Ring transformation and antimicrobial activity of indolyl-substituted 2(3H)-furanones

Wael S.I. Abou-Elmagd; Ahmed K. EL-Ziaty; Abdelaal A. Abdalha

doi:10.1515/hc-2015-0008

Article Open Access

Ring transformation and antimicrobial activity of indolyl-substituted 2(3H)-furanones

Wael S.I. Abou-Elmagd , Ahmed K. EL-Ziaty and Abdelaal A. Abdalha

Published/Copyright: April 22, 2015

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From the journal Heterocyclic Communications Volume 21 Issue 3

Abstract

A variety of heterocycles of synthetic and biological importance were prepared from 3-(indol-3-yl-methylene)-5-phenyl-2(3H)-furanone (1) and its hydrazide 2. Compounds 1 and 2 were used for the construction of pyridazin-3(4H)-ones 4 and 6; 1,3,4-oxadiazoles 7, 8, and 10; and 1,2,4-triazoles 12, 14, and 15, all bearing a 3-indolyl moiety. The antimicrobial activities of the synthesized compounds were examined against six types of bacteria and two types of fungi.

Keywords: 2(3H)-furanone; indole; oxadiazole; pyridazinone; triazole

Introduction

2(3H)-Furanones are key starting materials for the construction of many heterocyclic systems [1–16]. The key step in these transformations is the formation of the acid hydrazides, which are formed by the action of hydrazine hydrate on the furanones.

Indole-substituted compounds are common in nature [17]; one of the most important and simple derivatives is the amino acid tryptophan. Pyridazinones have been reported to possess antimicrobial [18], analgesic [19], anti-inflammatory [20], antidiabetic [21], herbicidal [22], antihypertensive [23], anticancer [24], antifungal [25], and other pharmacological properties [26]. Compounds containing 1,3,4-oxadiazole moiety have a broad biological spectrum. Two examples of compounds currently used in clinical medicine are raltegravir, an antiretroviral drug [27], and zibotentan, an anticancer agent [28]. 1,2,4-Triazoles are broad-spectrum antifungal agents used as pesticides and pharmaceuticals. They inhibit the biosynthesis of ergosterol, which is an essential component of fungal membranes [29, 30].

These reported diverse biological activities prompted us to attempt the conversion of furanone 1 into pyridazinones, 1,3,4-oxadiazoles, and 1,2,4-triazoles, all bearing an indolyl moiety. Some of the obtained products were evaluated for their antimicrobial activity.

Results and discussion

The 2(3H)-furanone 1 has previously been prepared by one of us [3]. Hydrazide 2 has previously been prepared [4] via treating furanone 1 with hydrazine hydrate. In this work, pyridazinone 4 was synthesized by ring closure of benzohydrazide 3, which was obtained by the reaction of acid hydrazide 2 with benzoyl chloride. The structure of 3 was supported by comparison with an authentic sample prepared by the treatment of furanone 1 with benzoyl hydrazine. The treatment of hydrazide 2 with naphthoyl chloride afforded naphthohydrazide derivative 5. Ring closure of 5 by using HCl/AcOH (1:1) mixture afforded N-napthopyridazinone derivative 6 (Scheme 1). The structures of 3–6 are in full agreement with their analytical and spectral data.

Scheme 1

Synthesis of pyridazinone derivatives.

The treatment of benzohydrazide derivative 3 with phosphorus oxychloride yielded 1,3,4-oxadiazole derivative 7. Oxadiazolethione derivative 8 was obtained when hydrazide 2 was allowed to react with carbon disulfide in refluxing alcoholic sodium hydroxide. By contrast, the treatment of hydrazide 2 with formic acid under reflux for 10 h yielded N-formyl derivative 9, which was easily cyclized through dehydration by heating with phosphorus pentoxide in dry toluene to give 1,3,4-oxadiazole derivative 10 (Scheme 2). The structures of compounds 7–10 were elucidated from their analytical and spectroscopic data. The treatment of hydrazide 2 with potassium isothiocyanate afforded thiosemicarbazide derivative 11, which was also formed by the reaction of furanone 1 with thiosemicarbazide. Ring closure of 11 in 2N NaOH yielded triazolethione derivative 12. Semicarbazide derivative 13 was also prepared by the reaction of hydrazide 2 with potassium isocyanate and/or treatment of furanone 1 with semicarbazide hydrochloride/sodium acetate mixture. Triazolone derivative 14 was prepared by ring closure of semicarbazide derivative 13 using 2N NaOH. By contrast, hydrazide 2 was allowed to react with phenyl isothiocyanate in sodium hydroxide (10%) followed by acidification to yield 4-phenyltriazolethione derivative 15 (Scheme 3). The structures of compounds 11–15 were confirmed by the analysis of the analytical and spectroscopic data.

