Ultrasonic Synthesis and Antimicrobial activity of some

Diazenyl-1,3,4-Thiadizole Derivatives

 

Mustafa K. Shneshil¹, Waseela Abdulreda Abdul Razaq¹, Omar D. Abdul Sattar²,

Sahar H. Mourad¹, Mustafa K. Mohammed¹, Ansam N. Khurshid¹

¹Department of Chemistry, College of Education for Pure Science, University of Diyala, Iraq.

²Department of Chemistry, College of Science, University of Diyala, Iraq.

 

ABSTRACT:

Some novel azo-1,3,4-thiadiazole derivatives were greenly synthesized by the reaction of terephthalic acid with thiosemicarbazide in the presence of phosphorus oxychloride (POCl₃) under ultrasonic irradiation forming1,4-bis(2-amino-1,3,4-thiadiazol-5-yl) benzene. The later was diazotized with different substituted phenols to give 1,4-bis(2-substituted phenyldiazenyl-1,3,4-thiadiazol-5-yl) benzene (1-8).The structures of the compounds synthesized identified by using spectral analysis methods (F.T-IR, ¹H-NMR and ¹³C-NMR).The compounds (1-8) tested for their anti-microbial (Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa) activities using disc diffusion method. The minimum inhibitory concentrations (MICs) of the compounds also calculated by agar streak dilution method. The compounds (6) was the most active compound against the above strains of microbes.

 

 

 

INTRODUCTION:

The green chemistry is one of the important branches of chemistry that serve to give friendly compounds to our environment thatminimizes the harmful chemicals (synthesis and use of chemical products) [1,2]. Sonochemistry is the study of the effects of ultrasound waves to generate acoustic cavitation in water. It is an important way of green chemistry, to reduce the energy consumption [3,4]. Santosh A. Jadhav et. al [5], prepared 2-amino-thiadiazole using conditions with ultrasonic irradiation. Thiadiazoles and their derivatives are heterocyclic class of compounds and have significant biological activity and synthetic applications. The metal complexes compounds that contain in their structures 1,3,4-thiadiazole moiety is used as anticorrosion paints [6], anti-fouling in marine [7], thiadiazole show different physical properties such as liquid crystal, optical brightening and fluorescent properties[8].

 

Many of thiadiazole compounds used as antibacterial activity [9,10], antifungal activity [11], inhibitory activity against matrix metalloproteinase (MMP) and Bacterial Collagenase [12], anticancer activity [13], anti-Helicobacter pylori (Helicobacter pylori is a Gram-negative microaerophilic bacterium found in the stomach) [14], anticonvulsant activity [15],non-steroidal anti-inflammatory drugs (NSAIDs)[16], antitubercular and antinociceptive agents [17], anti-HIV [18], anti-leishmanial activity[19], trypanocidal (anti-epimastigote) activity [20], carbonic anhydrase inhibitory activity[21,22] and somethiadiazoles are used as miscellaneous materials [23].

 

EXPERIMENTAL:

The synthesis of the target molecules (1-8) shown in the sequences of reactions depicted in the scheme below. The F.T.IR spectral data recorded on F.T.IR-8400 Fourier Transform Infrared Spectrophotometer SHIMADZU using potassium bromide disc.¹H-NMR and ¹³C-NMRwas recorder on Bruker Ultra Shield, 400MHz, using DMSO as solvent and TMS as internal standard. Melting points (^oC) recorded on hot stage Gallen Kamp melting point apparatus and were uncorrected. Chemical names follow the IUPAC nomenclature. Some starting materials purchased from EMD Millipore Corporation, Germany and used without purification.

 

i) Thiosemicarbazide, POCl₃, ultrasonic irradiation (50 min), H₂O, ultrasonic irradiation (80 min). ii) HCl, NaNO₂, substituted phenol.

 

Synthesis of 1,4-bis(2-amino-1,3,4-thiadiazol-5-yl) benzene

Terephthalic acid (0.01 mol, 1.66 g) and thiosemicarbazide (0.01 mol, 0.91 g) and were dissolved in (12 mL) phosphorous oxychloride and irradiated with ultrasound for 50 min at 80^oC.After cooling (50 mL) of distilled water was added to the mixture and irradiated again with ultrasound for 80 min at 80^oC.After cooling, the yellow precipitate was filtered, washed with distilled water [5,24]. Yield 72% m.p. 215^oC. F.T-IR (KBr) cm^-1 (3278-3205) cm^-1, 3095 cm^-1, 1625 cm^-1, 1590 cm^-1.

