Synthesis and antimicrobial activity of some novel 2-thienyl substituted heterocycles

Mohamed Salah K. Youssef; Ahmed Abdou O. Abeed

doi:10.1515/hc-2013-0197

Article Open Access

Synthesis and antimicrobial activity of some novel 2-thienyl substituted heterocycles

Mohamed Salah K. Youssef and Ahmed Abdou O. Abeed

Published/Copyright: January 23, 2014

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From the journal Heterocyclic Communications Volume 20 Issue 1

Abstract

A series of 2-thienyl substituted derivatives of thiazoles, oxazoles and spiro(indole-azole) were synthesized. The structures of the synthesized compounds were confirmed by IR, NMR and mass spectral data.

Keywords: 2-acetylthiophene; antimicrobial activity; MIC; spiro; thiazolidines

Introduction

Thiophene derivatives are important compounds [1–8] with considerable biological activity, such as antimicrobial [9, 10], anti-inflammatory and analgesic activities [11–14]. Spiroindoles possessing a stereogenic center at C-3 [15, 16] and thiazolidine derivatives have also wide applications in synthetic and medicinal chemistry [17–21]. In view of the above mentioned findings and as continuation of our efforts in the synthesis of new biologically active heterocycles [22, 23]. We report herein the synthesis of thiazolidines and spiroindoles linked to thiophene and evaluation of their antimicrobial activities.

Results and discussion

Chemistry

The reaction of 2-acetylthiophene (1) with thiosemicarbazide afforded 1-(thiophen-2-yl)ethanone thiosemicarbazone (2) according to a previously described method [24]. Treatment of the thiosemicarbazone 2 with freshly distilled acetic anhydride gave ethylidene thiosemicarbazide derivative 3. Compound 3 was cyclized by heating to give 5-acetamidothiazolidine 4. Compound 4 was also obtained by heating of 2 with acetic anhydride in pyridine. The structure of 4 was confirmed by IR, NMR and mass spectral analyses.

The reaction of thiosemicarbazone 2 with ethyl chloroacetate, chloroacetamide or chloroacetone afforded the thiazolidinones 5 and 6. It is of interest to mention that the products of reacting 2 with ethyl chloroacetate or chloroacetamide were identical. The IR spectrum of 5 contains bands at ν 3120 cm^-1 due to NH function and the C=O band of the thiazolidine ring at ν 1720 cm^-1. The ¹H NMR spectrum shows methylene protons signals of the thiazolidine function and NH signals at 3.82 and 11.93 ppm, respectively. The ¹³C NMR spectrum of 5 is also consistent with the given structure. Compound 5 contains active methylene group. As such, it was condensed with aromatic aldehydes and D-glucose in the presence of piperidine to yield the arylidenes 7a–d. Subjecting the prepared aldehydo-hexose chalcone 7d to acetylation using a mixture of acetic anhydride and pyridine gave the crystalline product 8. The ¹H NMR spectrum of 8 contains signals for five OAc groups in the range of δ 2.30–2.60 ppm. These acetyl groups show a characteristic absorption band around ν 1670 cm^-1 in the IR spectrum (Scheme 1).

Scheme 1

Condensation of 1 with malononitrile in the presence of morpholine led to the formation of dicyanoethylidene derivative 9. The IR spectrum of 9 shows a strong band at ν 2200 cm^-1 for two cyano groups. Treatment of 9 with phenylhydrazine in boiling ethanol furnished one isolable product for which structures 10, 11 and 12 seemed possible (Scheme 2). The IR spectrum of the isolated product shows a lack of the CN absorption band and the presence of absorption band at 3385 cm^-1 for an NH group. Furthermore, the ¹H NMR spectrum contains a broad singlet signal at 7.90 ppm (D₂O exchangeable) for the NH proton. These findings provide firm support for the structure 12 and exclude the pyrazoline derivative 10. The structure of 12 was supported by its independent synthesis as shown in Scheme 2.

Scheme 2

The chalcone 14 was prepared according to a previously described method [25]. Hydrazinolysis of 14 in ethanol yielded spiro[indole-pyrazole]-2(1H)-one 15. Otherwise, the hydrazinolysis in acetic acid gave the acetyl derivative 16. The presence of acetyl group in the product 16 was established using IR and ¹H NMR spectra. The reaction of 14 with hydroxylamine in ethanol containing AcONa produced spiro[indole-oxazole]-2(1H)-one 17. Finally, phenyl-substituted spiro[indole-pyrazole]-2(1H)-one 18 was obtained by condensation of chalcone 14 with phenylhydrazine. Analytical and spectral data (IR, ¹H NMR, ¹³C NMR and EI-MS) confirmed the structures of the synthesized compounds 17 and 18 (Scheme 3).

