption bands of hydroxyl groups in the region 3600-3480 cm-1, bond N-H – at 3380 and 3408 cm-1 , intense bands of valence vibrations of quinoid carbonyl groups at 1686-1640 cm-1 for (4a) and (4b) respectively, and absorption bands corresponding to C-Cl at 7070 cm-1. The IR spectra of amino acid derivatives (c, d) were similar also containing intense absorption band of the C=O bond of carboxyl group at 1730-1728 cm-1. The ¹H NMR spectra of the products (5a-d) contain all the signals of protons, and their intensity indicators correspond with those referring protons.

Table 1. Physico-chemical constants of the synthesized hydroxynaphtoquinones (4 a-d)

##

No.

of substance

Yield,

%

Melting point,

ºС

Rf*

IR, сKBr, cm-¹

¹H NMR (b, m.p., Hz)

1

90

206-207

0,56

3600-3480, 3380, 1686, 1664, 1610, 1590, 1530,

1240, 790

1.65 s (3H, CH3),

1.71 s (3H, CH3),

2.48 m (2H, CH2),

4.62 m (1H, -CH=),

5.63 s (NH),

7.32 s (2H6,7),

7.70 s (1H8),

12.42 s (H, OH)

2

4b

89

215-217

0,43

3600-3450, 3374, 1672, 1456, 1608,

1592, 1525, 1230, 786

1.61 s (3H, CH3),

1.70 s (3H, CH3),

2.47 m (2H, CH3),

4.60 m (1H, -CH=),

5.60 s (NH),

7.36 s (2H6,7),

12.40 s (H, OH)

12.46 s (H, OH)

3

4c

95

186-187

0,72

3600-3400, 3360, 1730, 1686, 1660,

1608, 1590,

1510, 1238, 764

1.64 s (3H, CH3),

1.73 s (3H, CH3),

2.45 m (2H, CH2),

4.62 m (1H, -CH=),

5.58 s (NH),

7.38 s (2H6,7),

7.68 s (1H8),

12.38 s (1H, OH)

12.46 s (1H, OH)

4

4d

85

198-200

0,67

3600-3400, 3372, 1728, 1682, 1664, 1610, 1596, 1525, 1236, 770

1.65 s (3H, CH3),

1.70 s (3H, CH3),

2.48 m (2H, CH2),

4.63 m (1H, -CH=),

5.61 s (1H, NH),

7.34 s (2H6,7),

12.38 s (1H, OH)

12.46 s (1H, OH)

* TLC eluent – C2H5OH:CH3COOH:n-C4H9OH = 2:2:1.

The preliminary screening of the synthesized analogues (4a-d) have shown that they belong to the low-toxic compounds for hematothermal animals (LD50 is in the range 700-1000 mg/kg) and, therefore, it was interesting to determine and compare the biological activity of newly synthesized hydroxynaphthoquinones (4a-d) with natural shikonin (1) and juglone (2). The fungicidal activity was selected as a characteristic parameter. The results are presented in Table 2.

 

Table 2. Fungicidal activity of the synthesized substances*

##

No. of the substance in text

Inhibition of the growth of fungal mycelium, % to control

F.oxysporum

H.sativum

P.expansum

B.cinerea

A.niger

1

4a

92

89

93

84

94

2

94

96

100

98

100

3

83

86

98

90

92

4

92

90

86

87

100

5

1

86

82

90

95

100

6

2

78

84

100

90

100

7

3

dichloro-naphtoquinone

65

65

80

80

65

8

TMTD

90

90

100

95

100

As can be seen from the results in the Table 2 naphthazarin derivatives (4b, d) surpass not only comparison models - natural quinones (1, 2), but also performance standards – dichloronaphtoquinone and TMTD by the strength  of fungicidal activity. Thus, the synthesized nitrogen-containing hydroxynaphthoquinones (4a-d) have rather strong antifungal action.

It should be noted that the presence of chlorine atom in naphthoquinone molecules contributes, in our opinion, to the strengthening of antimicrobial action.

Conclusions

  1. The simple and convenient preparative method of obtaining new nitrogen-containing hydroxynaphthoquinones - synthetic analogs of natural shikonin and juglone was developed.
  2. It was determined that the synthesized naphthazarin and juglone derivatives naftazarynu and possess strong fungicidal activity.
  3. The results indicate the prospects of further development of the research for both search of the ways of synthesis of new compounds of this series, and biological screening of the obtained analogues by other types of activity.

References

1.Dobrochaeva D.N., Borage pants (Boraginales Hutch.) of the European part of the USSR. Doctoral thesis. Institute of botanics. Kiev, 1977. p. 269-290.
  1. Plant Resources of the USSR. Flowering plants, their chemical composition, application / Ed. Sokolova P.D. Leningrad: Nauka. 1990. p. 109-133.
  2. A.G. Medentsev, V.K. Akimenko. Naphthoquinonic metabolites of fungi. Applied Biochemistry and Microbiology, 1996. Vol. 32, No. 1. p. 10-33.
  3. Vogel R. u. Reischauer C.- BuchnerNeuesRepert. FürPharm., 1856, Bd5, b.106.
  4. N. Donaldson. Chemistry and technology of the naphthalene series compounds. M: Goskhimizdat 1963.- 656 P.
  5. Methodical guidelines on the determination of the fungicidal activity of new compounds.-Cherkassy: VNIIHSZR, NIITEZIM, 1994-4-26 P.

 

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