Synthesis, Identification, Theoretical Study and effect of 1,3,4-Oxadiazole Compounds Substituted on Creatinine ring on the activity of some Transfers Enzymes

 

Zahraa T. Khudhair, Entesar O. Al-Tamimi

Department of Chemistry, College of Science, University of Baghdad, Jadiriya, Baghdad, Iraq

*Corresponding Author E-mail: zzo64052@gmail.com

 

ABSTRACT:

The present report describes the synthesis of 1,3,4-oxadiazole compounds on shiff base substituted on creatinine ring, the Synthetic route started from reaction shiff base derivatives with α-chloroethylacetate to give compounds(1e-2e). Hydrazide derivatives were synthesized by the reaction compounds (1e-2e) with hydrazine hydrate to give compounds (3e-4e). The compounds (3e-4e) reacts with phenylisothiocyanate to give compounds (5e-6e). The synthesized compounds characterized by FT-IR and1HNMRspectroscopy.Beside the experimental work, we worked theoretical study involving calculated the spectra, total energy, dipole moment etc. Also this study was designed to show the effects of creatinine derivatives on the activities of some transferase enzymes such as: GOT, and GPT enzymes in sera. This compounds demonstrated activation effects on GOT and GPT activities. These effects increased with increasing the concentration of the compounds. The causes of the increases in the enzymes activities are discussed.

 

KEYWORDS: Oxadiazole, GOT, GPT, Shiff base, Sera, Spectra.

 

 


1.    INTRODUCTION:

It is well known in the literature that nitrogen and oxygen-containing compounds are mainly used in medicine to treat various types of fungal and bacterial infections, gastric ulcer, cancer, etc. [1]. The organic moiety with nitrogen atoms results in higher efficiency against different diseases [2]. Five heterocyclic compounds have different types of biological activity. 2,5-Disustituted 1,3,4-oxadiazole also exhibits a wide range of activities such as antibacterial [3], antimalarial [4], anti-inflammatory [5], antifungal [6] and anticonvulsant [7]. Replaced 1,3,4-oxadiazoles are of considerable pharmaceutical and material interest, as evidenced by a steadily increasing number of patents and publications. For example, 2-amino-1,3,4-oxadiazoles actas muscle relaxants [8] and 5-aryl-2-hydroxymethyl-1,3,4-oxadiazole derivatives have antimitotic activity analgesic, anti-inflammatory, diuretic and antiemetic properties [9].

 

Some material applications of derivatives of 1,3,4-oxadiazole are in the field of photosensitizers and liquid crystals [10-11]. Common synthetic oxadiazoles approaches [12] involve the diacylhydrazine cycling. A variety of conditions of reaction affect the cyclization reaction. In general, heat and anhydrous reagents, including thionyl chloride [13], promote the reaction. Phosphorous oxychloride [14], pentoxide phosphorus [15], triphenylphosphine [16], Lawesson’s reagent [17] and triflic anhydride [18]. Alternative synthetic methods include carboxylic hydrazide reaction with keteneylidene triphenylphosphorane [19] or trichloroacetic acid hydrazone cyclization reaction [20].

 

2. EXPERIMENTAL:

2.1. Materials and physical measurements:

All starting materials and solvents were purchased from Sigma-Aldrich and Fluka and used without further purification. Melting points were measured on Gallen Kamp capillary melting point apparatus and were uncorrected, FT-IR measurements were recorded on Shimadzu model FTIR-8400S. 1HNMR spectra were obtained with Bruker spectrophotometer model ultra-shield at 400 MHz in D2O solution with the TMS as internal standard.

2.2. Synthesis of the organic compounds:

2.2.1. Synthesis of compounds (1e-2e) [21]:

Shiff base derivatives (0.01mole) were dissolved in absolute ethanol (20 mL), then NaOH (1M, 10 mL) were added at (0°C). α-chloroethylacetate (0.01) was added to the mixture. This mixture was stirred at room temperature overnight. The precipitate was filtered and then dried. The product was collected and recrystallized with ethanol. The Physical properties of synthesized compounds (1e-2e) are given in Table1.

