Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 12  |  Issue : 1  |  Page : 11-19

Synthesis and DPPH radical-scavenging activity of some new 5-(N-substituted-1H-indol-3-yl)-5H-thiazolo[4,3-b]-1,3,4-thiadiazole derivatives


1 Chemistry Department of Natural Compounds, National Research Centre, Dokki, Giza, Egypt
2 Medicinal and Aromatic Plants Department, National Research Centre, Dokki, Giza, Egypt

Date of Submission07-Oct-2012
Date of Acceptance03-Jan-2013
Date of Web Publication18-Jul-2014

Correspondence Address:
Eslam R. El-Sawy
Chemistry Department of Natural Compounds, National Research Centre, Dokki 12311, Giza
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EPJ.0000426585.93667.87

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  Abstract 

Background and objectives

Heterocyclic systems with thiadiazole nucleus show a wide spectrum of biological activities such as antioxidant, analgesic, antitumor, and anti-inflammatory activities. The aim of this study is to describe the synthesis of some new 5-(N-substituted-1H-indol-3-yl)-5H-thiazolo[4,3-b]-1,3,4-thiadiazole derivatives and to evaluate their antioxidant activity using 2,2º-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity.

Materials and methods

A one-pot reaction of N-substituted-1H-indol-3-carboxaldehyde 1a,b with thioglycolic acid and thiosemicarbazide in concentrated sulfuric acid yielded novel 2-amino-5-(N-substituted-1H-indol-3-yl)-5H-thiazolo[4,3-b]-1,3,4-thiadiazoles 2a,b. The reaction of 2a,b with some benzenesulfonyl chlorides and/or benzoyl chlorides yielded sulfonamides 3a,b and 4a,b and benzamide 5a,b and 6a,b derivatives, respectively, whereas, the reaction of 2a,b with chloroacetyl chloride yielded chloroacetamide derivatives 7a,b, which, on cyclization with potassium thiocyanate, yielded thiazolidinone derivatives 8a,b. The reaction of 2a,b with sodium azide yielded tetrazole derivatives 9a,b. However, the reaction of 2a,b with benzaldehyde yielded Schiff bases 10a,b, which cyclized with chloroacetyl chloride and/or phenacyl bromide to yield azetidinone derivatives 11a,b and 12a,b, respectively. However, the reaction of 10a,b with sodium cyanide, followed by acid hydrolysis yielded the α-amino acid derivatives 14a,b. Diazotization of 2a,b yielded diazonium salt A, which, on coupling with sodium azide, yielded the azido derivatives 15a,b. Cyclization of 15a,b with ethylacetoacetate yielded tetrazole derivatives 16a,b, whereas the coupling reaction of A with malononitrile yielded dicyano derivatives 17a,b, which, on cyclization with hydrazine hydrate, yielded 3,5-diaminopyrazole derivatives 18a,b. The newly synthesized compounds were screened for their antioxidant activity using 2,2º-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity.

Results and conclusion

4-{5-[(1H-Indol-3-yl)-5H-thiazolo[4,3-b]-1,3,4-thiadiazol-2-yl]diazo}-1H-pyrazole-3,5-diamine (18a) was highly active with radical-scavenging activity (IC50 of 69.14 μg/ml) compared with ascorbic acid (IC50 of 6.50 μg/ml).

Keywords: DPPH radical-scavenging activity, indole-3-carboxaldehyde, synthesis, tetrazole, thiazolo[4,3-b]-1,3,4-thiadiazole


How to cite this article:
Abo-Salem HM, Ebaid MS, El-Sawy ER, El-Gendy AE, Mandour AH. Synthesis and DPPH radical-scavenging activity of some new 5-(N-substituted-1H-indol-3-yl)-5H-thiazolo[4,3-b]-1,3,4-thiadiazole derivatives. Egypt Pharmaceut J 2013;12:11-9

