Synthesis of Novel Bioactive compounds of

5-arylidene-2-imino-thiazolidin-4-ones as Antimicrobial agents

 

Ahmed N. Ayyash1*, Entesar J. Fadhil2, Zainab H. Mohammad3

1,2Department of Applied Chemistry, College of Applied Science, University of Fallujah, Anbar, Iraq.

3Department of Applied Chemistry, College of Applied Science, University of Samarra, Saladin, Iraq.

*Corresponding Author E-mail: ayyash1982@gmail.com ; ahmedn.ayyash@uofallujah.edu.iq

 

ABSTRACT:

In this study, a variety of 3,3'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-imino-5-(5-substitutedpyridine-2-yl)-1,3-thiazolidin-4-one] derivatives have been synthesized with good yields starting by reaction of  pyrazine-2,3-dicarboxylic acid and thiosemicarbazide. The resulted compound 2-amino-1,3,4-thiadiazole was treated with chloroacetic acid to give the corresponding chloroacetamide which further refluxed with potassium thiocyanate. The condensation of the product 2-imino-1,3-thiazolidin-4-one with different 5-substitutedpyridine-2-carbaldehyde produced the titled compounds. An agreement for the proposed structures were approved based on the elemental analysis, FT-IR, 1H NMR and 13C NMR spectra. Antimicrobial activity of the newly thiazolidinones have been estimated with powerful results.

 

KEYWORDS: Antimicrobial, Amino-1,3,4-thiadiazole, 1,3-Thazolidin-4-one, Pyrazine-2,3-dicarboxylic acid, Pyridine-2-carbaldehyde.

 

 

INTRODUCTION:

1,3-Thiazolidin-4-ones are 5-membered heterocycles containing two hetero-atoms; sulfur and nitrogen as well as the carbonyl group located at the 4th. position. Due to their important biological activities, 4-thiazolidinone derivatives have a remarkable attraction for the few last years1-6. However, by the literature survey, many derivatives of thiazolidinones have been reported as antimicrobial7-10, antibacterial11,12, anti-inflammatory11, antifungal13,14. Some new derivatives of 2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones and their 5-arylidene derivatives have been reported and examined for their antifungal activity15. Some New 2-Imino-3-substitued-5-arylidene-4-thiazolidinone were synthesized and assayed in vitro for their antibacterial activity against Gram positive and Gram-negative bacteria by the cup-plate method16. Furthermore, a series of 5-substituted-arylidene-3-substituted-benzyl-thiazolidine-2,4-dione derivatives were synthesized from thaizolidinedione and substituted benzyl chloride followed by the addition of substituted aromatic aldehydes17.

 

In addition, the various Schiff bases were treated with thioglycolic acid to obtain thaizolidine-4-one derivatives18. Also, 2-substituted-1,3-thiazolidine-4-one derivatives were synthesized by the reaction of chloroacetic acid and thiosemicarbazones19. Based on the findings above, we decided to the synthesis of some new substituted-1,3-thiazolidin-4-ones and evaluated of their antimicrobial activities.

 

MATERIALS AND METHODS:

Materials and Instruments:

All the chemicals and reagents have been used as purchased from their suppliers (BDH, Fluka, Merck and Sigma-Aldrich) companies. Reactions monitoring was performed by (TLC) thin-layer chromatography on pre-coated aluminum plates. Uncorrected melting points were determined in Celsius degree on open-capillary Electro-thermal apparatus. For IR spectra, FTIR Shimadzu 8400s spectrophotometer was operated using KBr disc. Bruker spectrometer (400 and 100 MHz in DMSO-d6) was utilized to predict 1H NMR and 13C NMR spectra and are expressed as part per million (δ ppm) downfield from an internal reference (TMS). Elemental Analyzer Model (Fison EA1108) was turned-on for C. H. N analysis. All chemical structures were illustrated with Chem Draw Ultra (6.0) application.