 

2.2.2. Synthesis of compounds (3e-4e)[22]:

Generally, a solution of compounds (1e-4e) (0.01mole), hydrazine hydrate(0.01 mole,85%)in absolute ethanol (50mL) were prepared. The reaction mixture was refluxed for 24hr. The obtained product was filtered, and recrystallized from ethanol. The physical properties of synthesized compounds (3e-4e) are given in Table 1.

 

2.2.3. Synthesis of compounds (5e-6e) [23]:

A mixture of (5e-8e) compounds (6.39, 0.01mol) and phenylisothiocynate (0.04 mol, 4.3 ml) in DMF (50 ml) were refluxed for 10 hours on steam bath. the reaction mixture was recrystallized from ethanol. The physical properties of synthesized compounds (5e-6e) are given in Table 1.


 

Table1: The physical properties of synthesized compounds (1e- 6e).

No. of compd.

Structure and name of compounds

Chemical formula

Color

Molecular weight

M. P. °C Dec.

Yield%

 1e

 

ethyl 2-(1-methyl-4-oxo-2-(2-(1-phenylethylideneamino) oxazol-5-ylamino)-4,5-dihydro-1H-imidazol-5-yl) acetate

C15H15N5O2

Yellow

383.40

152-155

79

 2e

 

ethyl 2-(2-(2-( benzylideneamino) thiazol-5-ylamino)-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-5-yl)acetate

C18H19N5O3S

Yellow

385.44

168-170

98

 3e

 

2-(1-methyl-4-oxo-2-(2-(1-phenylethylideneamino)oxazol-5-ylamino)-4,5-dihydro-1H-imidazol-5-yl)acetohydrazide

C16H16N8O5

White

383.40

209-210

79

 4e

 

2-(2-(2-(benzylideneamino)thiazol-5-ylamino)-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-5-yl)acetohydrazide

C16H17N7O2S

White

371.42

185-187

70

 5e

 

1-methyl-5-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)methyl)-2-(2-(1-phenylethylideneamino)oxazol-5-ylamino)-1H-imidazol-4(5H)-one

C24H22N8O2S

Off white

486.55

210-212

68

 6e

 

2-(2-(benzylideneamino)oxazol-5-ylamino)-1-methyl-5-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)methyl)-1H-imidazol-4(5H)-one

C23H20N8OS2

Off white

488.59

227-230

76

 


3. BIOLOGICAL ACTIVITY:

3.1. Effect of compounds (5e-6e) on SGOT, and SGPT activities Colorimetric determination of SGOT or SGPT activity according to the following reactions:

 

The pyruvate or oxaloacetate formed was measured in its derived from 2,4-dinitrophenylhydrazine, which was absorbed at wave length 546 nm (SYRBIO kit).

 

3.2. A stock solution (0.01 M) of compound (5e-6e):

A stock solution (0.01 M) of compounds (5e-6e) were prepared by dissolving it in distilled water, and the following concentrations (10-2, 10-3, 10-4, 10-5 M) were prepared by diluting with distilled water. The enzymes SGOT, and SGPT activities were measured in human serum by using the same methods of these enzymes with replace 100 µl of buffer with 100 µl of compounds (5e-6e). The activation percentage was calculated by comparing the activity with and without compounds (5e-6e) and under the same conditions, according to the equation:

 

% Activation

=100×The activity in the presence of activator/The activity in the absence of activator–100

 

The activation constant (Ki) was calculated according to the following equation:

 

Vmax+A= Vmax–A/ (1+ [A]/ Ki)

Where A is activation constant.