Scheme 2

Synthesis of 1,3,4-oxadiazole derivatives.

Scheme 3

Synthesis of 1,2,4-triazole derivatives.

The synthesized compounds were evaluated for their in vitro antimicrobial activity using four types of gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, and Kocuria rhizophila), two types of gram-negative bacteria (Salmonella typhimurium and Escherichia coli), and two fungus (yeast Candida albicans and mould Aspergillus niger); novobiocin, chloramphenicol, and nystatin were used as standard drugs for antibacterial and antifungal activities (Tables 1–3). The results revealed that the majority of the synthesized compounds show varying degrees of inhibition against the tested microorganisms. Only pyridazinones and triazoles show significant antimicrobial activities. More specifically, compounds 1, 4, and 11–15 exhibit high antibacterial and antifungal activities compared with the standard drugs, whereas compounds 2, 6–8, and 10 exhibit no antimicrobial activity.

Table 1

Antibacterial and antifungal activities (as inhibition zone in mm diameter).

Compound	Staphylococcus aureus	Kocuria rhizophila	Salmonella typhimurium	Escherichia coli	Candida albicans	Aspergillus niger
1	20	15	11	11	12	0
4	22	24	14	15	15	0
11	20	19	16	12	13	0
13	17	11	13	10	0	0
14	21	20	14	13	0	0
12	0	0	0	0	13	13
15	0	0	0	0	14	15
Novobiocin	23	22	10	11	0	0
Chloramphenicol	23	21	17	17	0	0
Nystatin	0	0	0	0	14	0

Table 2

MIC (μg/mL) for the active compounds.

Compound	Staphylococcus aureus	Kocuria rhizophila	Salmonella typhimurium	Escherichia coli	Candida albicans
1	30	25	30	50	60
4	0	50	60	60	50
11	25	30	25	30	25
13	50	50	60	70	0
14	30	30	30	25	0
12	0	0	0	0	60
15	0	0	0	0	30
Novobiocin	30	25	60	50	0
Chloramphenicol	30	25	30	30	0
Nystatin	0	0	0	0	40

Table 3

Minimum bactericidal concentration (MBC, μg/mL) for active compounds.

Compound	Staphylococcus aureus	Kocuria rhizophila	Salmonella typhimurium	Escherichia coli	Candida albicans
1	80	70	80	70	110
4	0	70	100	110	70
11	50	70	90	130	50
13	50	80	100	100	0
14	60	50	100	50	0
12	0	0	0	0	120
15	0	0	0	0	60
Novobiocin	50	50	100	100	0
Chloramphenicol	40	40	50	50	0
Nystatin	0	0	0	0	50

Conclusion

A series of novel pyridazinones,1,3,4-oxadizole, and 1,2,4-triazole derivatives has been synthesized using a facile strategy and screened for antimicrobial activities. Some of the prepared compounds exhibit high antibacterial and antifungal activities compared with the standard drugs.

Experimental

Uncorrected melting points were measured on a Gallen Kamp electric melting point apparatus. Infrared spectra were recorded using potassium bromide disks on FTIR Thermo Electron Nicolet 7600 (USA) infrared spectrometer at the central laboratory of Faculty of Science, Ain Shams University. ¹H-NMR (300 MHz) and ¹³C-NMR (75 MHz) spectra were measured in DMSO-d₆ on a Varian plus instrument. Mass spectra were recorded on a Shimadzu GC-MS QP-1000EX mass spectrometer operating at 70 eV at the Micro Analytical Center of Cairo University. The progress of all reactions was monitored by thin layer chromatography using Merck Kiesel gel 60 F₂₅₄ aluminum-backed plates. The spots were developed using a UV lamp.