Scheme 3

Antimicrobial evaluation

Antibacterial evaluation

All compounds were screened for their antibacterial activities against Gram-positive bacteria (Staphylococcus aureus AUMC B-54, Micrococcus luteus AUMC B-112, Bacillus cereus AUMC B-52, Escherichia coli AUMC B-53, Pseudomonas aeruginosa AUMC B-73, Serratia marcescens AUMC B-55). Chloramphenicol was used as the reference (Table 1). The minimum inhibitory concentrations (MICs) were recorded. All compounds exhibit significant antibacterial activities. Thiazolidinones 7b–d and phenyl substituted spiro[indole-pyrazole]-2-one 18 are remarkably active against the tested antibacterial species at the MIC range of 5–41 μg/mL. Substitution of hydrogen atom at para position of the aromatic ring in compounds 7a–c by a chlorine atom, or nitro group results in increasing of the antibacterial activity.

Table 1

The antibacterial activity of the synthesized compounds, MIC (μg/mL).

No.	S. aureus (Gram+)	M. luteus (Gram+)	B. cereus (Gram+)	E. coli (Gram-)	P. aeruginosa (Gram-)	S. marcescens (Gram-)
2	130	100	50	64	100	70
3	125	90	20	38.5	80	34.5
4	65	60	15	30	55	25
5	78	78	17	35	72	30
6	72	68	20	34	72	28
7a	49	60	15	25	59	15
7b	21.5	41	10	20	30	11
7c	10	30	10	15	20	10
7d	5	20	5	10	10	5
8	10	11	10	–	90	20
9	74	–	37	29	19	40
12	15	38	52	48	125	10
13	50	49	30	55	80	22
14	70	60	60	100	120	50
15	48	50	50	80	79	42
16	30	41	40	64	51	30
17	42	28	49	35	46	27
18	34	20	28	30	40	17
Ref.^a	10	10	10	10	10	4.5

^aChloramphenicol was used as antibacterial standard. –, no activity.

Antifungal evaluation

The compounds were also screened for their antifungal activities against six antifungal species, Candida albicans AUMC 1299, Geotrichum candidum AUMC 226, Fusarium oxysporum AUMC 5119, Aspergillus flavus AUMC 1276, Trichophyton rubrum AUMC 1804 and Scopulariopsis brevicaulis AUMC 361. As shown in Table 2, most of the tested compounds are active. The spiro compounds 15–18 show strong antifungal activities in comparison to chalcone 14.

Table 2

The antifungal activity of the synthesized compounds, MIC (μg/mL).

No.	C. albicans	G. candidum	T. rubrum	F. oxysporum	A. flavus	S. brevicaulis
2	110	120	100	90	80	69
3	20	80	34	100	57	66
4	15	62	20	80	30	52
5	20	65	32	96	48	63
6	21	56	30	78	44	62
7a	12	46	20	58	34	36
7b	10	41	15	47	32	24
7c	8	25	10	25	20	20
7d	5	15	10	15	10	10
8	100	40	26	26	55	48
9	–	–	–	–	–	–
12	24	35	30	23	13	32
13	50	55	64	44	70	100
14	64	72	95	68	96	120
15	48	62	73	30	68	90
16	40	50	61	20	50	70
17	31	42	49	15	38	52
18	30	40	45	12	30	41
Ref.^a	10	20	10	10	10	20

^aClotrimazole was used as antifungal standard. –, no activity.

Conclusion

A novel series of thiazolidines and spiro(indole-azole) derivatives was synthesized. The antimicrobial activity of these compounds was evaluated. Compounds 7a–d and 15–18 display remarkable antimicrobial potency.

Experimental

Chemistry

Melting points were determined with an APP Digital ST 15 melting point apparatus. Infrared spectra were recorded in KBr pellets using a Pye-Unicam SP3–100 spectrophotometer. The ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were determined using a JNM-LA Series 400 spectrometer and DMSO-d₆. Mass spectra were measured using a JOEL JMS 600 spectrometer. Elemental analyses were carried out on a Vario EL C, H, N, S Analyzer.