How to cite this URL:
Abo-Salem HM, Ebaid MS, El-Sawy ER, El-Gendy AE, Mandour AH. Synthesis and DPPH radical-scavenging activity of some new 5-(N-substituted-1H-indol-3-yl)-5H-thiazolo[4,3-b]-1,3,4-thiadiazole derivatives. Egypt Pharmaceut J [serial online] 2013 [cited 2020 Aug 5];12:11-9. Available from: http://www.epj.eg.net/text.asp?2013/12/1/11/136939


  Introduction Top


Thiadiazole is a versatile moiety that shows a wide variety of biological activities, viz, antioxidant, analgesic, anticonvulsant, anti-hepatitis B, antitubercular, antitumor, antidepressant, anti-inflammatory, antimicrobial, and anti-Helicobacter pylori 1–6. Besides these, fused 5H-thiazolo [4,3-b]-1, 3, 4-thiadiazoles have been prepared and become a substance among 1, 3, 4-thiadiazoles that has drawn the attention of researchers 7–9. Moreover, indole, which is the potent basic pharmacodynamic nucleus, has been reported to have a wide variety of biological properties, viz, antioxidant 10, anti-inflammatory 11, 12, anti-cancer 13, and antimicrobial activities 12,14. On the basis of the above observations and as a part of our continuous work on the preparation of new poly-heterocycles with pharmaceutical values 11–16, the present study focuses on the synthesis of some new N-substituted-3-indolyl-5H-thiazolor-1, 3, 4-thiadiazoles for the evaluation of their antioxidant activity using 2,2º-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity starting from N-substituted indole-3-carboxaldehyde.


  Materials and methods Top


Chemistry

Melting points were determined in open capillary tubes on an Electrothermal 9100 digital melting point apparatus (Electrothermal Engineering Ltd, Serial No. 8694, Rochford, United Kingdom) and were uncorrected. Elemental analyses were carried out on a Perkin-Elmer 2400 analyzer (940 Winter Street, Waltham, Massachusetts, USA) and were found to be within ±0.4% of the theoretical values [Table 1]. IR spectra were recorded by Perkin-Elmer 1600 Fourier transform infrared spectroscopy against KBr discs. The 1H NMR spectra were measured using a mass spectrometer (JEOL Ltd. 1-2, Musashino 3-chome Akishima, Tokyo, Japan) 500 MHz in DMSO-d6, and chemical shifts were recorded in δ ppm relative to TMS as an internal standard. Mass spectra (EI) were run at 70 eV using a JEOL-JMS-AX500 mass spectrometer (Japan). All reagents and solvents were of commercial grade. 1H-indole-3-carboxaldehyde (1a) 17 and N-benzyl-1H-indole-3-carboxaldehyde (1b) have been prepared as reported 18.
Table 1: Physical and analytical data of the newly synthesized compounds

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2-Amino-5-(1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazole (2a) and 2-amino-5-(N-benzyl-1H-indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazole (2b)

N-substituted-1H-indole-3-carboxaldehydes 1a or 1b (0.02 mol) and thioglycolic acid (1.84 ml, 0.02 mol) were mixed for 10–15 min. To the reaction mixture, thiosemicarbazide (1.82 g, 0.02 mol) was added with stirring and then concentrated sulfuric acid (10 ml) was added in portions upon cooling. The reaction mixture was homogenized and left for 24 h in a deep freezer (−20°C). The reaction mixture was then treated with crushed ice (50 g) and the suspension obtained was neutralized with an aqueous sodium hydroxide solution (40%) to pH≃7–8. The precipitate that formed was filtered off, air dried, and crystallized from aqueous dioxane [Scheme 1] [Additional file 1] and [Table 1].

N-[5-(1H-Indol-3-yl1)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl] benzenesulfonamide (3a), N-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]benzenesulfonamide (3b), 4-chloro-N-[5-(1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]benzene-sulfonamide (4a), and 4-chloro-N-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolokr-1, 3, 4-thiadiazol-2-yl]benzenesulfonamide (4b)

A mixture of compounds 2a or 2b (0.001 mol) and benzenesulfonyl chloride, or 4-chlorobenzenesulfonyl chloride (0.001 mol) in dry dioxane (10 ml) containing a few drops of triethylamine was heated at reflux for 6 h. After cooling, the reaction mixture was poured onto cold water (10 ml). The solid that formed was filtered off, air dried, and crystallized from dioxane [Scheme 1] [Additional file 2] and [Table 1].