+A is with activator

-A is without activator

[A] is activator concentration

 

3.3. A constant concentration of compound (5e-6e) (10-2 M):

A constant concentration of compounds (5e-6e) (10-2 M) were used with different substrate concentrations of (40, 80, 120, 160, 200) mmol/L for SGOT and SGPT to study the type of activation. Buffers were used to prepared different substrates concentrations of these enzymes, SGOT, SGPT (phosphate buffer pH=7.40, 100 mmol/L). The enzymes velocity were determined with and without compounds (5e-6e), by using the Lin weaver and Burke equation and plotting 1/v against 1/[s] were evaluated values; Ki, apparent Vmax (Vmapp), apparent Km (Kmapp), type of inhibition or activation [24].

 

 

 

4. RESULT AND DISCUSSION:

4.1. Synthesis:

Scheme 1 included synthesiscreatininederivatives. Thecharacterization data of all compounds 1e–6e are given in the experimental section. All the newly synthesized compounds gave satisfactory analysis for the proposed structures, which were confirmed on the basis of, FTIR and1HNMR data.

 

Scheme1: The chemical steps for the synthesis of compounds (1e-6e).

 

4.2. FT-IR spectra:

4.2.1.The FTIR spectra of compounds (1e-2e) have important characteristic stretching vibration bands that corresponds to (C=O) ester band The FT-IR spectrum of compounds (1e-2e) arelisted in Table 2[25].

 

Table 2: FT-IR Spectral data of synthesized compounds (1e-2e) in cm-1.

Comp.

No.

n C-H

Aromatic

n C=O

Ester

n C=C Aromatic

n C=O

Cycl. amide

n N-H

1e

3072

1749

1670

1699

3269

2e

3041

1747

1643

1697

3249

 

4.2.2.The FTIR spectra of compounds (2e-3e) have important characteristic stretching vibration bands that corresponds to (C=O) ester band which are disappeared and stretching vibration bands that corresponds to (C=O) amide band which are appeared[25], show Table 3.

 

Table 3: FT-IR Spectral data of synthesized compounds (3e-4e) in cm-1.

Comp.

No.

n C-H

Aromatic

n C-H

Aliphatic

n C=O

Amide

n NH2

n N-H

18

3002

2964

1668

Asy.= 3454

Sy.=3413

3250

19

3020

2902

1666

Asy.= 3353

Sy.=3413

3303

 

 

4.2.3. The FTIR spectra of compounds (5e-6e) have important characteristic stretching vibration bands that corresponds to (-C-O) of oxadiazole ring band which are appeared, also stretching vibration bands that corresponds to (NH2) and (C=O) amide band which are disappeared, Show Table 4.

 

Table 4: FT-IR Spectral data of synthesized compounds (5e-6e) in cm-1.

Comp.

No.

n C-O

n C=N

oxadiazole ring

n C=O

Amide

n NH2

n C-H

Aromatic

5e

1049

1604

------

------

3002

6e

1081

1600

-----

-----

3002

 

4.3. 1HNMR Spectra:

The 1HNMR spectra of compounds (5eand 6e) are listed in Table 5[26].

 

4.4. Biological activity of transferase enzymes (SGOT and SGPT).

This research addresses investigation of the effects of compounds (5e-6e) of SGOT and SGPT enzymes. The biochemical tests revealed that these compounds caused stimulation effects on SGOT and SGPT enzymes activities. Table (6) is listed below shows the effect of different concentration of compounds (5e-6e) on the activity of SGOT and GPT enzymes in human serum. This research addresses investigation of the effects of compounds (5e-6e) of SGOT and SGPT enzymes. The biochemical tests revealed that these compounds caused activatory effects on SGOT and SGPT enzymes activities. The normal value of the SGOT and SGPT enzyme activities were (14 and 16 U/L) respectively. The relationship between compounds (5e-6e) concentrations versus and the activity of enzymes were shown in Figures (5e-6e). These results observed that any increase in compound concentrations caused increase in percentage of activation of enzymes.

