Microwave-assisted synthesis and biological evaluation of thiazole-substituted dibenzofurans

N.H. Kumar Baba; D. Ashok; Boddu Ananda Rao; Sarasija Madderla; N.Y.S. Murthy

doi:10.1515/hc-2017-0247

Article Open Access

Microwave-assisted synthesis and biological evaluation of thiazole-substituted dibenzofurans

N.H. Kumar Baba , D. Ashok , Boddu Ananda Rao , Sarasija Madderla and N.Y.S. Murthy

Published/Copyright: May 9, 2018

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From the journal Heterocyclic Communications Volume 24 Issue 3

Abstract

New thiazole-substituted dibenzofurans 7a–j were synthesized from dibenzofuran derivatives 5a–b and substituted thiosemicarbazones 6a–h under conventional and microwave irradiation conditions. The structures of all products were established on the basis of analytical and spectral data. The synthesized compounds were evaluated for their in vitro antibacterial activity against Gram-positive and Gram-negative strains. Compounds 7b, 7d and 7h are active against Bacillus subtilis (+ve), and compound 7i displays good activity against Pseudomonas aeruginosa (-ve) strain. Compounds 7a–j were also evaluated for their in vitro antimycobacterial activity, and compound 7b shows antimycobacterial activity against Mycobacterium bovis strain.

Keywords: antibacterial; antimycobacterial; benzofuran; microwave irradiation; thiazole

Introduction

During the past decades, the synthesis of thiazoles and analogs has gained interest due to their broad range of biological and pharmaceutical properties, such as antibacterial [1], [2], [3], [4], anti-human immunodeficiency virus type 1 (HIV-1) [5], antihypertensive [6], anti-inflammatory [7], antiviral [8], [9] and anticancer activities [10]. Thiosemicarbazones have also gained importance in medicinal chemistry [11], [12] and are being extensively used in the synthesis of thiazoles [13]. In recent years, many thiazolyl hydrazone derivatives have been synthesized and screened for antimicrobial [14] and antimycobacterial [15] activities. Benzodifurans are also bioactive [16], [17]. In particular, benzo[b]furan derivatives substituted at the C-2 position show good biological activities [18], [19]. Microwave-assisted organic synthesis of heterocyclic compounds has become an effective technique for generating new heterocyclic scaffolds useful for drug discovery [20]. Currently, microwave irradiation methods, especially the synthesis of thiazolyl hydrazine derivatives via the condensation of α-bromoketones with thiosemicarbazones, have shown great promise as an attractive alternative to conventional methods. Inspired by the biological profile of thiazolyl hydrazine derivatives and in continuation of our previous work [21], we have focused our attention on the preparation of symmetrical thiazole and benzodifuran derivatives 7a–j. These products were synthesized by conventional and microwave methods and investigated in vitro for antibacterial and antimycobacterial activities.

Results and discussion

Compounds 7a–j were prepared from 2,4-diacetylresorcinol (1) which, in turn, was synthesized according to the literature procedure [22], as shown in Scheme 1. First, the starting material 1 was treated with two equivalents of a benzaldehyde in an aqueous solution of potassium hydroxide. The resulting bis-chalcones 2a–b were then hydrogenated using 10% Pd/C in ethyl acetate. The products 3a–b were treated with chloroacetone in acetone in the presence of potassium carbonate. Then, the products 4a–b were brominated by pyridinium tribromide in acetic acid. The reaction of products 5a–b with substituted thiosemicarbazones 6a–h in ethanol under microwave irradiation afforded the desired final compounds 7a–j in high yields (method B). The yields were lower for the same reactions conducted using the conventional heating method (method A). The structures of the synthesized compounds 3a,b, 4a,b, 5a,b and 7a–j were established by spectroscopic means [infrared (IR), proton nuclear magnetic resonance (¹H NMR), carbon-13 nuclear magnetic resonance (¹³C NMR), mass spectrometry (MS)] and elemental analyses.

