Received: November, 2015

DOI 10.17677/fn20714807.2016.02.03

Fluorine Notes, 2016, 105, 5-6

FLUORINE INFLUENCE ON PHARMACEUTICAL ACTIVITY OF TRIUROCYL DERIVATIVES

Е.S. Titova¹, P.M. Vassiliev², А.I. Rakhimov¹, V.V. Vorfolomeeva², L.R. Yanalieva²

¹Volgograd State Technical University, 400131, Russia, Volgograd, Lenin prospect, 28
e-mail: titova051@rambler.ru

²Volgograd State Medical University, Russia, 400131, Volgograd, sq. Pavshikh Borzhov, 1,
e-mail: pvassiliev@mail.ru

Abstract: Consensual forecast of pharmaceutical activity of 5-[4-(N,N-dimethylamino]-2-trioxohydropyrimidine-4,6-(1Н,5Н)-dione and its fluorine derivatives is made in the system PASS, IT «Microcosm», by doking method in AutoDock Vina and by quantum chemical QSAR-simulation method in order to discover a new perspective antidiabetic agents.

Keywords:5-[4-(N,N-dimethylamino)phenylmethylene]-2-trioxodihydriopyrimidine-4,6-(1Н,5Н)-dione and its fluorine derivaties, inhibitors glycogen phosphorylases, inhibitors α-glycocidases, inhibitors of nonenzymatic glycation of proteins, consensual forecast.

1. Introduction

Triurocyl derivatives have a wide range of biological activity [1,2],that is due to the properties of their electronic structure [3-8].

A non-insulin dependent diabetes (TYPE 2) has the form of the group of heterogeneous distortion of carbohydrate metabolism disorder, which one is due to insulin resistance, insulin secretory function of pancreatic disorder and the glucose escape in the liver. The prevalence of diabetes has reached epidemic proportion as in the world and in Russia at the present time. [9].

A hepatic form of glycogen phosphorylase (PYGL) is mostly involved into glucose homeostatic in the body and it is the object for therapeutic intervention at TYPE 2 [10]. The decreasing activity of PYGL is significantly reduced hyperglycosemia, which one does not lead to hyperglycosemia [11]. Therefore a search of antidiabetic drugs among PYGL inhibitors is of immediate interest.

α-glycocidase (MGAM) is settled in small bowel and catalyzing hydrolytic degradation of di-, oligo- and polysaccharides. The inhibitors MGAM blocks this process slowing down the absorption of monosaccharides, as a result a postprandial blood glucose is reduced (postprandial hyperglycosemia caused by eating) [12].

A nonenzymatic glycation of proteins becomes more strong at diabetes due to chronic hyperglycaemia, which is caused to different difficult complications, such as nephroparthy, encephaloparthy and others. That is why the search of inhibitors for Maillard reaction (MRI) is perspective direction of a new type of antidiabetic drugs creation [13].

2. Experimental

As a new perspective antidiabetic agents we considered the functional derivatives of triurocyl: 5-[4-(N,N-dimethylamino)phenylmethylene]-2-tioxodihydropyrimidine-4,6-(1Н,5Н)-dione (I) and its fluorine derivatives, where is fluorine atom in о- and m-positions towards to N,N-(dimethylamino)-group (II) and (III) respectively.

 

The effect of fluorine atom on the electron density of thiopyrimidine cycle differs in o - and m-positions. The conjugation of lone electronic pair of fluorine and nitrogen atoms with p-electronic system of aromatic rings is decreased along with the removal of fluoride from o - to m-position to N,N-(dimethylamino)-group. Negative inductive effect of the fluorine atom appears both in (II) and (III).

We made a consensual forecast of pharmaceutical activity of compounds (I) - (III) in the system PASS [14], in IT «Microcosm» [15, 16], by doking method in AutoDock Vina [17] and by quantum chemical QSAR-simulation method [18]. According to the forecast of investigated compounds it is expected the presence of activity as the inhibitors of non-enzymatic glycation of proteins (MRI), inhibitors glycogen phosphorylases (PYGL), inhibitors α-glycocidases (MGAM). The calculation date are provided in the table 1.

Table 1. The results of a consensual forecast of pharmaceutical activity of triurocyl derivatives.

Compound	Activity	Consensus type	Estimated figure	Value of estimated figure
(I)	MRI	PC1QM	Ind	1.00
			Fb	0.4002
			Rank	3.33
	PYGL	PC1Dock	Ind	0.40
			Fb	0.1615
			Rank	3.20
	MGAM	PC2	Ind	0.86
			Fb	0.3335
			Rank	3.00
(II)	MRI	PC1QM	Ind	1.00
			Fb	0.4002
			Rank	3.33
	PYGL	PC1Dock	Ind	0.30
			Fb	0.1293
			Rank	2.70
	MGAM	PC2	Ind	0.86
			Fb	0.3335
			Rank	3.00
(III)	MRI	PC1QM	Ind	1.00
			Fb	0.4002
			Rank	4.00
	PYGL	PC1Dock	Ind	0.30
			Fb	0.1293
			Rank	2.40
	MGAM	PC2	Ind	0.71
			Fb	0.2918
			Rank	3.71

Reference.
PCK1_QM – partial key consensus of the first level: two positive forecast evaluations from three one, at normative positive evaluation by quantum chemical QSAR-simulation method.

PCK1_Dock – partial key consensus of the first level: two positive forecast evaluations from three one, at normative positive evaluation by doping method.

PC2 – partial key consensus of the second level: three positive forecast evaluations from four equal one.

Ind – average grade of perceptivity of activity presence (the most best value = 3, the worst value = 0); calculation method is described in [19, 20].

Fb – membership function to active compounds class (the best value = 1, the worst value = 0); calculation method is described in [21].

Rank – average evaluation grade of activity presence by all forecast methods, it is calculated for each activity in each consensus group (the most best value = 1, the worst value = 6).

As it is seen from the table 1,inhibiting ability of MRI and MGAM is not changing at transferring from the structure (I) to the structure (II). However, during fluorine atom introduction into m-position N,N-(dimethylamino)-group it is observed Rank parameter degradation for MRI activity at 0.67. It points to possible decreasing of reactivity of compound (III) in Maillard reaction. Rank parameter for a ability of inhibit α-glucocidase (MGAM) is also decreased. The decreasing consists of 0,71. Simultaneously at fluorine atom introduction is going on the improvement of Rank parameter for PYGL activity for structure (II) at 0,5 in compassion with (I) and for structure (III) at 0,8 in compression with the structure (I). At the same time Ind and Fb parameterы are worse a little bit.

3. Conclusion

It is established that fluorine atom introduction into m- and o-positions to N,N-(dimethylamino)-group in 5-[4-(N,N-dimethylamino)phenylmethylene]-2-trioxodihydropyrimidine-4,6-(1Н,5Н)-dione decreases the occurrence probability of compounds inhibiting Maillard reaction and inhibiting α-glycocidase activities. But it increases the occurrence probability of the presence of inhibiting glycogen phosphorylase activity. The most signified influence is observed at fluorine introduction in m-position.

This study was supported by Russian Scientific Fund (project # 14-25-00139).

 

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Recommended for publication by Prof. A. Rahimov

Fluorine Notes, 2016, 105, 5-6