 


Table (5) 1HNMR data of compounds (5e and 6e) in ppm.

Comp. No.

Compound structure

1HNMR data of (δ-H) in ppm

5e

 

Singlet 1H of -NH (8.35); multiplet 11H of aromatic rings (7.37-7.87); Singlet 1H of –NH group (4.64); Singlet 1H of –CO-CH group (3.70); Singlet 3H of -N-CH3 group (3.12); Singlet 2H of -CH2 group (2.91); Singlet 3H of –CH3 group (1.25).

6e

 

Singlet 1H of -NH (8.10); singlet 1H of

–N=CH (8.08); multiplet 11H of aromatic rings (7.33-7.72); Singlet 1H of –NH group (4.37); Singlet 1H of –CO-CH group (3.56); Singlet 3H of -N-CH3 group (3.44); Singlet 2H of -CH2 group (3.13).

 

Table 6: The effect of different concentration of compounds (5e-6e) on the activity of SGOT and SGPT enzymes in human serum.

Concentration (M)

GOT activity (U/L)

Activation (%)

GPT activity (U/L)

Activation (%)

Sample

 

 

 

 

0

14

0.000

16

0.000

Compound (5e)

 

 

 

 

10-2

77

450.000

97

506.250

10-3

43

207.142

63

293.750

10-4

31

121.428

39

143.750

10-5

17

21.285

20

25.000

Compound (6e)

 

 

 

 

10-2

117

680.000

98

476.470

10-3

73

386.666

75

341.176

10-4

51

240.000

40

135.294

10-5

22

46.666

21

23.529

 

Figure.1: (a) The relationship between concentration of compounds (5e) and SGOT enzyme activity. (b) The relationship between concentration of compounds (5e) and SGPT enzyme activity.


 

Figure. 2: (a) The relationship between concentration of compounds (5e) and SGOT enzyme activity. (b) The relationship between concentration of compounds (5e) and SGPT enzyme activity.

 

 

Figure. 3: (a) The percentage of activation SGOT enzyme and compounds (6e) concentration. (b) The percentage of activation SGPT enzyme and compounds (6e) concentration.

 

Figure. 4: (a) The percentage of activation SGOT enzyme and compounds (6e) concentration. (b) The percentage of activation SGPT enzyme and compounds (6e) concentration.

 

 

Competitive, non-competitive and uncompetitive activators can easily be distinguished by using the Lineweaver–Burk plot's double reciprocal plot. Two sets of rate determination were performed in which the concentration of enzymes was kept constant. In the first experiment, the speed of the unactivated enzyme was determined, and in each enzyme test the second experimental constant amount of activator was included. Various substances are capable of reducing or eliminating the catalytic activity of a particular enzyme. [27].

 

Table 7 and Figures (5-6) showed that the type of enzyme activation using Lineweaver–Burk plot for compounds (5e-6e) on SGOT and SGPT activity. The Vmax and Km values determined with 10-2 M of compounds (5e-6e) and without it. Vmax without compounds (5e-6e) were greater than Vmax in the presence compounds (5e-6e). A liquate 10-2 M of compounds (5e-6e) were noncompetitive activation for enzymes activity. Noncompetitive activation changed the Vmax of the enzyme but not the Km. By using Lineweaver–Burk equation, the Ki values of enzyme for compound which was studied in different concentrations.

 

Figure.5: Lineweaver-Burk plots for compounds (5e) effects on (a) SGOT, (b) SGPT.

 

Figure.6: Lineweaver-Burk plots for compounds (6e) effects on (a) SGOT, (b) SGPT.

 

 

 

 

 

Table 7: The kinetic properties of SGOT and SGPT with compounds (5e-6e).

Enzymes

Km

(mmole/L)

Vmax

(mmole/ L). min.