 

General Synthetic Procedures:

Synthesis of 5,5'-(pyrazine-2,3-diyl)bis[2-amino-1,3,4-thiadiazole), compound 2: In a round bottom flask equipped with a condenser, a solution of (1.68g, 0.01 mole) of pyrazine-2,3-dicarboxylic acid and (1.82g, 0.02mole) of thiosemicarbazide in (15mL) of absolute ethanol, conc. H2SO4 (8mL) was added under stirring and refluxed for 3h. After cooling at 25°C. The mixture was poured onto ice-bath, then the solid was separated out, filtered, and recrystallized from ethanol20.

 

Synthesis of N,N'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2-chloroacetamide), compound 3: In a round bottom flask equipped with a condenser, a solution of (2.78g, 0.01mole) of compound 2 dissolved in (30mL) dry benzene, (5mL, 0.04mole) of chloroacetyl chloride was added slowly with stirring. Then, the reaction mixture was heated under reflux for 4h. The reaction contents were washed with sodium bicarbonate (5%), followed with water. The solid obtained was filtered and crystallized from ethanol.

 

Synthesis of 3,3'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2-imino-1,3-thiazolidin-4-one), compound 4: In a round bottom flask equipped with a condenser, a solution of (0.43g, 0.001mole) of compound 3 and (0.4 g, 0.004mole) of KSCN dissolved in (60mL) of dry acetone and heated for 4h. under reflux and stirring. After cooling at 25oC, the mixture was washed with water and the product was separated-off and recrystallized from ethanol.

 

Synthesis of 3,3'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-imino-5-(5-substitutedpyridine-2-yl)-1,3-thiazolidin-4-one], compound 5a-d; (general procedure): In a round bottom flask equipped with a condenser, a mixture of (0.476g, 0.001mole) of compound 4 and (0.004mole) of appropriate pyridine-2-carbaldehyde was refluxed  in presence of  piperidine (0.5mL) for 3h. The reaction mixture was cooled and poured onto cold water. The separated solid was filtered, washed, dried and recrystallized from acetone.

 

RESULTS AND DISCUSSION:

Chemistry:

The target compounds were synthesized as outlined in scheme 1. All the Physiochemical properties and spectal data are listed in Table 1 and 2. Chemically, the first step of the general synthetic pathway was the direct cyclization reaction of pyrazine-2,3- dicarboxylic acid 1, and thiosemicarbazide in a solution of concentrated sulfuric acid of absolute ethanol under reflux conditions to yield 5,5'-(pyrazine-2,3-diyl)bis(2-amino-1,3,4-thiadiazole), 2. The reaction proceeds via treatment of  compound 2 with chloroacetyl chloride to produce N,N'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2-chloroacetamide), 3 which further was refluxed with potassium thiocyanate in acetone to afford the 3,3'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2-imino-1,3-thiazolidin-4-one), 4. Finally, compound 4 was condensed with different 5-substitutedpyridine-2-carbaldehyde to give the target compounds 3,3'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-imino-5-(5-substitutedpyridine-2-yl)-1,3-thiazolidin-4-one], 5a-d. The chemical structures of newly synthesized compounds were in conformity based on their physiochemical properties, elemental and spectroscopic analysis.


 

Scheme 1. General synthetic route for the titled compounds.

Table 1. Physiochemical properties of newly synthesized compounds

Compd

R

Yield%

m.p °C

Appearance

M.wt (g/mole)

Empirical Formula

2

 

77

122–124

yellow crystals

278.32

C8H6N8S2

3

 

82

143–145

yellow powder

431.28

C12H8Cl2N8O2S2

4

 

69

130–131

white crystals

476.54

C14H8N10O2S4

5a

H

55

189–191

white powder

654.73

C26H14N12O2S4

5b

CH3

51

172–174

pale yellow powder

682.79

C28H18N12O2S4

5c

OCH3

57

199–201

yellow powder

714.79

C28H18N12O4S4

5d

Cl

45

180–181

Pale-yellow powder

723.62

C26H12Cl2N12O2S4

 

Table 2. Spectroscopy and microanalysis data of all newly synthesized compounds

Compd.