Antimicrobial activity was conducted at El-Rashidi Elmizan Confectionery Company, 2nd industrial zone, 6th of October City, Cairo, Egypt, and Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University.

Synthesis of N-[2-((1H-indol-3-yl)methylene)-4-oxo-4-phenylbutanoyl]benzohydrazide (3)

Benzoyl chloride (10 mmol) was added to a solution of hydrazide 2 (10 mmol) in dry benzene (20 mL). The reaction mixture was heated under reflux for 3 h. The solvent was distilled under reduced pressure, and the deposited solid was filtered, washed several times with cold water, dried, and then crystallized from ethanol to give compound 3. The same product 3 was obtained by heating a solution of furanone 1 (10 mmol) in ethanol (20 mL) with benzoyl hydrazine (10 mmol) under reflux for 2 h. The solvent was evaporated, and the solid residue was filtered, dried, and then crystallized from ethanol to give compound 3 in 60% yield as colorless crystals; mp 230–231°C; IR (ν_max, cm¹): 3321, 3255, 3195 (NH), 1692, 1658 (C=O); ¹HNMR: δ 3.15 (d, 1H, J = 7.2 Hz), 3.42 (d, 1H, J = 7.2 Hz), 6.69–7.59 (m, 16H), 8.92 (s, 1H), 11.78 (br s, 2H); ¹³C NMR: δ 38.8, 111.1, 111.9, 119.7, 120.1, 121.9, 122.2, 127.5, 127.9, 128.3, 128.7, 129.1, 130.8, 132.3, 133.2, 134.9, 135.2, 136.1, 138.3, 164.9, 165.7, 194.7; MS m/z (%): 423 (M⁺, 15), 330 (100), 299 (27), 271 (29), 167 (32), 104 (44), 77 (48). Anal. Calcd for C₂₆H₂₁N₃O₃: C, 73.74; H, 5.00; N, 9.92. Found: C, 73.98; H, 4.93; N, 9.73.

Synthesis of N-[2-((1H-indol-3-yl) methylene)-4-oxo-4-phenylbutanoyl]naphthohydrazide (5)

Naphthoyl chloride (10 mmol) was added to a solution of hydrazide 2 (10 mmol) in dry benzene (20 mL). The reaction mixture was heated under reflux for 3 h. The solvent was distilled under reduced pressure, and the deposited solid was filtered, washed several times with cold water, dried, and then recrystallized from ethanol to give compound 5 in 65% yield as colorless crystals; mp 240–242°C; IR (ν_max, cm^-1): 3295, 3215, 3120 (NH), 1692, 1645 (C=O); ¹HNMR: δ 3.19 (d, 1H, J = 7.2 Hz), 3.22 (d, 1H, J = 7.2 Hz), 6.55–8.17 (m, 18H), 8.86 (s, 1H), 11.21 (br s, 2H,); ¹³C NMR: δ 39.7, 110.6, 111.7, 119.0, 120.2, 120.5, 122.5, 126.1, 127.3, 127.4, 128.5, 128.8, 129.5, 130.3, 130.9, 131.8, 132.3, 133.7, 134.1, 134.4, 134.7, 135.2, 135.5, 136.8, 138.5, 165.7, 166.9, 194.3. MS, m/z (%): 473 (M⁺, 18), 371 (21), 339 (22), 177 (22), 99 (27), 69 (28), 57 (100). Anal. Calcd for C₃₀H₂₃N₃O₃: C, 76.09; H, 4.90; N, 8.87. Found: C, 76.28; H, 4.95; N, 9.01.

General method for ring closure of benzohydrazides 3 and 5 using HCl/AcOH

A solution of 3 or 5 (1 g) in a mixture of HCl/AcOH, 1:1 (30 mL), was heated under reflux for 1 h and then cooled. The resultant solid was filtered, washed with water, and crystallized from ethanol to give the respective product 4 or 6.