1-[1-(2-Thienyl)ethylidene]-2,4-diacetylthiosemicarbazide (3)

A solution of thiosemicarbazone 2 (0.99 g, 0.005 mol) in acetic anhydride (20 mL) was heated under reflux for 2 h. After cooling, excess acetic anhydride was decomposed in an ice water mixture. The solid formed was filtered, dried and crystallized from ethanol to afford yellow powder; yield 65%; mp 173–175°C; ¹H NMR: δ 2.02 (s, 3H, CH₃), 2.31 (s, 3H, COCH₃), 2.49 (s, 3H, NCOCH₃), 7.04–7.46 (m, 3H, thiophene-H), 11.70 (s, 1H, NH, D₂O exchangeable); ¹³C NMR: δ 14.7, 22.2, 23.9, 122.3, 129.1, 134.7, 140.7, 155.9, 163.9, 171.0, 183.1; IR: ν 3200 (NH), 2920 (CH-aliph.), 1650 and 1670 for 2 (C=O), 1590 (C=N) cm^-1; MS: m/z 283.23 ([M]⁺, 87%). Anal. Calcd for C₁₁H₁₃N₃O₂S₂ (283.37): C, 46.62; H, 4.62; N, 14.83; S, 22.63. Found: C, 46.65; H, 4.58; N, 14.80; S, 22.58.

N-(3-Acetyl-5-methyl-5-(thiophen-2-yl)-1,3,4-thiadiazolidin-2-ylidene)acetamide (4)

Method A

A mixture of thiosemicarbazone 2 (0.99 g, 0.005 mol) and acetic anhydride (3 mL) in pyridine (25 mL) was heated under reflux for 3 h, then cooled and poured onto ice water. The solid formed was filtered, dried and crystallized from ethanol to afford red powder; yield 70%; mp 183–184°C; ¹H NMR: δ 2.02 (s, 3H, acetyl), 2.13 (s, 3H, acetyl), 2.31 (s, 3H, CH₃), 7.04–7.46 (m, 3H, thiophene-H), 11.70 (s, 1H, NH, D₂O exchangeable);¹³C NMR: δ 22.5, 23.9, 27.6, 76.0, 120.9, 129.1, 134.7, 140.7, 148.7, 168.0, 169.5; IR: ν 3350 (NH), 2920 (CH-aliph.), 1720 and 1700 cm^-1 (C=O); MS: m/z 283.28 ([M]⁺, 91). Anal. Calcd for C₁₁H₁₃N₃O₂S₂ (283.37): C, 46.62; H, 4.62; N, 14.83; S, 22.63. Found: C, 46.58; H, 4.59; N, 14.85; S, 22.57.

Method B

The thiosemicarbazide 3 was heated in an oil bath at 176°C for 10 min. The solid was triturated with petroleum ether (bp 60–80°C), filtered, dried and crystallized from ethanol. The product was identical to that produced by method A.

2-[(1-(2-Thienyl)ethylidene)hydrazono]thiazolidin-4-one (5)

Method A

Thiosemicarbazone 2 (0.99 g, 0.005 mol) and ethyl chloroacetate (0.62 mL, 0.005 mol) were dissolved in hot absolute ethanol (20 mL) containing anhydrous sodium acetate (1 g). The reaction mixture was heated under reflux for 5 h, then cooled and poured onto crushed ice. The solid product was filtered, dried and crystallized from ethanol to afford pale yellow crystals; yield 74%; mp 278–279°C; ¹H NMR: δ 2.30 (s, 3H, CH₃), 3.82 (s, 2H, CH₂ thiazolidine), 7.00–7.57 (m, 3H, thiophene-H), 11.93 (s, 1H, NH, D₂O exchangeable);¹³C NMR: δ 14.9, 32.9, 123.8, 129.1, 134.7, 141.7, 156.3, 163.6, 174.0; IR: ν 3120 (NH), 2825 (CH-aliph.), 1720 cm^-1 (C=O thiazolidine); MS: m/z 239.24 ([M]⁺, 82%). Anal. Calcd for C₉H₉N₃OS₂ (239.32): C, 45.17; H, 3.79; N, 17.56; S, 26.80. Found: C, 45.16; H, 3.81; N, 17.53; S, 26.78.