N-[5-(1H-Indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl] benzamide (5a), N-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]benzamide (5b), 2-chloro-N-[5-(1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]benzamide (6a), and 2-chloro-N-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]benzamide (6b)

A mixture of compounds 2a or 2b (0.001 mol) and benzoyl chloride or 2-chlorobenzoyl chloride (0.001 mol) in dry dioxane (10 ml) containing a few drops of triethylamine was heated at reflux for 8 h. After cooling, the reaction mixture was poured onto cold water (20 ml). The solid that formed was filtered off, air dried, and crystallized from dioxane [Scheme 1 and [Table 1].

N-[5-(1H-Indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl]-2-chloroacetamide (7a) and N-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]-2-chloroacetamide (7b)

To a solution of compounds 2a or 2b (0.02 mol) in dry benzene (60 ml), a solution of chloroacetyl chloride (5 ml, 0.04 mol) in dry benzene (20 ml) was added dropwise under vigorous stirring at 0–5°C. After complete addition, the reaction mixture was heated at reflux for 3 h. The solvent was evaporated in vacuo and the solid that formed was washed with sodium hydrogen carbonate (20 ml, 5%) and then with water, air dried, and crystallized from chloroform [Scheme 1 and [Table 1].

3-[5-(1H-Indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl]-2-iminothiazolidin-4-one (8a) and 3-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl]-2-iminothiazolidin-4-one (8b)

A mixture of compounds 7a or 7b (0.003 mol) and potassium thiocyanate (0.58 g, 0.006 mol) in dry acetone (10 ml) was heated at reflux for 3 h. The solid that formed was filtered off, air dried and crystallized from chloroform [Scheme 1 and [Table 1].

5-(1H-Indol-3-yl)-2-(1H-tetrazol-1-yl)-5H-thiazolor-1, 3, 4-thiadiazole (9a) and 5-(N-benzyl-1H-indol-3-yl)-2-(1H-tetrazol-1-yl)-5H-thiazolor-1, 3, 4-thiadiazole (9b)

A mixture of compounds 2a or 2b (0.001 mol), triethyl orthoformate (0.15 ml, 0.001 mol), and sodium azide (0.065 g, 0.001 mol) in glacial acetic acid (10 ml) was stirred under reflux for 2 h. After cooling, the reaction mixture was neutralized with concentrated hydrochloric acid (10 ml). The solid that formed was filtered off, washed with water, air dried, and crystallized from absolute ethanol [Scheme 1 and [Table 1].

N-Benzylidene-(5-(1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl)-2-amine (10a) and N-benzylidene-[(5-(N-benzyl-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]-2-amine (10b)

A mixture of compounds 2a or 2b (0.01 mol) and benzaldehyde (1.06 g, 0.01 mol) in glacial acetic acid (20 ml) was heated at reflux for 6 and 8 h. After cooling, the reaction mixture was poured onto ice water (50 ml). The solid that formed was filtered off, air dried, and crystallized from benzene [Scheme 2 and [Table 1].

1-[5-(1H-Indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]-3-chloro-4-phenylazetidin-2-one (11a), 1-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]-3-chloro-4-phenylazetidin-2-one (11b), 1-(5-(1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl)-3,4-diphenylazetidin-2-one (12a), and 1-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]-3,4-diphenylazetidin-2-one (12b)

To a solution of Schiff bases 10a or 10b (0.01 mol) in dry dioxane (5 ml), a solution of chloroacetyl chloride and/or phenacyl bromide (0.01 mol) in dry dioxane (5 ml) and triethylamine (0.59 ml, 0.01 mol) was added. The reaction mixture was heated at reflux for 12–14 h. The reaction mixture was filtered off while hot and the solvent was removed in vacuo. The residue solid was treated with water and filtered, air dried, and crystallized from absolute ethanol [Scheme 2 and [Table 1].