4-[(1H-Indol-3-yl)methylene]-1-benzoyl-6-phenyl-1,2-dihydropyridazin-3(4H)-one (4)

This compound was obtained in 80% yield as colorless crystals; mp 136–138°C; IR (ν_max, cm^-1): 3297, 3115 (NH), 1667, 1650 (C=O); ¹H NMR: δ 6.20 (s, 1H), 6.50–8.59 (m, 16H), 8.90 (s, 1H), 10.11 (br s, 1H); ¹³C NMR: δ 84.3, 110.7, 112.4, 119.6, 121.4, 122.2, 126.5, 126.9, 127.9, 128.1, 128.7, 128.9, 131.1, 132.3, 133.9, 134.4, 135.6, 135.9, 136.8, 139.7, 149.4, 169.9; MS m/z (%): 405 (M⁺, 20), 382 (18), 330 (100), 299 (27), 286 (21), 271 (29), 155 (33), 104 (44), 77 (45), 59 (26). Anal. Calcd for C₂₆H₁₉N₃O₂: C, 77.02; H, 4.72; N, 10.36. Found: C, 77.17; H, 4.55; N, 10.78.

4-((1H-Indol-3-yl)methylene)-1-(1-naphthoyl)-6-phenyl-1,2-dihydropyridazin-3(4H)-one (6)

This compound was obtained in 70% yield as colorless crystals; mp 163–165°C; IR (ν_max, cm^-1): 3301, 3212 (NH), 1662, 1653 (C=O); ¹H NMR: δ 7.17 (s, 1H_.), 7.20–8.43 (m, 18H), 8.82 (s, 1H), 10.21 (br s, 1H); ¹³C NMR: δ 80.7, 110.6, 111.5, 119.6, 120.3, 122.2, 124.5, 126.1, 126.3, 126.5, 126.9, 127.9, 128.3, 128.5, 128.7, 128.9, 130.3, 130.9, 132.3, 133.5, 133.9, 134.3, 135.1, 135.9, 139.4, 139.9, 149.6, 169.7; MS m/z (%): 455 (M⁺, 12), 354 (20), 330 (21), 279 (20), 177 (27), 151 (21), 99 (27), 69 (28),57 (100), 55 (38). Anal. Calcd for C₃₀H₂₁N₃O₂ (455): C, 79.10; H, 4.65; N, 9.22. Found: C, 79.23; H, 4.39; N, 9.40.

Synthesis of 4-(1H-indol-3-yl)-1-phenyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)but-3-en-1-one (7)

Phosphorus oxychloride (10 mL) was added dropwise to 1 g of diaroylhydrazine 3. The reaction mixture was heated under reflux for 20 min, then cooled and poured onto crushed ice. The resultant solid was filtered, washed with water, and crystallized from ethanol to give compound 7 in 40% yield as pale yellow powder; mp 178–180°C; IR (ν_max, cm^-1): 3312 (NH), 1671 (C=O); ¹H NMR: δ 3.15 (d, 1H, J = 7.0 Hz), 3.25 (d, 1H, J = 7.0 Hz), 7.40–8.20 (m, 16H), 8.84 (s, 1H); ¹³C NMR: δ 43.6, 110.6, 111.3, 119.0, 120.1, 121.7, 126.3, 126.7, 127.5, 128.1, 128.3, 128.7, 129.8, 130.3, 133.2, 135.9, 136.4, 140.3, 164.3, 164.7, 193.9; MS m/z (%): 405 (M⁺, 67), 171 (28), 145 (20), 129 (100), 117 (14), 105 (71), 88 (41), 76 (55). Anal. Calcd for C₂₆H₁₉N₃O₂: C, 77.02; H, 4.72; N, 10.36. Found: C, 77.37; H, 4.78; N, 10.73.

Synthesis of 4-(1H-indol-3-yl)-1-phenyl-3-(5-thioxo-4, 5-dihydro-1,3,4-oxadiazol-2-yl)but-3-en-1-one (8)

Carbon disulfide (10 mL) was added to a solution of hydrazide 2 (10 mmol) in 10% alcoholic NaOH (3 g NaOH in 30 mL ethanol) whereby the reaction mixture became brown. The mixture was heated under reflux for 2 h, then cooled and poured onto ice-cold water. Acidification with concentrated HCl gave a yellow precipitate, which was filtered and crystallized from ethanol to give compound 8 in 80% yield as yellow powder; mp 218–220°C; IR (ν_max, cm^-1): 3273, (NH), 1666 (C=O); ¹H NMR: δ 3.35 (d, 1H, J = 7.2 Hz), 3.93 (d, 1H, J = 7.2 Hz), 6.94–7.66 (m, 11H), 9.13 (s, 1H), 13.12 (br s, 1H); ¹³C NMR: δ 35.4, 110.9, 113.4, 119.6, 120.3, 122.2, 126.5, 128.7, 128.9, 131.1, 133.2, 134.1, 134.4, 135.6, 136.4, 160.1, 165.6, 196.5; MS m/z (%): 361 (M⁺, 76), 259 (16), 219 (23), 173 (16), 105 (36), 76 (45), 51 (100). Anal. Calcd for C₂₀H₁₅N₃O₂S (361): C, 66.46; H, 4.18; N, 11.63; S, 8.87. Found: C, 66.62; H, 4.23; N, 11.50; S, 8.65.