IUPAC Nomenclature / Spectral data

2

5,5'-(pyrazine-2,3-diyl)bis[2-amino-1,3,4-thiadiazole) / IR spectrum, ν, cm–1: 3410–3232 (N–H), 3082 (C-H), 1651 (C=N), 1234–1115 (C–N). 1H NMR spectrum, δ, ppm: 9.63 d (2H, 2-pyrazine), 3.99 s (4H, aromatic C-NH). 13C NMR spectrum, δ, ppm: 146.5 (CH=N, pyrazine), 156.0 (CH=N, thiadiazole). Found, %: C, 34.52; H, 2.17; N, 40.26. C8H6N8S2. Calculated, %: C, 34.47; H, 2.20; N, 41.04

3

N,N'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2-chloroacetamide) / IR spectrum, ν, cm–1: 3410–3235 (N–H), 3065-2955 (C-H), 1677 ( C=O), 1641 (C=N), 1232–1110 (C–N), 738 ( C-Cl). 1H NMR spectrum, δ, ppm: 9.69 d (2H, 2-pyrazine), 7.49 s (2H, N-H), 3.98 s (4H, CO-CH2-Cl). 13C NMR spectrum, δ, ppm: 165.6 (CO-NH), 155.8 (CH=N, thiadiazole), 144.2 (CH=N, pyrazine), 52.4 (CH2-Cl). Found, %: 34.18; H, 1.92; N, 26.27. C12H8Cl2N8O2S2. Calculated, %: C, 33.42; H, 1.87; N, 25.98.

4

3,3'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2-imino-1,3-thiazolidin-4-one) / IR spectrum, ν, cm–1: 3242 (N–H), 3072, 2922 (C-H), 1676 ( C=O), 1604 (C=N), 1257–1157 (C–N). 1H NMR spectrum, δ, ppm: 8.45 d (2H, 2-pyrazine), 7.78 s (2H, N-H), 4.22 s (4H, CO-CH2-S). 13C NMR spectrum, δ, ppm: 166.7 (CO-NH), 156.2 (C=NH), 139.8 (CH=N, thiadiazole), 131.7 (CH=N, pyrazine), 30.8 (CH2). Found, %: C, 35.83; H, 1.89; N, 30. C14H8N10O2S4. Calculated, %: C, 35.29; H, 1.69; N, 29.39.

5a

3,3'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-imino-5-(pyridine-2-yl)-1,3-thiazolidin-4-one] / Yield 0.26g (IR spectrum, ν, cm–1: 3405–3229 (N–H), 3088, 3012 (C-H), 1676 (C=O), 1643 (C=N), 1232–1124 (C–N). 1H NMR spectrum, δ, ppm: 9.04 d (2H, 2-pyrazine), 7.35-7.92 m ( 8H, aromatic protons and 2H, C=NH), 6.24 s ( 2H, C=CH). 13C NMR spectrum, δ, ppm: 166.3 (CO-NH), 133.1 (CH=N, pyrazine), 131.5, 129.9 (C=CH). Found, %: C, 49.20; H, 2.38; N, 26.17. C26H14N12O2S4. Calculated, %: C, 47.70; H, 2.16; N, 26.17.

5b

3,3'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-imino-5-(5-methylpyridine-2-yl)-1,3-thiazolidin-4-one] / IR spectrum, ν, cm–1: 3405–3229 (N–H), 3088, 2994 (C-H), 1674 ( C=O), 1642 (C=N), 1235–1112 (C–N). 1H NMR spectrum, δ, ppm: 7.95 d (2H, 2-pyrazine), 7.74-7.33 m (8H, aromatic protons and 2H, C=NH), 7.30 s (2H, C=CH), 2.51 s (6H, CH3). 13C NMR spectrum, δ, ppm: 157.0 (CO-NH), 138.04 (CH=N, thiadiazole), 131.6 (CH=N, pyrazine), 129.6, 128.4 (C=CH), 22.9 (-CH3). Found, %: C, 50.08; H, 2.82; N, 25.21. C28H18N12O2S4. Calculated, %: C, 49.25; H, 2.66; N, 24.62.