2-[5-(1H-Indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl amino]phenylacetonitrile (13a) and 2-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl amino]phenylacetonitrile (13b)

To a solution of Schiff bases 10a or 10b (0.01 mol) in glacial acetic acid (20 ml) sodium cyanide (0.49 g, 0.01 mol) was added and the reaction mixture was heated at reflux for 6 h. After cooling, the reaction mixture was poured onto cold water (10 ml) and the solid that formed was filtered off, washed with water, air dried, and crystallized from acetic acid–water [Scheme 2 and [Table 1].

2-[5-(1H-Indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl amino] phenyl acetic acid (14a) and 2-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl amino]phenyl acetic acid (14b)

A solution of compounds 13a or 13e (0.01 mol) in sulfuric acid (30 ml, 50%) was heated at reflux for 10 h. After cooling, the dark reaction mixture was poured onto cold water (20 ml) and then neutralized with ammonia solution (25%). The precipitate that formed was filtered off, washed with water, air dried, and crystallized from aqueous acetic acid [Scheme 2 and [Table 1].

2-Azido-5-(1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazole (15a) and 2-azido-5-(N-benzyl-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazole (15b)

To a cold solution of compounds 2a or 2b (0.02 mol) in a mixture of concentrated hydrochloric acid (5 ml) and ice water (5 ml), a cold aqueous solution of sodium nitrite (1.73 g, 0.025 mol) in ice water (5 ml) was added dropwise under stirring at 0–5°C. After 10 min, the reaction mixture was decanted. To the decanted solution of the diazonium salt thus formed (A), sodium azide (1.3 g, 0.02 mol) in water (5 ml) was added dropwise. The reaction mixture was left for 15 min at room temperature and the azide was extracted by chloroform (3–10 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was used without subsequent purification, and used in the reaction immediately after its formation because of its instability [Scheme 2 and [Table 1].

1-[5-(1H-Indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl]-5-methyl-1H-1, 2, 3-triazole-4-carboxylic acid (16a) and 1-[5-(N-benzyl-1H-indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl]-5-methyl-1H-1, 2, 3-triazole-4-carboxylic acid (16b)

To a solution of sodium (0.23 g, 0.01 mol) in absolute methanol (20 ml) ethylacetoacetate (1.34 g, 0.01 mol) and compounds 15a or 15b (0.01 mol) were added dropwise under cooling in an ice bath. The reaction mixture was kept in an ice water bath for 30 min and then gradually heated under reflux for 1 h. After cooling, the reaction mixture was neutralized by diluted hydrochloric acid (1 : 1). The solid that formed was filtered off, washed with water, air dried, and crystallized from methanol [Scheme 2 and [Table 1].

2-{5-[(1H-Indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl] hydrazono}malononitrile (17a) and 2-{5-[(N-benzyl-1H-indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl]hydrazono}malononitrile (17b)

To a cold solution of compounds 2a or 2b (0.02 mol) in a mixture of concentrated hydrochloric acid (5 ml) and ice water (5 ml), a cold aqueous solution of sodium nitrite (1.73 g, 0.025 mol) in ice water (5 ml) was added dropwise under stirring at 0–5°C. After 10 min, the reaction mixture was decanted. To the decanted solution of the diazonium salt thus formed (A), a cold solution of malononitrile (1.3 g, 0.02 mol) and sodium acetate trihydrate (5.4 g, 0.04 mol) in ethanol (10 ml) was added under stirring at 0–5°C. The stirring was continued for an additional 3 h at 0–5°C, and then left overnight in the refrigerator. The reaction mixture was poured onto water (250 ml) and the solid that formed was filtered off, air dried, and crystallized from absolute ethanol [Scheme 2 and [Table 1].