The in vitro antimicrobial activities of compounds 7a–j were investigated against four pathogenic microorganisms, namely Staphylococcus aureus (MTCC 737), Escherichia coli (MTCC 443), Bacillus subtilis (MTCC 441) and Pseudomonas aeruginosa (MTCC 741) at a concentration of 100 μg/mL using norfloxacin and ofloxacin as standard drugs by the cup-plate agar diffusion method. The results are presented in Table 1. As can be seen, compounds 7b, 7d, 7h (inhibition zone>20 mm) show excellent growth inhibition against B. subtilis as compared to norfloxacin (20 mm). Compound 7i is more potent than the standard (oflaxin) against Gram-negative bacterial strain P. aeruginosa. The investigation of in vitro antimycobacterial activity (Table 2) revealed that compounds 7b and 7h are active compared to the standard mixture of isoniazid and rifampicin (Scheme 1).

Table 1

Antibacterial activity of compounds 7a–j.

Compound	Zone of inhibition after 24 h (mm)
	Gram-positive bacteria		Gram-negative bacteria
	S. aureus(MTCC 737)	B. subtilis(MTCC 441)	E. coli(MTCC 443)	P. aeruginosa(MTCC 741)
7a	8.5	11	4.5	6
7b	14	25	5.5	7
7c	4	7	5.5	7
7d	11	21	4.5	6
7e	6.5	12	2.5	2.5
7f	4.5	6	5.5	5
7g	7.5	10	4	6.5
7h	9	21	6	8
7i	5.5	8	9	11
7j	5.5	9	5.5	6
Norfloxacin	16	20
Ofloxacin			18	10

Table 2

Antimycobacterial activity of compounds 7a–j.

Compound	Zone of inhibition (mm)
Compound	M. bovis
7a	15.1
7b	42.2
7c	19.5
7d	26.9
7e	27.8
7f	32.5
7g	16.9
7h	36.6
7i	10.9
7j	21.5
Isoniazid+rifampicin	40.0

Scheme 1

Conclusions

New antibacterial and antimycobacterial inhibitors 7a–j were synthesized via symmetrical construction of a thiazole ring at each C-2 position of benzodifuran using both conventional and microwave irradiation methods. Compounds 7b, 7d, 7h show excellent growth inhibition against B. subtilis as compared to norfloxacin. In comparison to oflaxin, compound 7i is highly effective against Gram-negative bacterial strain P. aeruginosa. Compound 7b shows excellent in vitro antimycobacterial activity.

Experimental

IR spectra were recorded on a Shimadzu FTIR-8400S spectrometer using KBr pellets. ¹H NMR spectra (300 MHz) and ¹³C NMR spectra (75 MHz) were acquired on a Bruker Avance 300 spectrometer in CDCl₃ or dimethyl sulfoxide-d6 (DMSO-d₆) using tetramethylsilane (TMS) as the internal standard. Mass spectra were recorded using electrospray ionization (ESI) on a Shimadzu LCMS2020 spectrometer. Elemental analyses were performed on a Carlo Erba EA1106 elemental analyzer. Melting points were determined in open capillary tubes on a Stuart SMP3 melting point apparatus and are uncorrected. Microwave reactions were carried out in an Anton Paar Monowave 300 microwave instrument (850 W maximum power, 2.45 GHz). Analytical thin-layer chromatography (TLC) was performed on precoated Merck 60 F₂₅₄ silica gel plates with visualization under ultraviolet (UV) light. Substituted thiosemicarbazones 6a–h were synthesized as previously described [23], [24], [25].

Compounds 3a,b

A solution of bis-chalcone 2a or 2b (5.34 mmol) in ethyl acetate (20 mL) in a Parr hydrogenation bottle was treated with Pd/C (20%, 400 mg), and the mixture was hydrogenated under a pressure of 3 atm for 3 h at room temperature. The catalyst was removed by filtration using a celite pad. The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with a gradient of 10–20% of ethyl acetate in hexanes [26].