Method B

A mixture of thiosemicarbazone 2 (0.99 g, 0.005 mol) and chloroacetamide (0.46 g, 0.005 mmol) in ethanol (20 mL) containing anhydrous sodium acetate (1 g) was heated under reflux for 5 h, then cooled and poured onto crushed ice. The solid product was filtered, dried and crystallized from ethanol to afford pale yellow crystals. The product was identical to compound 5 obtained by method A.

4-Methyl-2-[(1-(2-thienyl)ethylidene)hydrazono]-2,3-dihydrothiazole (6)

To a solution of thiosemicarbazone 2 (0.99 g, 0.005 mol) in absolute ethanol (20 mL) was added the equivalent amount of chloroacetone (0.46 mL, 0.005 mol) and anhydrous sodium acetate (1 g). The mixture was heated under reflux for 5 h, cooled and poured onto ice water. The solid product was collected by filtration, dried and crystallized from ethanol to afford yellow powder; yield 65%; mp 201–203°C; ¹H NMR: δ 1.80 (s 3H, CH₃), 2.30 (s, 3H, CH₃ thiazolidine), 6.20 (s, 1H, CH-thiazolidine), 6.40 (s, 1H, CH thiazolidine), 6.90–7.40 (m, 3H, thiophene-H), 9.30 (s, 1H, NH, D₂O exchangeable);¹³C NMR: δ 14.9, 24.2, 98.4, 120.9, 129.1, 134.7, 140.9, 150.1, 155.3, 162.1; IR: ν 3250 (NH), 2978 cm^-1 (CH-aliph.); MS: m/z 237.28 ([M]⁺, 69). Anal. Calcd for C₁₀H₁₁N₃S₂ (237.34): C, 50.60; H, 4.67; N, 17.70; S, 27.02. Found: C, 50.62; H, 4.69; N, 17.68; S, 27.06.

General procedure for the synthesis of 7a–d

A mixture of 5 (1.20 g, 0.005 mol), aromatic aldehyde (0.005 mol) and piperidine (0.005 mol) in dioxane (20 mL) was heated under reflux for 3 h, then cooled and poured onto ice water. The solid product 7a–d was collected by filtration, washed with water and crystallized from ethanol.

5-Benzylidene-2-[(1-(2-thienyl)ethylidene)hydrazono]thiazolidin-4-one (7a)

A brown powder; yield 69%; mp 232–234°C; ¹H NMR: δ 2.20 (s, 3H, CH₃), 6.90–7.75 (m, 8H, aromatic-H + thiophene-H), 8.25 (s, 1H, =CH), 11.20 (s, 1H, NH, D₂O exchangeable);¹³C NMR: δ 15.8, 115.8, 123.7, 129.2, 129.8, 131.2, 133.1, 134.8, 135.8, 137.2, 138.1, 140.3, 142.7, 163.3, 164.6, 173.0; IR: ν 3120 (NH), 3015 (CH arom.), 2920 (CH aliph.), 1690 cm^-1 (C=O thiazolidine); MS: m/z 327.40 ([M]⁺, 67%). Anal. Calcd for C₁₆H₁₃N₃OS₂ (327.42): C, 58.69; H, 4.00; N, 12.83; S, 19.59. Found: C, 58.65; H, 4.03; N, 12.80; S, 19.63.

5-p-Chlorobenzylidene-2-[(1-(2-thienyl)ethylidene)hydrazono]thiazolidin-4-one (7b)

A red powder; yield 67%; mp 223–225°C; ¹H NMR: δ 2.15 (s, 3H, CH₃), 6.90–7.80 (m, 7H, aromatic-H + thiophene-H), 8.20 (s, 1H, =CH), 11.10 (s, 1H, NH, D₂O exchangeable); IR: ν 320 (NH), 3015 (CH arom.), 2960 and 2855 (CH aliph.), 1690 cm^-1 (C=O thiazolidine); MS: m/z 361.81 ([M]⁺, 67%), 363.64 ([M+2]⁺, 23%). Anal. Calcd for C₁₆H₁₂ClN₃OS₂ (361.87): C, 53.11; H, 3.34; Cl, 9.80; N, 11.61; S, 17.72. Found: C, 53.09; H, 3.31; Cl, 9.77; N, 11.63; S, 17.74.