Ki (mmole/L)

Type of effect

SGOT

 

 

 

 

Without compound

200

1.649

------

------

Compound (5e)

200

0.023

0.00014

Noncompetitive

SGPT

 

 

 

 

Without compound

100

0.061

------

-------

Compound (6e)

100

0.031

0.0103

Noncompetitive

 

The enzymes play important role in amino acid metabolism and in urea and tricarboxylic acid cycles. We suggested that compounds (5e-6e) have (N– and O=) groups by which, it activities the active sides of amino acids of GOT and GPT enzymes by increasing affinity of active sides of enzymes to react with the substrates.

 

5. Theoretical details:

5.1. Optimize geometry of compound (6e).

The Optimize geometry of atoms forthe compound (6e) calculating byusing semi-empirical (PM3) method was depicted in figure 7

 

Figure 7. a) The Optimize geometry, b) The numbering Optimize geometry for compound (6e).

 

The result of the calculated optimized structural parameters for compound (6e) such as bonds length and bonds angle (A˚) were calculating by using semi-empirical (PM3) method. The Table 8 and 9 respectively revealed that the results of this work were in good agreement with experimental data.

 

Table 8. Some calculated bonds length for the compound (6e).

Optimal

Actual

Atoms

1.1000

1.1000

C(31)-H(51)

1.1000

1.1000

C(15)-H(41)

1.1000

1.1000

C(13)-H(40)

1.1130

1.1130

C(8)-H(39)

1.1130

1.1130

C(8)-H(38)

1.8560

1.4590

S(21)-C(17)

1.8560

1.4590

C(20)-S(21)

1.2600

1.1918

N(19)-C(20)

1.4180

1.2480

N(18)-N(19)

1.5230

1.5230

C(3)-C(16)

1.2600

1.2600

N(14)-C(15)

1.4560

1.2600

C(11)-N(14)

1.3370

1.3370

C(13)-C(9)

1.4560

1.2600

N(12)-C(13)

1.2600

1.3793

C(11)-N(12)

1.8560

1.4590

S(10)-C(11)

1.856

1.4590

C(9)-S(10)

1.4620

1.2660

N(7)-C(9)

1.4700

1.4700

N(4)-C(8)

1.4620

1.2660

C(5)-N(7)

1.208

1.2080

C(2)-O(6)

1.2600

1.2600

C(5)-N(1)

1.4620

1.2660

N(4)-C(5)

1.4700

1.1972

C(3)-N(4)

1.5090

1.5090

C(2)-C(3)

1.4260

1.2600

N(1)-C(2)

 

Table 9. Some calculated bonds angle for thecompound (6e).

Optimal

Actual

Atoms

118.0000

120.0000

H(44)-N(22)-C(20)

124.0000

120.0000

C(29)-N(22)-C(20)

98.5000

98.5000

C(17)-S(21)-C(20)

-------

128.1796

N(22)-C(20)-S(21)

126.0000

128.1796

N(22)-C(20)-N(19)

126.0000

103.6408

S(21)-C(20)-N(19)

107.5000

122.8592

C(20)-N(19)-N(18)

107.5000

104.0000

N(19)-N(18)-C(17)

126.0000

111.0000

S(21)-C(17)-N(18)

120.0000

124.5000

S(21)-C(17)-C(16)

115.1000

124.5000

N(18)-C(17)-C(16)

109.4000

109.5200

H(43)-C(16)-H(42)

109.4100

109.4618

H(43)-C(16)-C(17)

123.5000

111.0000

C(9)-C(13)-N(12)

115.0000

109.9630

C(13)-N(12)-C(11)

120.0000

125.2315

N(14)-C(11)-N(12)

126.0000

125.2315

N(14)-C(11)-S(10)

126.0000

109.5370

N(12)-C(11)-S(10)

98.5000

98.5000

C(11)-S(10)-C(9)

119.0000

111.0000

C(13)-C(9)-S(10)

120.0000

124.5000

C(13)-C(9)-N(7)

-------

124.5000

S(10)-C(9)-N(7)

107.9000

117.2521

H(35)-C(3)-C(2)

109.9000

112.7442

C(16)-C(3)-C(2)

122.5000

124.5000

O(6)-C(2)-C(3)

124.3000

124.5000

O(6)-C(2)-N(1)

116.5000

111.0000

C(3)-C(2)-N(1)

115.0000

104.0000

C(5)-N(1)-C(2)

 

Table 10. Some energies and physical properties for compound (6e).