1,1′-(4,6-Dihydroxy-1,3-phenylene)bis(3-phenylpropan-1-one) (3a)

White solid; yield 95%; mp 88–90°C; IR: 3023, 1653 cm⁻¹; ¹H NMR (CDCl₃): δ 12.97 (s, 2H, OH), 8.04 (s, 1H, Ar), 7.34–7.20 (m, 10H, Ar), 6.42 (s, 1H, Ar), 3.19 (t, 4H, J=7.3 Hz, CH₂), 3.04 (t, 4H, J=7.3 Hz, CH₂); ¹³C NMR (CDCl₃): δ 203.5, 168.7, 140.4, 134.6, 128.7, 128.4, 126.5, 113.1, 105.1, 39.6, 30.2; MS: m/z 374.9 [(M+H)⁺, 100%]. Anal. Calcd for C₂₄H₂₂O₄: C, 76.99; H, 5.92. Found: C, 76.94; H, 5.89.

1,1′-(4,6-Dihydroxy-1,3-phenylene)bis(3-(4-methoxyphenyl)propan-1-one) (3b)

White solid; yield 90%; mp 120–122°C; IR: 2910, 1634 cm⁻¹; ¹H NMR (CDCl₃): δ 12.98 (s, 2H, N-H), 8.07 (s, 1H, Ar), 7.13 (d, 4H, J=7.1 Hz, Ar), 6.83 (d, 4H, J=7.1 Hz, Ar), 6.41 (s, 1H, Ar-H), 3.77 (s, 6H, OCH₃), 3.16 (t, 4H, J=7.5 Hz, CH₂), 2.98 (t, 4H, J=7.5 Hz, CH₂); ¹³C NMR (CDCl₃): δ 203.6, 168.7, 158.2, 134.6, 132.4, 129.4, 114.1, 113.1, 105, 55.2, 39.9, 29.4; MS: m/z 435.1 [(M+H)⁺, 100%]. Anal. Calcd for C₂₆H₂₆O₆: C, 71.87; H, 6.03. Found: C, 71.82; H, 5.98.

Compounds 4a,b

A mixture of 1,1′-(4,6-dihydroxy-1,3-phenylene)bis(3-substituted propan-1-one) 3a or 3b (10 mmol), chloroacetone (22 mmol) and potassium carbonate (30 mmol) in dried acetone (10 mL) was heated under reflux for 6 h. Then the mixture was quenched with crushed ice and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by silica gel (60–120 mesh) column chromatography eluting with a gradient of 20–30% of ethyl acetate in hexanes.

1,1′-(3,5-Diphenethylbenzo[1,2-b:5,4-b′]difuran-2,6-diyl)diethanone (4a)

White solid; yield 90%; mp 138–140°C; IR: 3087, 2923, 1670, 1558 cm⁻¹; ¹H NMR (CDCl₃): δ 7.56 (s, 1H, Ar), 7.22 (m, 11H, Ar), 3.36 (t, 4H, J=8 Hz, CH₂), 2.95 (t, 4H, J=8 Hz, CH₂), 2.62 (s, 6H, CH₃); ¹³C NMR (CDCl₃): δ 190.8, 154.3, 148.8, 141.3, 128.6, 128.3, 127.8, 126.4, 126.2, 113.6, 94.9, 35.6, 27.8, 26.4; MS: m/z 451 [(M+H)⁺, 100%]. Anal. Calcd for C₃₀H₂₆O₄: C, 79.98; H, 5.82. Found: C, 79.94; H, 5.78.

1,1′-(3,5-Bis(4-methoxyphenethyl)benzo[1,2-b:5,4-b′]difuran-2,6-diyl)diethanone (4b)

White solid; yield 90%; mp 136–138°C; IR: 3059, 2934, 1685, 1571 cm⁻¹; ¹H NMR (CDCl₃): δ 7.56 (s, 1H, Ar), 7.25 (s, 1H, Ar), 7.12 (d, 4H, J=8 Hz, Ar), 6.77 (d, 4H, J=8 Hz, Ar), 3.70 (s, 6H, OCH₃), 3.33 (t, 4H, J=8 Hz, CH₂), 2.89 (t, 4H, J=7.7 Hz, CH₂), 2.62 (s, 6H, CH₃); ¹³C NMR (CDCl₃): δ 190.7, 158, 154.3, 148.9, 133.4, 127.9, 128, 126.5, 113.7, 113.7, 94.9, 55.1, 34.8, 27.8, 26.6; MS: m/z 511 [(M+H)⁺, 100%]. Anal. Calcd for C₃₂H₃₀O₆: C, 75.28; H, 5.92. Found: C, 75.23; H, 5.89.