 

Synthesis of 1,4-bis(2-substitutedphenyldiazenyl-1,3,4-thiadiazol-5-yl)benzene (1-8)

1,4-bis(2-amino-1,3,4-thiadiazol-5-yl) benzene (0.01 mol) was dissolved in 15 mL of5 M HCl with stirring, The mixture was then cooled to 0 °C in an ice bath, then15 mL of1 M sodium nitrite solution was added with stirring and the temperature kept below 0 ^oC (solution 1). Substituted phenols (0.01 mol) in 15 mL of1 M NaOH at 0 ^oC (solution 2). (solution 1) was added slowly with stirring to(solution 2). After 30 min with temperature at 0 ^oC the precipitate was washed with water several times and filtered [25].

 

1,4-bis(2-(4-hydroxy phenyldiazenyl)-1,3,4-thiadiazol-5-yl)benzene(1),yield 65%, m.p. 230^o C, F.T-IR (KBr) cm^-1, (3360-3210) cm^-1, 3095 cm^-1, 1635 cm^-1, 1610 cm^-1, 1557 cm^-1, ¹H-NMR (DMSO) δ:,6.9-8.1 (m,12H), 6.2 (s,2H),¹³C-NMR (DMSO) δ: 110, 115, 125, 130, 135, 140, 175, 185.

1,4-bis(2-(2,4-dihydroxyphenyldiazenyl)-1,3,4-thiadiazol-5-yl)benzene(2), yield 70%,m.p. 252^o C,F.T-IR (KBr) cm^-1,(3410-3258) cm^-1, 3115 cm^-1, 1645 cm^-1, 1602 cm^-1, 1550 cm^-1, ¹H-NMR (DMSO) δ:,6.3-8.2 (m,10H), 5.9 (s,4H),¹³C-NMR (DMSO) δ: 115, 119, 130, 135, 140, 146, 177, 183.

 

1,4-bis(2-(3-methyl-4-hydroxyphenyldiazenyl)-1,3,4-thiadiazol-5-yl)benzene(3), yield 60%,m.p. 223^o C,F.T-IR (KBr) cm^-1, (3405-3215) cm^-1, 3105 cm^-1, (2955-2867) cm^-1, 1640 cm^-1, 1613 cm^-1, 1569 cm^-1, ¹H-NMR (DMSO) δ:,7.2-8.7 (m,10H), 5.7 (s,2H), 2.5 (s,6H),¹³C-NMR (DMSO) δ: 19, 112, 118, 129, 133, 136, 142, 171, 183.

 

1,4-bis(2-(3-methoxy-4-hydroxyphenyldiazenyl)-1,3,4-thiadiazol-5-yl)benzene(4), yield72%, m.p. 233^o C,F.T-IR (KBr) cm^-1, (3395-3255) cm^-1, 3101 cm^-1, (2949-2850) cm^-1, 1633 cm^-1, 1611 cm^-1, 1560 cm^-1, ¹H-NMR (DMSO) δ:,7.5-8.9 (m,10H), 5.3 (s,2H), 3.6 (s,6H),¹³C-NMR (DMSO) δ: 55, 110, 114, 125, 137, 139, 146, 174, 188.

 

1,4-bis(2-(2-nitro-4-hydroxyphenyldiazenyl)-1,3,4-thiadiazol-5-yl)benzene(5), yield 68%,m.p. 219^o C,F.T-IR (KBr) cm^-1, (3382-3203) cm^-1, 3107 cm^-1, 1630 cm^-1, 1605 cm^-1, 1580 cm^-1, ¹H-NMR (DMSO) δ:,7.1-8.5 (m,10H), 5.9 (s,2H), ¹³C-NMR (DMSO) δ: 105, 111, 127, 139, 142, 155, 169, 175.

 

1,4-bis(2-(3-chloro-4-hydroxyphenyldiazenyl)-1,3,4-thiadiazol-5-yl)benzene(6), yield 55%,m.p. 237^o C,F.T-IR (KBr) cm^-1, (3397-3183) cm^-1, 3074 cm^-1, 1625 cm^-1, 1602 cm^-1, 1562 cm^-1, ¹H-NMR (DMSO) δ:,7.5-8.3 (m,10H), 6.3 (s,2H), ¹³C-NMR (DMSO) δ: 115, 121, 129, 135, 148, 165, 173, 182.

 

1,4-bis(2-(2-chloro-4-hydroxyphenyldiazenyl)-1,3,4-thiadiazol-5-yl)benzene(7), yield 59%,m.p. 228^o C,F.T-IR (KBr) cm^-1, (3381-3174) cm^-1, 3116 cm^-1, 1629 cm^-1, 1607 cm^-1, 1582 cm^-1, ¹H-NMR (DMSO) δ:,6.8-8.1 (m,10H), 5.7 (s,2H), ¹³C-NMR (DMSO) δ: 109, 120, 125, 137, 144, 164, 171, 179.