5-p-Nitrobenzylidene-2-[(1-(2-thienyl)ethylidene)hydrazono]thiazolidin-4-one (7c)

Yellow crystals; yield 65%; mp 211–213°C; ¹H NMR: δ 2.15 (s, 3H, CH₃), 6.90–8.00 (m, 7H, aromatic-H + thiophene-H), 8.20 (s, 1H, =CH), 13.40 (s, 1H, NH, D₂O exchangeable); IR: ν 3150 (NH), 3020 (CH arom.), 2930 (CH aliph.), 1695 (C=O thiazolidine), 1570 cm^-1 (NO₂); MS: m/z 372.39 ([M]⁺, 67%). Anal. Calcd for C₁₆H₁₂N₄O₃S₂ (372.42): C, 51.60; H, 3.25; N, 15.04; S, 17.22. Found: C, 51.58; H, 3.21; N, 15.01; S, 17.25.

5-Glucosylidene-2-[(1-(thien-2-yl)ethylidene)hydrazono]thiazolidin-4-one (7d)

White crystals; yield 61%; mp 201–203°C; ¹H NMR: δ 2.22 (s, 3H, CH₃), 2.90–3.02 (m, 2H, alditolyl 2H), 3.10–3.30 (m, 2H, alditolyl 2H), 4.10–4.30 (m, 2H, alditolyl 2H), 4.60 (s, 2H, 2 OH, D₂O exchangeable), 4.90–5.30 (2 m, 1H each, 2 OH, D₂O exchangeable), 5.70 (d, 1H, 1 OH, D₂O exchangeable), 6.10 (s, 1H each, CH=C), 6.49–7.98 (m, 3H, thiophene-H), 11.10 (s, 1H, NH, D₂O exchangeable); IR: ν 3150 (NH), 2950 (CH-aliph.), 1680 cm^-1 (C=O thiazolidine); MS: m/z 401.83 ([M]⁺, 70%). Anal. Calcd for C₁₅H₁₉N₃O₆S₂ (401.46): C, 44.88; H, 4.77; N, 10.47; S, 15.97. Found: C, 44.86; H, 4.74; N, 10.46; S, 15.94.

2,3,4,5,6-Penta-O-acetyl-aldehydo-D-glucose-3-acetyl-2-[(1-(2-thienyl)ethylidene) hydrazono]thiazolidin-4-one (8)

A solution of 7d (2.0 g, 0.005 mol) in pyridine (15 mL) was treated with acetic anhydride (20 mL) and the mixture was stirred at ambient temperature for 24 h, then was poured onto ice water and extracted with CHCl₃ (3 × 20 mL). The organic layer was washed with 10% NaHSO₄ solution (2 × 20 mL), dried (Na₂SO₄), cooled and poured onto crushed ice. The precipitate was collected, dried and crystallized from ethanol to give white powder; yield 61%; mp 156–158°C; ¹H NMR: δ 2.10 (s, 3H, CH₃), 2.30–2.60 (m, 15H, 5 COCH₃), 3.20 (s, 3H, NCOCH₃), 4.30–5.50 (5 m, 6H, alditolyl H), 6.00–6.20 (m, 1H, C=CH), 6.90–7.45 (m, 3H, thiophene-H);¹³C NMR: δ 14.8, 19.0, 20.1, 21.2, 21.9, 22.5, 23.5, 60.6, 62.1, 63.9, 65.5, 68.7, 118.6, 123.7, 124.5, 135.6, 142.7, 145.1, 163.1, 165.0, 170.0, 175.0, 175.7, 175.2, 176.1, 176.9, 178.1; IR: ν 2920 (CH-aliph.), 1680 (C=O thiazolidine), 1670 (C=O) alditolyl, 1590 cm^-1 (C=N); MS: m/z 653.60 ([M]⁺, 91%). Anal. Calcd for C₂₇H₃₁N₃O₁₂S₂ (653.68): C, 49.61; H, 4.78; N, 6.43; S, 9.81. Found: C, 49.58; H, 4.82; N, 6.45; S, 9.78.