Compounds 5a,b

Pyridinium tribromide (70 mmol) was added in portions to a stirred solution of compound 4a or 4b (28 mmol) in acetic acid (100 mL) at 50–55°C and stirring was continued for 4 h. Then the mixture was quenched with crushed ice and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography eluting with a gradient from 20% to 30% of ethyl acetate in hexanes.

1,1′-(3,5-Diphenethylbenzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis(2-bromoethanone) (5a)

Off-white solid; yield 85%; mp 138–140°C; IR: 2924, 1682, 1571, 818 cm⁻¹; ¹H NMR (CDCl₃): δ 7.59 (s, 1H, Ar), 7.22 (m, 11H, Ar), 4.53 (s, 4H, CH₂), 3.38 (t, 4H, J=8 Hz, CH₂), 2.96 (t, 4H, J=8 Hz, CH₂); ¹³C NMR (CDCl₃): δ 183.3, 154.8, 146.8, 141, 130.9, 128.7, 128.4, 126.5, 126.3, 114.2, 95.4, 35.6, 32.1, 26.5; MS: m/z 609.3 [(M+2H)⁺, 100%]. Anal. Calcd for C₃₀H₂₄Br₂O₄: C, 59.23; H, 3.98. Found: C, 59.19; H, 3.94.

1,1′-(3,5-Bis(4-methoxyphenethyl)benzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis(2-bromoethanone) (5b)

Off-white solid; yield 82%; mp 134–136°C; IR: 2931, 1678, 1577, 819 cm⁻¹; ¹H NMR (CDCl₃): δ 7.59 (s, 1H, Ar), 7.27 (s, 1H, Ar), 7.10 (d, 4H, J=8 Hz, Ar-H), 6.77 (d, 4H, J=8 Hz, Ar), 4.53 (s, 4H, CH₂), 3.70 (s, 6H, OCH₃), 3.36 (t, 4H, J=8 Hz, CH₂), 2.90 (t, 4H, J=8 Hz, CH₂); ¹³C NMR (CDCl₃): δ 183.5, 158.1, 154.9, 146.7, 133.1, 131.2, 129.6, 126.5, 114.4, 113.8, 95.4, 55.2, 34.7, 32.1, 26.7; MS: m/z 669.2 [(M+2H)⁺, 100%]. Anal. Calcd for C₃₂H₂₈Br₂O₆: C, 57.50; H, 4.22. Found: C, 57.45; H, 4.18.

General procedures for the preparation of compounds 7a–j

Conventional heating method A

To a stirred solution of 5a or 5b (0.001 mol) in ethanol (10 mL), was added substituted thiosemicarbazone 6a–h (0.002 mol) in ethanol (10 mL). The mixture was heated under reflux for a period of time indicated below and then concentrated under reduced pressure, and the residue was subjected to column chromatography on basic alumina eluting with a gradient from 30 to 40% of ethyl acetate in hexanes.

Microwave irradiation method B

A mixture of 5a or 5b (0.001 mol), substituted thiosemicarbazone 6a–h (0.002 mol) and ethanol (10 mL) in a microwave tube was subjected to microwave irradiation at 180 W for 8–20 min. Work-up and purification were conducted as described above.