 

1,4-bis(2-(2-bromo-4-hydroxyphenyldiazenyl)-1,3,4-thiadiazol-5-yl)benzene(8), yield 63%,m.p. 245^o C,F.T-IR (KBr) cm^-1, (3375-3163) cm^-1, 3107 cm^-1, 1639 cm^-1, 1617 cm^-1, 1569 cm^-1, ¹H-NMR (DMSO) δ:,7.1-8.8 (m,10H), 5.9 (s,2H), ¹³C-NMR (DMSO) δ: 119, 126, 133, 139, 148, 167, 176, 185.

 

Antimicrobial Screening:

The antibacterial activity of the synthesized compounds was tested against four Gram-positive bacteria (S. aureus, S. epidermidis, M. luteus and B. cereus) and two Gram-negative bacteria (E. coli and P. aeruginosa) using nutrient agar medium. The sterilized [26] (autoclaved at 120 ^oC for 30 min) medium (40-50 ^oC) was inoculated (1 mL/100 mL of medium) with the suspension (105 cfu mL^-1) of the microorganism (matched to McFarland barium sulfate standard) and poured into a petridish to give a depth of 3-4 mm. The paper was impregnated with the test compounds. The paper impregnated with the test compounds (µg mL^-1in DMF) was placed on the solidified medium. The plates were incubated at 37 ^oC for 24. Ciprofloxacin (100 µg/disc) was used as standard. The inhibition zones is shown in Table (3).MIC [27] for the synthesized compounds was calculated by agar streak dilution method. A stock solution of the compound (100 µg mL^-1) in DMF was prepared and graded quantities of the test compounds were incorporated in a specified quantity of molten sterile agar (nutrient agar). A specified quantity of the medium (40-50^oC) containing the compound was poured into a petridish to give a depth of 3-4 mm and allowed to solidify. Suspension of the microorganism was prepared to contain approximately 105 cfu mL^-1and applied to plates with serially diluted compounds in DMF to be tested and incubated at 37 ^oC for 24 hrs. The MIC represents the lowest concentration of the tested substance showing no visible growth of bacteria on the plate. The MIC is shown in Table (1).

 

Table (1): Antibacterial activity and MIC for the synthesized compounds (1-8).

Compound No.	S.aureus	S.epidermidis	M.luteus	B.cereus	E.coli	P.aeruginosa
1	10(9.2)	12(6.3)	13(5.3)	9(8.1)	15(4.6)	8(9.3)
2	9(9.7)	14(5.7)	17(10.3)	8(15.3)	13(12.9)	18(19.2)
3	10(13.8)	14(18.7)	6(9.5)	5(11.4)	13(13.1)	6(15.8)
4	9(10.7)	11(18.4)	13(13.2)	5(14.9)	9(19.5)	12(18.2)
5	7(19.8)	13(11.2)	11(14.6)	14(13.3)	7(10.6)	9(11.9)
6	22(9.2)	19(6.1)	18(5.9)	21(11.2)	18(10.3)	20(7.6)
7	4(14.1)	7(15.5)	13(13.8)	10(11.7)	13(11.4)	11(11.8)
8	9(13.2)	6(10.9)	11(15.6)	12(9.7)	5(13.5)	10(12.4)
Ciprofloxacin (100 µg/disc)	28	33	32	25	30	5

 

RESULTS AND DISCUSSION:

The synthesis involves anultrasonic cyclization of terephthalic acidwith thiosemicarbazide,using phosphorus oxychloride (POCl₃) chloride to form1,4-bis(2-amino-1,3,4-thiadiazol-5-yl) benzene.The compound was purified by multiple recrystallization from absolute ethanol.The compounds (1-8) were prepared by the diazotization reaction of 1,4-bis(2-amino-1,3,4-thiadiazol-5-yl) benzene with different substituted phenols to give 1,4-bis(2-substituted phenyldiazenyl-1,3,4-thiadiazol-5-yl) benzene (1-8). All the synthesized compounds were characterized by usingF.T.IR, ¹H-NMRand ¹³C-NMR.The anti-microbial screening activity were measuredusing disc diffusion method. The minimuminhibitory concentrations (MICs) of the compounds estimated by using agar streak dilution method. The results show that the compound (6)was the most active compound against the used microbes.

 

ACKNOWLEDGMENTS:

I am especially grateful to the Department of Chemistry and Biology, College of Education for Pure Science, Diyala University for their great help.

 

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Received on 12.12.2017          Modified on 05.01.2018

Accepted on 15.03.2018         © RJPT All right reserved