Property

PM3 method

Point group

C1

Symmetry

A

Etot(kcal/mole)

-115127.5667

Eb (kcal/mole)

-5889.6391

ΔHof (kcal/mole)

179.2298

EHOMO ( a.u.)

-0.3295

ELOMO ( a.u.)

-0.0514

∆E HOMO-LUMO( a.u.)

0.2781

µ (debye)

7.9605

 

Figure 8. The calculated a- HOMO, b- LUMO for the compound (6e).

 

The following figure 9 electron distribution governs the electrostatic potential of the molecules. The electrostatic potential (E.P) describes the interaction of energy of the molecular system with a positive point charge. The E.P is useful for finding sites of reaction in a molecule, positively charged species tends to attack a molecule where the electrostatic potential is strongly negative [28,29].

 

 

Figure 9. The calculated electrostatic potential a- 2D, b- 3D for the compound (6e).

 

5.2- Partial atomic charge of compound (6e)

The calculated partial atomic charge using the PM3 method for individual atoms were illustrated in figure 9. The PM3 method give more reasonable value, showing that the O, N atoms have negative partial charge and positive in C atoms, figure 9Since the O, N atom have more electronegativity than C atom.

 

Figure 10. The partial atomic charges for the compound (6e).

 

5.3. The vibrational spectra of compound (6e)

compound (6e) belongs to (C1) point group and symmetry (A),The Table are shown below revealed that the theoretical data of this work were in good agreement with experimental data, calculating by using semi-empirical method (PM3).

 

Table 11. PM3 vibration frequencies and IR absorption intensities for compound (6e).

Description

Theoretical

Experimental

Frequency cm-1

Intensity

Km/mole

Frequency

C-H str.(aromat.)

3005

14.56

3002

C=N str.

1623

13.86

1625

C=C str.

1674

32.92

1672

 C-H sr. (aliphat. )

2927

16.05

2929

 

Figure 11. Some Modes of vibration frequencies for compound (6e).

5.4. The 1HNMR spectra of compound (6e)

The Tables are shown below revealed that the theoretical data were in good agreement with experimental data, calculating by using DFT and B3LYP methods (3-21G).

 

Table 12. DFT and B3LYP (3-21 G)1HNMR for compound (6e).

Description

Chemical shift ppm

Experimental

Theoretical

1H of –C=N group

3.56

3.55

1H of –CH-CO

3.44

3.40

1H of -CH=

4.68

4.66

1H of -NH

3.81

3.79

 

6. CONCLUSION:

Shiff base derivatives substituted on creatinine ring were synthesized and structurally characterized by using spectroscopic techniques. The Synthetic route started fromreaction shiff base derivatives with α-chloroethylacetate to give compounds(1e-2e). Hydrazide derivatives were synthesized by the reaction compounds (1e-2e) with hydrazine hydrate to give compounds (3e-4e). The compounds (3e-4e) reacts with phenylisothiocyanate to give compounds (5e-6e).The biochemical studies revealed that the creatinine derivatives caused activator effects on GOT and GPT enzymes activities. Finally, we worked theoretical study For the purpose of comparison with the experimental results,there are good agreement between theoretical and experimental results.

 

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Received on 11.02.2019           Modified on 02.03.2019

Accepted on 02.04.2019         © RJPT All right reserved

Research J. Pharm. and Tech. 2019; 12(8):3581-3588.

DOI: 10.5958/0974-360X.2019.00611.5