4,4′-(3,5-Diphenethylbenzo[1,2-b:5,4-b′]difuran-2,6-diyl)bis(2-(2-benzylidenehydrazino)thiazole) (7a)

Reaction time 8 h, yield 85%, method A; reaction time 10 min, yield 92%, method B; off-white solid; mp 170–172°C (dec); IR: 3464, 1563, 1491, 1359, 753 cm⁻¹; ¹H NMR (DMSO-d₆): δ 12.16 (s, 2H, NH), 8.13 (s, 2H, CH=N), 7.71 (s, 1H, Ar), 7.69 (d, 4H, J=7 Hz, Ar), 7.40 (m, 11H, Ar), 7.27 (m, 6H, Ar, thiazole), 7.17 (t, 2H, J=7 Hz, Ar), 3.47 (t, 4H, J=7 Hz, CH₂), 2.98 (t, 4H, J=7 Hz, CH₂); ¹³C NMR (DMSO-d₆): δ 168.7, 151.8, 146.8, 142.9, 142.5, 141.7, 134.3, 129.3, 128.8, 128.6, 128.1, 127.6, 126.3, 125.8, 115.6, 109.3, 106, 93.5, 35.5, 25.1; MS: m/z 769.1 [(M+H)⁺, 100%]. Anal. Calcd for C₄₆H₃₆N₆O₂S₂: C, 71.85; H, 4.72; N, 10.93. Found: C, 71.80; H, 4.69; N, 10.94.

4,4′-(3,5-Bis(4-methoxyphenethyl)benzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis(2-(2-benzylidenehydrazino)thiazole) (7b)

Reaction time 10 h, yield 80%, method A; reaction time 15 min, yield 86%; method B; off-white solid; mp 114–116°C (dec); IR: 3463, 1564, 1509, 1364, 754 cm⁻¹; ¹H NMR (DMSO-d₆+D₂O): δ 8.12 (s, 2H, CH=N), 7.68 (d, 4H, J=7 Hz, Ar), 7.55 (s, 1H, Ar), 7.52–7.36 (m, 7H, Ar), 7.18 (s, 2H, thiazole), 7.14 (d, 4H, J=8 Hz, Ar), 6.77 (d, 4H, J=8 Hz, Ar), 3.61 (s, 6H, OCH₃), 3.44–3.25 (m, 4H, CH₂), 2.87 (t, 4H, J=7 Hz, CH₂); ¹³C NMR (DMSO-d₆): δ 168.6, 157.4, 151.8, 146.8, 142.9, 141.6, 134.3, 133.6, 129.6, 129.3, 128.8, 128.6, 126.3, 115.6, 113.5, 109.4, 106, 93.4, 54.8, 34.7, 25.5; MS: m/z 829.2 [(M+H]⁺, 100%]. Anal. Calcd for C₄₈H₄₀N₆O₄S₂: C, 69.54; H, 4.86; N, 10.14. Found: C, 69.50; H, 4.81; N, 10.15.

4,4′-(3,5-Bis(phenethyl)benzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis((2-(3-hydroxybenzylidene)hydrazino)thiazole) (7c)

Reaction time 12 h, yield 75%, method A; reaction time 20 min, yield 86%, method B; off-white solid; mp 138–140°C (dec); IR: 3463, 1560, 1491, 1364, 748 cm⁻¹; ¹H NMR (DMSO-d₆): δ 12.09 (s, 2H, N-H), 9.66 (s, 2H, OH), 8.03 (s, 2H, CH=N), 7.71 (s, 1H, Ar), 7.43 (s, 1H, Ar), 7.41–7.04 (m, 18H, Ar, thiazole), 6.80 (d, 2H, J=7 Hz, Ar), 3.49 (m, 4H, CH₂), 2.94 (m, 4H, CH₂); ¹³C NMR (DMSO-d₆): δ 168.7, 157.6, 151.9, 146.9, 142.9, 142, 141.7, 135.6, 129.9, 128.7, 128.2, 126.3, 125.9, 118, 116.8, 115.6, 112.1, 109.3, 106.1, 93.5, 35.6, 25.2; MS: m/z 801.3 [(M+H)⁺, 100%]. Anal. Calcd for C₄₆H₃₆N₆O₄S₂: C, 68.98; H, 4.53; N, 10.49. Found: C, 68.93; H, 4.49; N, 10.50.