Synthesis of 2-[(1H-indol-3-yl)methylene]-N-formyl-4-oxo-4-phenyl butane hydrazide (9)

A solution of 2 (1 g) in formic acid (10 mL) was heated under reflux. The deposited solid during heating after 7 h was filtered, washed several times with water, dried, and then recrystallized from dioxane to give compound 9 in 50% yield as colorless crystals; mp 256–257°C; IR (ν _max, cm^-1): 3320, 3255, 3170 (NH), 1710, 1672, 1650 (C=O); ¹H NMR: δ 3.18 (d, 1H, J = 7.0 Hz), 3.25 (d, 1H, J = 7.0 Hz), 6.89–8.45 (m, 11H), 8.60 (s, 1H), 9.05 (s, 1H), 10.1 (br s, 1H), 10.5 (s, 1H); ¹³C NMR: δ 39.8, 110.9, 111.9, 119.7, 120.1, 122.2, 126.5, 127.9, 128.3, 131.1, 133.8, 135.3, 135.7, 136.9, 138.3, 165.1, 166.7, 195.1; MS m/z (%): 347 (M⁺, 21), 204 (56), 173 (85), 145 (100), 117 (22), 105 (76), 90 (87), 76 (50), 55 (45). Anal. Calcd For C₂₀H₁₇N₃O₃ (347): C, 69.15; H, 4.93; N, 12.10. Found: C, 69.47; H, 4.73; N, 12.37.

Synthesis of 4-(1H-indol-3-yl)-3-(1,3,4-oxadiazol-2-yl)-1-phenyl but-3-en-1-one (10)

A mixture of compound 9 (1 g) and phosphorus pentoxide (1 g) in dry toluene (20 mL) was heated under reflux for 3 h. The deposited solid was filtered, washed several times with water, dried, and crystallized from ethanol to give compound 10 in 60% yield as pale yellow powder; mp 230–233°C; IR (υ_max, cm^-1): 3242 (NH), 1655 (CO); ¹HNMR: δ 3.10 (d, 1H, J = 7.0 Hz), 3.15 (d, 1H, J = 7.0 Hz), 7.02–8.14 (m, 12H), 8.93 (s, 1H); ¹³C NMR: δ 42.3, 110.6, 111.3, 119.0, 120.1, 126.3, 126.7, 127.5, 128.7, 129.8, 130.3, 133.2, 135.9, 140.3, 155.9, 157.2, 194.1; MS m/z (%): 329 (M⁺, 56), 171 (27), 145 (45), 129 (100), 117 (64), 105 (30), 88 (41). Anal. Calcd for C₂₀H₁₅N₃O₂: C, 72.94; H, 4.59; N, 12.76. Found: C, 72.77; H, 4.43; N, 12.57.

Synthesis of thiosemicarbazide 11 and semicarbazide 13

A solution of potassium thiocyanate or potassium cyanate (12 mmol) in water (10 mL) was added dropwise with stirring at 0°C to a solution of hydrazide 2 (10 mmol) in AcOH/H₂O (1:1 by volume) mixture. The reaction mixture was stirred at room temperature for 3 h. The product obtained was filtered, washed thoroughly with water, and finally recrystallized from ethanol/dioxane mixture to give thiosemicarbazide 11 (from thiocyanate) and semicarbazide 13 (from cyanate).

The same product 11 was also obtained by heating under reflux a solution of 2(3H)-furanone 1 (10 mmol) in ethanol (30 mL) with thiosemicarbazide (10 mmol) for 1 h. Heating 1 (10 mmol) with a mixture of semicarbazide hydrochloride (10 mmol) and anhydrous sodium acetate (10 mmol) for 1 h gave product 13. The solid obtained was filtered, washed thoroughly with water, and recrystallized to give compounds 11 and 13, respectively.