2-[1-(2-Thienyl)ethylidene]malononitrile (9)

To solution of 1 (0.63 mL, 0.005 mol) in absolute ethanol (20 mL) was added malononitrile (0.33 g, 0.005 mol) and a catalytic amount of morpholine. The mixture was heated under reflux for 3 h and then cooled. The solid product was collected, dried and crystallized from ethanol to give pale yellow crystals; yield 74%; mp 197–199°C; ¹H NMR: δ 2.40 (s, 3H, CH₃), 6.90–7.45 (m, 3H, thiophene-H); ¹³C NMR: δ 30.2, 90.7, 118.1, 118.9, 122.7, 124.8, 135.7, 142.9, 161.5; IR: ν 2940 (CH-aliph.), 2200 cm^-1 (CN); MS: m/z 174.20 ([M]⁺, 64%). Anal. Calcd for C₉H₆N₂S (174.22): C, 62.05; H, 3.47; N, 16.08; S, 18.40. Found: C, 62.08; H, 3.49; N, 16.11; S, 18.46.

N-[1-(2-Thienyl)ethylidene]- N′-phenylhydrazine (12)

Method A

Phenylhydrazine (0.57 g, 0.005 mol) was added to a solution of 1 (0.63 mL, 0.005 mol) in ethanol (25 mL) and the mixture was heated under reflux for 1 h. Upon cooling, the precipitate was collected by filtration, dried and crystallized from ethanol to give white powder; yield 70%; mp 177–178°C; ¹H NMR: δ 2.40 (s, 3H, CH₃), 6.85–7.90 (m, 9H, Ar-H + thiophene-H + NH, D₂O exchangeable);¹³C NMR: δ 15.2, 120.4, 123.7, 126.2, 126.9, 135.8, 141.8, 147.3, 150.1, 160.5; IR: ν 3385 (NH), 3040, 3010 (CH-arom.), 2920 cm^-1 (CH-aliph.); MS: m/z 216.22 ([M]⁺, 61%). Anal. Calcd for C₁₂H₁₂N₂S (216.30): C, 66.63; H, 5.59; N, 12.95; S, 14.82. Found: C, 66.61; H, 5.57; N, 12.92; S, 14.85.

Method B

A mixture of 9 (0.87 g, 0.005 mol) and phenyl hydrazine (0.54 g, 0.005 mol) in ethanol (20 mL) was heated for 3 h. Upon cooling, the precipitate was filtered, dried and crystallized from ethanol to give white powder. The product was identical to that obtained by method A.

3-Hydroxy-3-(2-oxo-2-(2-thienyl)ethyl)indolin-2-one (13)

A mixture of 1 (0.63 g, 0.005 mol), isatin (0.73 g, 0.005 mol), 3–4 drops of diethylamine and ethanol (25 mL) was heated under reflux on the steam bath for 30 min. After standing for several days at room temperature, the product was collected by filtration, dried and crystallized from ethanol to afford white powder; mp 177–178°C [25].

3-(2-Oxo-2-(2-thienyl)ethylidene)indolin-2-one (14)

A mixture of 13 (1.36 g, 0.005 mmol), concentrated hydrochloric acid (0.25 mL) and glacial acetic acid (8 mL) was heated on the steam bath for 15–30 min. After addition of ethanol and standing at room temperature, the product was filtered, dried and crystallized from ethanol; mp 176–177°C [25].

5′-4-(2-Thienyl)-2′,4′-dihydrospiro[indole-3,3′-pyrazole]-2(1H)-one (15)

A mixture of chalcone 14 (0.26 g, 0.001 mol) and hydrazine hydrate (5 mL) in ethanol (20 mL) was heated under reflux for 6 h. On cooling, the solid formed was filtered and crystallized from ethanol to afford pale yellow crystals; yield 71%; mp 197–199°C; ¹H NMR: δ 2.20 (s, 2H, CH₂), 6.95–7.90 (m, 7H, A-H + thiophene-H), 8.50 (s, 1H, pyrazole-NH, D₂O exchangeable), 10.20 (s, 1H, NH, D₂O exchangeable); IR: ν 3250 and 3150 (NH), 2920 (CH-aliph.), 1690 cm^-1 (C=O indole); MS: m/z 269.30 ([M]⁺, 71%). Anal. Calcd for C₁₄H₁₁N₃OS (269.32): C, 62.43; H, 4.12; N, 15.60; S, 11.91. Found: C, 62.41; H, 4.10; N, 15.63; S, 11.94.