4,4′-(3,5-Bis(4-methoxyphenethyl)benzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis(2-(2-(3-hydroxybenzylidene)hydrazino)thiazole) (7d)

Reaction time 16 h, yield 70%, method A; reaction time 20 min, yield 85%; method B; brown solid; mp 124–126°C (dec); IR: 3465, 1562, 1508, 1365, 730 cm⁻¹; ¹H NMR (DMSO-d₆): δ 12.09 (s, 2H, N-H), 9.65 (s, 2H, O-H), 8.03 (s, 2H, CH=N), 7.70 (s, 1H, Ar), 7.33 (s, 1H, Ar), 7.29–7.19 (m, 8H, Ar, thiazole), 7.13 (s, 2H, Ar), 7.06 (d, 2H, J=7 Hz, Ar), 6.81 (m, 6H, Ar), 3.66 (s, 6H, OCH₃), 3.53 (m, 4H, CH₂), 2.91 (t, 4H, J=7Hz, CH₂); ¹³C NMR (DMSO-d₆): δ 168.7, 157.6, 157.5, 151.8, 146.8, 142.9, 141.9, 135.6, 133.6, 129.9, 129.6, 126.4, 118, 116.8, 115.7, 113.5, 112.1, 109.4, 106, 93.5, 54.9, 34.7, 25.5; MS: m/z 861.2 [(M+H)⁺, 100%]. Anal. Calcd for C₄₈H₄₀N₆O₆S₂: C, 66.96; H, 4.68; N, 9.76. Found: C, 66.91; H, 4.63; N, 9.78.

4,4′-(3,5-Diphenethylbenzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis(2-(2-(4-methoxybenzylidene)hydrazino)thiazole) (7e)

Reaction time 12 h, yield 85%, method A; reaction time 8 min, yield 91%, method B; off-white solid; mp 112–114°C (dec); IR: 3465, 1557, 1506, 1362, 742 cm⁻¹; ¹H NMR (DMSO-d₆): δ 11.99 (s, 2H, N-H), 8.07 (s, 2H, CH=N), 7.69 (s, 1H, Ar), 7.62 (d, 4H, J=8 Hz, Ar), 7.43 (s, 1H, Ar), 7.36 (d, 4H, J=7 Hz, Ar), 7.29 (m, 4H, Ar, thiazole), 7.18 (d, 4H, J=7 Hz, Ar), 7.01 (d, J=8 Hz, 4H, Ar), 3.80 (s, 6H, OCH₃), 3.55–3.44 (m, 4H, CH₂), 3.04–2.89 (m, 4H, CH₂); ¹³C NMR (DMSO-d₆): δ 168.8, 160.2, 151.8, 146.9, 142.9, 141.7, 141.2, 128.6, 128.1, 127.8, 126.9, 126.3, 125.8, 115.5, 114.3, 109.2, 105.7, 93.4, 55.2, 35.5, 25.1; MS: m/z 829.2 [(M+H])⁺, 100%]. Anal. Calcd for C₄₈H₄₀N₆O₄S₂: C, 69.54; H, 4.86; N, 10.14. Found: C, 69.50; H, 4.81; N, 10.16.

4,4′-(3,5-Bis(4-methoxyphenethyl)benzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis(2-(2-(4-methoxybenzylidene)hydrazino)thiazole) (7f)

Reaction time 15 h, yield 72%, method A; reaction time 15 min, yield 86%, method B; off-white solid; mp 110–112°C (dec); IR: 3465, 1562, 1508, 1364, 731 cm⁻¹; ¹H NMR (DMSO-d₆+D₂O): δ 8.02 (s, 2H, CH=N), 7.63 (s, 1H, Ar), 7.57 (d, 4H, J=8 Hz, Ar), 7.28 (s, 1H, Ar), 7.19 (d, 4H, J=7 Hz, Ar), 7.12 (s, 2H, thiazole), 6.96 (d, 4H, J=8 Hz, Ar), 6.75 (d, 4H, J=7 Hz, Ar), 3.78 (s, 6H, OCH₃), 3.60 (s, 6H, OCH₃), 3.47–3.21 (m, 4H, CH₂), 2.88 (m, 4H, CH₂); ¹³C NMR (DMSO-d₆): δ 168.7, 160.2, 157.4, 151.8, 146.8, 142.9, 141.7, 133.6, 129.6, 127.8, 126.9, 126.3, 115.6, 114.3, 113.5, 109.3, 105.6, 93.4, 55.2, 54.8, 34.7, 25.5; MS: m/z 889.2 [(M+H)⁺, 100%]. Anal. Calcd for C₅₀H₄₄N₆O₆S₂: C, 67.55; H, 4.99; N, 9.45. Found: C, 67.50; H, 4.94; N, 9.47.