1-[2-((1H-Indol-3-yl)methylene)-4-oxo-4-phenylbutanoyl]thiosemicarbazide (11)

This compound was obtained in 50% yield as colorless crystals; mp 159–160°C; IR (υ_max, cm^-1): 3325, 3216, 3195, 3117 (NH), 1677, 1640 (C=O), 1252 (C=S); ¹HNMR: δ 3.22 (s, 2H), 6.99–7.86 (m, 11H), 8.63 (s, 1H), 11.40 (br s, 1H), 11.63 (br s, 2H), 12.09 (br s, 1H); ¹³C NMR: δ 39.3, 110.7, 111.3, 119.1, 120.3, 122.2, 126.3, 128.3, 128.9, 130.3, 133.5, 135.3, 135.7, 136.9, 138.3, 165.3, 182.5, 194.3; MS m/z (%): 378 (M⁺, 11), 181 (78), 153 (32), 148 (38), 120 (84), 106 (38), 93 (100), 77 (88), 66 (47). Anal. Calcd for C₂₀H₁₈N₄O₂S: C, 63.47; H, 4.79; N, 14.80; S, 8.47. Found: C, 64.12; H, 4.53; N, 15.03; S, 8.87.

1-[2-((1H-indol-3-yl)methylene)-4-oxo-4-phenylbutanoyl]semicarbazide (13)

This compound was obtained in 56% yield as colorless crystals; mp 200–202°C; IR (υ_max, cm^-1): 3320, 3212, 3170, 3110 (NH), 1677, 1630 (C=O); ¹H NMR: δ 3.20 (s, 2H), 7.03–7.97 (m, 11H), 8.52 (s, 1H), 11.97 (br.s, 2H), 12.86 (br s, 2H); ¹³C NMR: δ 38.7, 110.3, 111.1, 119.3, 120.6, 121.7, 126.1, 127.9, 128.2, 130.1, 134.9, 135.1, 136.3, 138.0, 158.1, 165.1, 193.7; MS, m/z (%): 362 (M⁺, 9), 186 (42), 257 (21), 154 (35), 127 (24), 117 (34), 104 (53), 93 (46), 77 (100), 65 (38), 51 (46). Anal. Calcd for C₂₀H₁₈N₄O₃: C, 66.29; H, 5.01; N, 15.46. Found: C, 66.07; H, 4.92; N, 15.10.

Synthesis of triazol-5-thione 12 and triazol-5-one 14

A solution of 2N NaOH (40 mL) was added to thiosemicarbazide 11 (10 mmol) or semicarbazide 13 (10 mmol). The reaction mixture was heated under reflux for 2 h, filtered while hot, acidified with ice-cold HCl, and diluted with 100 mL of water. The solid obtained was filtered, washed with water, and crystallized from ethanol to give triazol-5-thione 12 or triazol-5-one 14, respectively.

3-(1-(1H-Indol-3-yl)-4-oxo-4-phenylbut-1-en-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole (12)

This compound was obtained in 70% yield as colorless crystals; mp 204–206°C; IR (υ_max, cm^-1): 3302, 3213, 3125 (NH), 1663 (C=O); ¹HNMR: δ 3.23 (s, 2H), 6.75–8.02 (m, 11H), 9.30 (s, 1H), 12.98 (br s, 2H);¹³C NMR: δ 35.3, 110.7, 111.1, 119.7, 120.1, 121.9, 126.2, 128.3, 128.7, 130.8, 132.3, 133.2, 134.9, 135.2, 136.9, 156.1, 189, 194.3; MS m/z (%): 360 (M⁺, 35), 310 (49), 293 (51), 187 (51), 117 (52), 84 (58), 58 (100). Anal. Calcd for C₂₀H₁₆N₄OS: C, 66.65; H, 4.47; N, 15.54; S, 8.90. Found: C, 66.92; H, 4.32; N, 15.13; S, 8.77.