5c

3,3'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-imino-5-(5-methoxypyridine-2-yl)-1,3-thiazolidin-4-one] / IR spectrum, ν, cm–1: 3405–3229 (N–H), 3072, 2988 (C-H), 1678 ( C=O), 1640 (C=N), 1232–1117 (C–N). 1H NMR spectrum, δ, ppm: 8.33 d (2H, 2-pyrazine), 7.99-7.34 m ( 8H, aromatic protons and 2H, C=NH), 3.69 s (6H, OCH3). 13C NMR spectrum, δ, ppm: 167.05 (CO-NH), 157.5 (C=NH), 151.8 (CH=N, thiadiazole), 137.3 (CH=N, pyrazine), 131.5 ( C=CH), 60.8 (-OCH3). Found, %: C, 48.83; H, 2.72; N, 24.61. C28H18N12O4S4. Calculated, %: C, 47.05; H, 2.54; N, 23.51.

5d

3,3'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-imino-5-(5-chloropyridine-2-yl)-1,3-thiazolidin-4-one] / IR spectrum, ν, cm–1: 3334–3123 (N–H), 3068, 2998 (C-H), 1678 ( C=O), 1646 (C=N), 1230–1113 (C–N), 748 (C-Cl). 1H NMR spectrum, δ, ppm: 8.23 d (2H, 2-pyrazine), 7.28-6.97 m (8H, aromatic protons and 2H, C=NH), 6.63 s (2H, C=CH). 13C NMR spectrum, δ, ppm: 167.42 CO-NH), 166.8 (C=NH), 149.5 (CH=N, thiadiazole), 137.3 (CH=N, pyrazine), 135.0, 125.8 (C=CH). Found, %: C, 43.95; H, 1.92; N, 24.94. C26H12Cl2N12O2S4. Calculated, %: C, 43.15; H, 1.67; N, 23.23.

 

Figure 1. 1H NMR Spectrum of compound 5b.

 

Figure 2. 13C NMR Spectrum of compound 5b.

 

Figure 3. 1H NMR Spectrum of compound 5c.

 

Figure 4. 13C NMR Spectrum of compound 5c.

 

Figure 5. 1H NMR Spectrum of compound 5d.

 

Bioactivity Screening:

The titled compounds 5a-d have been examined for their antimicrobial activity against Staphylococcus Sciuri as gram-positive and Escherichia coli as gram-negative strains. Also, they were investigated as antifungal agents against two fungal strains; Aspergillus flavus and Candida albicans by diffusion method21. DMSO solvent has been used to dissolve and preparing (100 µg/mL) concentration of the tested compounds. The plates of the bacterial culture were incubated at 37°C for 24h. Whereas, for fungal culture, the plates were incubated at 25°C and examined after 72h. The results are given in Table 3, were measured relative to the ciprofloxacin and ketoconazole as antibacterial and antifungal standard references, respectively.

 

Table 3. Antimicrobial activity of newly synthesized compounds

Compd.

Zone of inhibition (mm)

Bacterial Strains

Fungal Strains

Staph. Sciuri

Escherichia coli

Aspergillus Flavus

Candida Albicans

5a

11

10

07

12

5b

14

14

13

14

5c

12

14

11

13

5d

17

22

16

18

Ciprofloxacin

20

24

 

 

Ketoconazole

 

 

18

20

 

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

 

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Received on 19.08.2021            Modified on 04.11.2021

Accepted on 07.01.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(9):4187-4191.

DOI: 10.52711/0974-360X.2022.00702