4,4′-(3,5-Diphenethylbenzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis(2-(2-(2-bromobenzylidene)hydrazino)thiazole) (7g)

Reaction time 10 h, yield 75%, method A; reaction time 10 min, yield 89%, method B; brown solid; mp 206–208°C (dec); IR: 3463, 1560, 1508, 1348, 752 cm⁻¹; ¹H NMR (DMSO-d₆): δ 12.40 (s, 2H, N-H), 8.46 (s, 2H, CH=N), 8.02–7.86 (m, 2H, Ar), 7.84 (s, 1H, Ar), 7.68 (d, 2H, J=7.5 Hz, Ar), 7.52–7.19 (m, 17H, Ar-H, thiazole), 3.47 (t, J=7 Hz, 4H, CH₂), 2.98 (t, J=7 Hz, 4H, CH₂); ¹³C NMR (DMSO-d₆): δ 168.4, 152.1, 146.8, 142.4, 141.6, 139.8, 133.1, 133, 130.9, 128.5, 128.3, 128.1, 126.5, 125.8, 124.6, 122.7, 116.1, 109.2, 106.3, 93.7, 35.5, 25.6; MS: m/z 927.3 (M⁺, 100%). Anal. Calcd for C₄₆H₃₄Br₂N₆O₂S₂: C, 59.62; H, 3.70; N, 9.07. Found: C, 59.58; H, 3.65; N, 9.10.

4,4′-(3,5-Diphenethylbenzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis(2-(2-(3-bromobenzylidene)hydrazino)thiazole) (7h)

Reaction time 10 h, yield 78%, method A; reaction time 10 min, yield 87%, method B; brown solid; mp 216–218°C (dec); IR: 3463, 1558, 1479, 1359, 739 cm⁻¹; ¹H NMR (DMSO-d₆): δ 12.31 (s, 2H, N-H), 8.08 (s, 2H, CH=N), 7.86 (s, 2H, Ar), 7.71 (s, 1H, Ar), 7.68 (d, 2H, J=8 Hz, Ar), 7.58 (d, 2H, J=8 Hz Ar), 7.45 (s, 1H, Ar), 7.42 (d, 2H, J=8 Hz, Ar), 7.41–7.24 (m, 10H, Ar, thiazole), 7.17 (t, 2H, J=8 Hz, Ar), 3.47 (t, 4H, J=8 Hz, CH₂), 2.98 (t, 4H, J=8 Hz, CH₂); ¹³C NMR (DMSO-d₆): δ 168.5, 151.8, 146.8, 142.9, 141.6, 139.8, 136.8, 131.8, 131, 128.6, 128.4, 128.1, 126.3, 125.8, 125.2, 122.2, 115.6, 109.3, 106.3, 93.5, 35.5, 25.1; MS: m/z 926.9 (M⁺, 100%). Anal. Calcd for C₄₆H₃₄Br₂N₆O₂S₂: C, 59.62; H, 3.70; N, 9.07. Found: C, 59.57; H, 3.66; N, 9.09.