4-{5-[(1H-Indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl]diazo}-1H-pyrazole-3,5-diamine (18a) and 4-{5-[(N-benzyl-1H-indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl]diazo}-1H-pyrazole-3,5-diamine (18b)

A mixture of compounds 17a or 17b (0.01 mol) and hydrazine hydrate (0.75 ml, 0.015 mol) in absolute ethanol (20 ml) was heated at reflux for 6 h. The solvent was evaporated in vacuo to half of its volume and the solid that formed was filtered off, washed with water, air dried, and crystallized from absolute ethanol [Scheme 2 and [Table 1].

Biological assay

DPPH radical-scavenging activity

The antioxidant activity of the test compounds was measured in terms of hydrogen-donating or radical-scavenging ability using the stable radical 2,2º-diphenyl-1-picrylhydrazyl (DPPH) (Sigma Chemical Co., Steinheim, Germany) 19. A volume of 50 μl of a DMSO stock solution of tested compounds at four different concentrations (50, 100, 200, and 300 μg/ml) was added to 2 ml of 6×10–5 mol/l dimethylsulfoxide solution of DPPH (2.3659 mg from DPPH/100 ml DMSO). The mixtures were shacked in a vortex (2500 rpm) for 1 min and then placed in a dark room. Ascorbic acid (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany) was used as a reference. The decrease in absorbance at 517 nm was determined using a JENWAY 6315 spectrophotometer (Keison Products, Chelmsford, England) after 1 h for all samples. Dimethylsulfoxide was used to zero the spectrophotometer. The absorbance of the radical without a sample was used as a negative control. The amount of sample necessary to decrease the absorbance of DPPH (IC50) by 50% was calculated graphically. The inhibition percentage of the DPPH radical (scavenging activity) was calculated according to the following formula:

where I is the DPPH inhibition %, AB the absorbance of control (t=0 h), and AS the absorbance of a tested sample at the end of the reaction (t=1 h). Each assay was carried out in triplicate and the results were averaged.


  Results and discussion Top


Chemistry

The reaction route for the synthesis of the newly synthesized compounds has been described in Schemes 1 and 2. New 2-amino-5-(N-substituted-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazoles (2a,b) were prepared by a one-pot reaction of N-substituted-1H-indole-3-carboxaldehyde with thioglycolic acid and thiosemicarbazide in concentrated sulfuric acid according to the procedure of Shukurov et al. 7 [Scheme 1]. The IR spectra of compounds 2a,b showed characteristic absorption bands at ∼3241–3410/cm for (NH2) and showed no absorption band characteristic for C=O [Table 2]. Their 1H NMR (DMSO-d6) spectra showed two singlet signals at δ 12.12–9.90 ppm attributed to 5-H and 7-H of thiazolo [4,3-b]-1, 3, 4-thiadiazole moiety, besides the other aromatic protons located at their positions [Table 2].
Table 2: Spectral characterization of the newly synthesized compounds

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The reaction of compounds 2a or 2b with benzenesulfonyl chloride and 4-chlorobenzenesulfonyl chloride in dry dioxane and in the presence of triethylamine led to the formation of N-[5-(N-substituted-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]benzenesulfonamide derivatives 3a,b and 4a,b, respectively [Scheme 1]. However, the reaction of 2a,b with benzoyl chloride and 2-chlorobenzoyl chloride yielded N-[5-(N-substituted-1H-indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl]benzamide derivatives 5a,b and 6a,b, respectively [Scheme 1].

In contrast, the reaction of 2a or 2b with chloroacetyl chloride in dry benzene yielded N-[5-(N-substituted-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]-2-chloroacetamides (7a,b). Cyclization of the latter compounds through their reactions with potassium thiocyanate in dry acetone yielded 3-[5-(N-substituted-1H-indol-3-yl)-5H-thiazolor-1, 3, 4-thiadiazol-2-yl]-2-iminothiazolidin-4-ones (8a,b) [Scheme 1].