2′-Acetyl-5′-(2-thienyl)-2′,4′-dihydrospiro[indole-3, 3′-pyrazole]- 2(1H)-one (16)

A mixture of chalcone derivative 14 (0.26 g, 0.001 mol) and hydrazine hydrate (5 mL) in acetic acid (20 mL) was heated under reflux for 5 h. On cooling, the solid formed was filtered and crystallized from dioxane; yield 69%; mp 201–203°C; ¹H NMR: δ 2.30 (s, 2H, CH₂), 2.60 (s, 3H, COCH₃), 6.90–8.10 (m, 7H, Ar-H + thiophene-H), 10.50 (s, 1H, NH, D₂O exchangeable); IR: ν 3210 (NH), 3010 and 3000 (CH-arom.), 2920 (CH-aliph.), 1690 (C=O indole), 1660 cm^-1 (C=O); MS: m/z 311.32 ([M]⁺, 71%). Anal. Calcd for C₁₆H₁₃N₃O₂S (311.36): C, 61.72; H, 4.21; N, 13.50; S, 10.30. Found: C, 61.70; H, 4.18; N, 13.55; S, 10.24.

5′-(2-Thienyl)-1′,4′-dihydrospiro[indole-3,3′-oxazole]-2(1H)-one (17)

A solution of 14 (0.26 g, 0.001 mol) and hydroxylamine hydrochloride (0.07 g, 0.001 mol) in ethanol (20 mL) containing anhydrous sodium acetate (0.4 g) was heated under reflux for 5 h, then cooled and poured onto crushed ice. The solid product thus formed was collected by filtration, dried and crystallized from ethanol to give white powder; yield 69%; mp 193–195°C; ¹H NMR: δ 1.90 (s, 2H, CH₂), 6.90–8.00 (m, 7H, Ar-H + thiophene-H), 10.10 (s, 1H, NH, D₂O exchangeable); IR: ν 3310 (NH), 3010, 3000 (CH-arom.), 2960 (CH-aliph.), 1685 cm^-1 (C=O indole); MS: m/z 270.28 ([M]⁺, 64%). Anal. Calcd for C₁₄H₁₀N₂O₂S (270.31): C, 62.21; H, 3.73; N, 10.36; S, 11.86. Found: C, 62.18; H, 3.75; N, 10.39; S, 11.89.

5′-(2-Thienyl)-2′-phenyl-2′,4′-dihydrospiro[indole-3, 3′-pyrazole]-2(1H)-one (18)

A mixture of chalcone 14 (0.26 g, 0.001 mol) and phenylhydrazine (0.11 g, 0.001 mol) in ethanol (20 mL) was heated under reflux for 5 h and then cooled. The precipitate was filtered and crystallized from methanol to give white crystals; yield 60%; mp 183–185°C; ¹H NMR: δ 2.30 (s, 2H, CH₂), 6.70–8.15 (m, 12H, Ar-H + thiophene-H), 10.00 (s, 1H, NH, D₂O exchangeable); IR: ν 3300 (NH), 3010 and 3000 (CH-arom.), 2920 (CH-aliph.), 1690 cm^-1 (C=O indole); MS: m/z 345.46 ([M]⁺, 72%). Anal. Calcd for C₂₀H₁₅N₃OS (345.42): C, 69.54; H, 4.38; N, 12.17; S, 9.28. Found: C, 69.52; H, 4.36; N, 12.19; S, 9.30.

Antimicrobial screening

The screened compounds were dissolved in DMSO to form a solution of 5% concentration. Filter paper discs (Whatman No. 3 and 5 mm diameter) were saturated with this solution. The discs were placed on the surface of solidified Nutrient agar dishes seeded by the tested bacteria or Czapek Dox agar dishes seeded by the tested fungi. The diameter of inhibition zones (mm) were measured at the end of the incubation period (24–48 h at 37°C for bacteria and for 4–7 days at 28°C for fungi) [26]. Discs saturated with DMSO were used as control. Chloramphenicol and clotrimazole were used as reference drugs. The biologically active compounds were then diluted with DMSO to prepare a series of concentrations in order to determine the MIC of each compound. The MIC values were calculated as μg/mL. The antibacterial and antifungal activities data are given in Tables 1 and 2.

Corresponding author: Ahmed Abdou O. Abeed, Faculty of Science, Chemistry Department, Assiut University, Assiut 71516, Egypt, e-mail: ahmed_abeed76@yahoo.com

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Received: 2013-9-4

Accepted: 2013-11-16

Published Online: 2014-01-23

Published in Print: 2014-02-01

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Articles in the same Issue

https://doi.org/10.1515/hc-2013-0197

Keywords for this article

2-acetylthiophene; antimicrobial activity; MIC; spiro; thiazolidines

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