SYNTHESIS AND PREDICTION OF THE SPECTRUM OF BIOLOGICAL ACTIVITY 3-(8-BENZODIOXOCIN - 1,6 - IL) COUMARIN

ABSTRACT

The article discusses the modified synthesis of new chemical compounds of 3-heteroaryl-coumarins with 1,6 - benzodioxocine fragments with a more convenient and effective method under the conditions of the Knoevenagel reaction. Some physicochemical constants have been studied. РMR spectra of benzodioxocine fragments are presented. The results of the forecast of the spectrum of biological activity, the forecast of possible side and toxic effects based on clinical manifestations were studied using an improved method of an online computer system. The results allow us to recommend modified substances for the development of complex drugs.

АННОТАЦИЯ

В статье рассматривается модифицированный синтез новых химических соединении 3-гетероарил-кумаринов с 1,6 - бензодиоксоциновыми фрагментами с более удобным и эффективным способом в условиях реакции Кнёвенагеля. Изучены некоторые физико-химические константы. Представлены ПМР спектры бензодиоксоциновых фрагментов. Результаты прогноза спектра биологической активности, прогноз возможных побочных и токсических эффектов, основанные на клинических проявлениях были изучены усовершенствованным способом компьютерной системы онлайн. Результаты позволяют рекомендовать модифицированные вещества к разработке комплексных лекарственных препаратов.

Keywords: synthesis, coumarin, benzodioxocin fragment, Knoevenagel reaction, biological activity.

Ключевые слова: синтез, кумарин, бензодиоксоциновый фрагмент, реакция Кнёвенагеля, биологическая активность.

Introduction. Research into the chemical structure and mechanism of action of natural biologically active substances and the identification of potential drugs among them is becoming increasingly important every year. The creation of highly effective medications with a wide range of biological effects and low toxicity is a problem of paramount importance.

One of the classes of heterocyclic compounds, many of whose representatives have all the necessary properties of medical drugs, are flavonoids, coumarins and isomeric isoflavonoids, which represent a large and unique group of natural compounds with a wide range of biological effects. Flavonoids, coumarins and isoflavonoids exhibit significant physiological activity and are non-toxic, therefore they are widely used for medicinal purposes.

Synthetic products, in particular modified flavonoids, are becoming increasingly important. In their molecules, the phenyl group is replaced by other radicals, including heterocyclic residues of predominantly aromatic nature. Such compounds are convenient precursors and models for the design of effective drugs with a different spectrum of physiological action based on them.

Oxygen-containing heterocyclic systems of pyran, dioxol, dioxane and their benzo analogues are widespread in nature. The 1,3-benzodioxole and 1,4-benzodioxane rings are structurally included in many phenolic compounds, even coumarins, which have a wide spectrum of biological activity and their own fluorescence, sensitive to changes in environmental conditions, belong to them.

Previously by the authors [1; 2] 3-heteroaryl-coumarins with 1,3-benzodioxole, 1,4-benzodioxane and 1,5-benzodioxepane fragments were synthesized. When carrying out primary screening for antimycobacterial activity with the resulting compounds in [3; 6] it was noted that unsubstituted 3-heteroaryl-coumarin with a 1,5-benzodioxane fragment was more active (86%) than with 1,3-benzodioxole and 1,4-benzodioxane fragments.

From the results obtained it is clear that these particular compounds can be modified to achieve antimycobacterial activity of up to 90% or more, they are promising in terms of the synthesis of anti-tuberculosis drugs based on them.

Thus, the presence of an unsubstituted hetaryl fragment in the structure of synthetic coumarin analogues contributed to the search for the preparation of a 3-heteroaryl-coumarin analogue with an expansion of the size of the heterocycle in the B ring, sensitive to changes in environmental conditions.

Materials and methods. A more convenient and effective way to obtain this compound is synthesis under the conditions of the Knoevenagel reaction, which occurs under milder conditions and with higher yields [1; 4].

A mixture of 10 mmol of heteroarylacetonitrile (2), 10 mmol of the corresponding aldehyde (1), 0.12 ml of piperidine and 10 ml of 95% ethanol was boiled for 5-6 hours. Then the reaction mixture was hydrolyzed with 5 ml of 2 N. hydrochloric acid for 1 hour. After cooling, the precipitate was filtered and washed with a 1% aqueous solution of NaHCO₃. The residue was crystallized from ethyl acetate (Fig. 1).

The course of the reaction and the purity of the resulting compounds (3) – (7) were monitored by thin layer chromatography on standard Silufol UV-254 plates in the benzene: ethanol (9:1) system, the spots were detected in ultraviolet light.

The resulting compounds (3) – (7) are colorless crystalline substances, highly soluble in most organic solvents and insoluble in water. Easily detected by blue fluorescence under UV light. Elemental analysis was carried out on a device for the microdetermination of carbon, hydrogen and halogen. The elemental analysis data for the compounds corresponded to those calculated (Table 1). PMR spectra were recorded on a Tesla-100 device at CDC1₃ (Table 2).

Figure 1. Synthesis of 3-hetaryl-coumarins with benzodioxocin fragment (3) – (7) under the conditions of the Knoevenagel reaction

  Table 1.

Some physicochemical constants of synthesized 3-hetaryl-coumarins with a benzodioxocine fragment (3) – (7)

Table 2.

PMR spectrum of 3-hetaryl-coumarins with benzodioxocin fragment (3) – (7)

The PASS online computer system (a program for predicting the spectrum of biological activity of substances) [5] made it possible to predict the spectrum of biological activity of a substance based on its structural formula, including pharmacological effects, mechanisms of action, toxic and drug-like side effects. It was shown that the efficiency of using this approach in screening a synthesized new substance (3) in comparison with other substances (4) – (7) was over 80% (Fig. 2).

The forecast results include activity names and probability estimates (Pa) of “to be active.”

Figure 2. Prediction of the spectrum of biological activity of the chemical compound 3-(8 - benzodioxocin - 1,6 - yl) coumarin (3)

The prediction of possible side and toxic effects of compound (3) showed over 70%, based on clinical manifestations, which are sometimes observed in several or even one patient (Fig. 3).

Figure 3. Prediction of possible side and toxic effects of the compound 3-(8 - benzodioxocin - 1,6 - yl) coumarin (3)

Conclusion. The synthesized new compounds 3-heteroaryl-coumarins with 1,6-benzodioxocinic fragments, an expanded size of the heterocycle in the B ring, which in the future can serve as the basis for an anti-tuberculosis drug, additionally predict other biologically active activities in which our compounds should be studied. By changing the structure of coumarin molecules, it is possible to increase the absolute indicators of their activity in biological tests.

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