3-(1-(1H-Indol-3-yl)-4-oxo-4-phenylbut-1-en-2-yl)-5-oxo-4,5-dihydro-1,2,4–triazole (14)

This compound was obtained in 74% yield as colorless crystals; mp 234–237°C; IR (υ_max, cm^-1): 3302, 3218, 3184 (NH), 1665, 1634 (C=O); ¹H NMR: δ 3.28 (s, 2H), 6.97–8.03 (m, 11H), 9.23 (s, 1H), 12.53 (br s, 2H); ¹³C NMR: δ 33.6, 110.3, 111.5, 119.1, 119.9, 121.7, 126.3, 128.3, 128.7, 130.8, 132.8, 133.1, 134.9, 135.5, 136.8, 156.3, 163, 194.7; MS m/z (%): 344 (M⁺,7), 285 (69), 257 (77), 242 (44), 154 (35), 127 (41), 104 (37), 91 (28), 77 (100), 65 (88), 51 (35). Anal. Calcd for C₂₀H₁₆N₄O₂: C, 69.76; H, 4.68; N, 16.27. Found: C, 69.47; H, 4.42; N, 15.98.

Synthesis of 3-(1-(1H-indol-3-yl)-4-oxo-4-phenylbut-1-en-2-yl)-4-phenyl-5-thioxo-4,5-dihydro-1,2,4-triazole (15)

A mixture of 2 (10 mmol) and phenyl isothiocyanate (1.6 mL, 10 mmol) in (10%) sodium hydroxide (20 mL) was heated under reflux for 3 h, then cooled and acidified with cold dilute hydrochloric acid. The deposited solid was filtered, washed several times with cold water, dried, and crystallized from dioxane to give compound 15 in 55% yield as colorless crystals; mp 215–217°C; IR (υ_max, cm^-1): 3312, 3214, 3184 (NH), 1677 (C=O); ¹H NMR: δ 3.32 (s, 2H), 6.62–7.99 (m, 16H), 9.08 (s, 1H), 11.35 (br s, 1H); ¹³C NMR: δ 43.1, 111.3, 111.8, 119.6, 120.4, 122.2, 124.7, 126.5, 128.5, 128.7, 129.4, 130.1, 132.3, 133.2, 133.9, 134.4, 135.9, 136.6, 136.8, 155.9, 160.7, 194.5; MS m/z (%): 436 (M⁺, 18), 362 (16), 308 (15), 279 (18), 252 (19), 169 (16), 151 (22), 94 (17), 78 (18), 66 (20), 58 (100). Anal. Calcd for C₂₆H₂₀N₄OS (436): C, 71.54; H, 4.62; N, 12.83; S, 7.35. Found: C, 70.92; H, 4.93; N, 12.65; S, 7.67.

Biological assays

All microorganisms were kindly provided from the culture collection of the Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University. Malt extract agar was used as a medium for fungal isolates, and nutrient agar medium was used for bacterial growth. Each medium was prepared by dissolving the solid ingredients in 1 L of cold distilled water and then by heating to 60–70°C with stirring. Media were sterilized by autoclaving at 121°C (1.5 atm) for 15–20 min.

By using a diffusion agar technique, antifungal and antibacterial activities were measured as the diameter of the inhibition zone. Inhibition zones developed due to active ingredients were measured after 24–48 h of incubation time. Minimum inhibitory concentration (MIC) was determined by a serial dilution technique [31, 32]. To determine the minimum bactericidal concentration (MBC), the dilution representing the MIC and at least two of the more concentrated test product dilutions were plated and enumerated to determine viable colony-forming unit (CFU) per milliliter. The MBC is the lowest concentration that demonstrates a predetermined reduction (such as 99.9%) in CFU per milliliter when compared with the MIC dilution [31, 32].

Corresponding author: Abdelaal A. Abdalha, Faculty of Science, Chemistry Department, Ain Shams University, Abassia, Cairo 11566, Egypt; and Chemistry Department, Tabuk University, Tabuk, KSA, e-mail: abdoelaal@yahoo.com

Acknowledgments

The authors acknowledge the El-Rashidi Elmizan Confectionery Company, Cairo, Egypt, and the Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University, for their help in determining biological activity.

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Received: 2015-1-17

Accepted: 2015-3-27

Published Online: 2015-4-22

Published in Print: 2015-6-1

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-2015-0008

Keywords for this article

2(3H)-furanone; indole; oxadiazole; pyridazinone; triazole

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