The treatment of 2a or 2b with triethyl orthoformate and sodium azide according to Abu-Hashem et al. 20 yielded the new 5-(N-substituted-1H-indol-3-yl)-2-(1H-tetrazol-1-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazols (9a,b) [Scheme 1].

The acid-catalyzed reaction of 2a,b with benzaldehyde in glacial acetic acid under reflux yielded the corresponding Schiff bases, N-benzylidene-[5-(N-substituted-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]-2-amines (10a,b) [Scheme 2]. Cyclocondensation of the latter Schiff bases with chloroacetyl chloride and/or phenacyl bromide under reflux in dry dioxane and in the presence of triethylamine yielded 3-chloro-4-phenylazetidin-2-one derivatives 11a,b and 3,4-diphenylazetidin-2-one derivatives 12a,b, respectively [Scheme 2].

However, the reaction of Schiff bases 10a or 10b with sodium cyanide in glacial acetic acid yielded 2-[5-(N-substituted-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl amino]phenylacetonitriles (13a,b) [Scheme 2]. Acid hydrolysis of the latter compounds 13a or 13b yielded the corresponding α-amino acid 14a,b [Scheme 2].

Diazotization of compounds 2a or 2b with concentrated hydrochloric acid and sodium nitrite at 0–5°C yielded the corresponding diazonium salts (A), which, under coupling with sodium azide, yielded the corresponding azides, namely, 2-azido-5-(N-substituted-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazols (15a,b). The freshly prepared azides 15a,b reacted with ethylacetoacetate in dry methanol and in the presence of freshly prepared sodium methoxide and yielded 1-[5-(N-substituted-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]-5-methyl-1H-1, 2, 3-triazole-4-carboxylic acids (16a,b) [Scheme 2].

However, coupling of diazonium salts (A) with malononitrile in the presence of sodium acetate trihydrate yielded 2-[(5-(N-substituted-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl hydrazono] malononitriles (17a,b). The reaction of the latter compounds with hydrazine hydrate in absolute ethanol under reflux yielded the corresponding pyrazoles (18a,b) [Scheme 2].

DPPH radical-scavenging activity

The preliminary DPPH radical-scavenging activity of the newly synthesized compounds was determined using ascorbic acid as a reference and IC50 of the most active compounds were calculated [Table 3] and [Figure 1]. From the data obtained, compounds 14a and 18a showed free radical-scavenging effects of 84.61 and 80.83% compared with that of ascorbic acid of 91.25% at a concentration of 300 μg/ml, whereas at a concentration of 200 μg/ml, only 18a showed a radical-scavenging effect of 79.56% compared with that of ascorbic acid of 85.41%. The amount of sample necessary to decrease the absorbance of DPPH by 50% (IC50) was calculated and it was found that 4-{5-[(1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]diazo}-1H-pyrazole-3,5-diamine (18a) was highly active with radical-scavenging activity (IC50 of 69.14 μg/ml) compared with ascorbic acid (IC50 of 6.50 μg/ml); this may be because of the presence of the N–H moieties of the two primary aromatic amino groups and secondary amine, which act as good hydrogen bond donors [Table 3] and [Figure 1].
Table 3: Scavenging activity % on DPPH radicals of the most active synthesized compounds and IC50 values

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Figure 1: Scavenging activity % on DPPH radicals of the most active synthesized compounds.

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  Conclusion Top


Some new heterocycles derived from novel 2-amino-5-(N-substituted-1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thidiazoles (2a,b) were prepared and screened for their antioxidant activity using 2,2º-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity. 4-{5-[(1H-indol-3-yl)-5H-thiazolo [4,3-b]-1, 3, 4-thiadiazol-2-yl]diazo}-1H-pyrazole-3,5-diamine (18a) was found to be highly active with radical-scavenging activity (IC50 of 69.14 μg/ml) compared with ascorbic acid (IC50 of 6.50 μg/ml); this may be because of the presence of the N–H moieties of the two primary aromatic amino groups and secondary amine, which act as good hydrogen bond donors.[20]

 
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