4,4′-(3,5-Bis(4-methoxyphenethyl)benzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis(2-(2-(3-bromobenzylidene)hydrazino)thiazole) (7i)

Reaction time 12 h, yield 75%, method A; reaction time 10 min, yield 86%, method B; brown solid; mp 118–120°C (dec); IR: 3462, 1565, 1511, 1366, 735 cm⁻¹; ¹H NMR (DMSO-d₆): δ 12.31 (s, 2H, N-H), 8.09 (s, 2H, CH=N), 7.86 (s, 2H, Ar), 7.70 (m, 3H, Ar), 7.58 (d, 2H, J=8 Hz, Ar), 7.41 (t, 2H, J=8 Hz, Ar), 7.34 (s, 1H, Ar), 7.25 (m, 6H, Ar, thiazole), 6.82 (d, 4H, J=8 Hz, Ar), 3.66 (s, 6H, OCH₃), 3.41 (m, 4H, CH₂), 2.91 (t, 4H, J=7 Hz, CH₂); ¹³C NMR (DMSO-d₆): δ 168.4, 157.4, 151.8, 146.7, 143, 139.7, 136.8, 133.6, 131.7, 130.9, 129.6, 128.4, 126.3, 125.2, 122.2, 115.7, 113.5, 109.4, 106.2, 93.4, 54.8, 34.7, 25.5; MS: m/z 986.79 (M⁺, 100%). Anal. Calcd for C₄₈H₃₈Br₂N₆O₄S₂: C, 58.42; H, 3.88; N, 8.52. Found: C, 58.38; H, 3.84; N, 8.54.

4,4′-(3,5-Diphenethylbenzo[1,2-b:5,4-b′]difuran-2,6-diyl)-bis(2-(2-(2-chlorobenzylidene) hydrazino)thiazole) (7j)

Reaction time 8 h; off-white solid; yield 70%, method A; reaction time 10 min, yield 86%, method B; mp 150–152°C (dec); IR: 3463, 1559, 1508, 1362, 748 cm⁻¹; ¹H NMR (DMSO-d₆): δ 12.40 (s, 2H, N-H), 8.49 (s, 2H, CH=N), 7.95 (dd, 2H, J=2.2, 6.7 Hz, Ar), 7.70 (s, 1H, Ar), 7.52 (dd, 2H, J=2.2, 6.7 Hz, Ar), 7.48–7.40 (m, 5H, Ar), 7.36 (d, 4H, J=7.1 Hz, Ar), 7.29 (d, 4H, J=7.1 Hz, Ar), 7.25 (s, 2H, thiazole), 7.17 (t, 2H, J=7.1 Hz, Ar), 3.46 (t, 4H, J=7.3 Hz, CH₂), 2.98 (t, 4H, J=7.3 Hz, CH₂); ¹³C NMR (DMSO-d₆): δ 168.3, 151.8, 146.7, 143, 141.7, 141.2, 137.4, 132.2, 131.5, 130.6, 129.9, 128.6, 128.1, 127.6, 126.1, 125.8, 115.7, 109.2, 106.3, 93.5, 35.5, 25.2; MS: m/z 837.5 (M⁺, 100%). Anal. Calcd for C₄₆H₃₄Cl₂N₆O₂S₂: C, 65.94; H, 4.09; N, 10.03. Found: C, 65.90; H, 4.04; N, 10.05.

Antibacterial assay

Gram-negative strains (P. aeruginosa and E. coli) and Gram-positive strains (B. subtilis and S. aureus) were obtained from the Microbial Type Culture Collection. The biological activities were assayed using the standard disc diffusion method [27] for 100 μg/mL solutions in DMSO. Inhibition zones were measured, compared with the standard positive control of norfloxacin (+ve stains) and ofloxacin (-ve stains) at 100 μg/mL.

Antimycobacterial assay

Isolated single colonies of Mycobacterium bovis, 7H10 agar plate and Middlebrook 7H9 medium were used. The activity was assayed by the turbidometry method [28] using a mixture of isoniazid and rifampicin as standard.

Acknowledgments

The authors are grateful to the Head, Department of Chemistry, Osmania University, Hyderabad and IICT, Hyderabad for providing analytical and biological facilities. The authors are thankful to Chemveda Life Sciences Pvt. Ltd., IDA, Uppal, Hyderabad, for providing laboratory facilities. Ananda Rao thanks CSIR, New Delhi, India for a research fellowship.

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Received: 2017-12-1

Accepted: 2018-3-14

Published Online: 2018-5-9

Published in Print: 2018-6-27

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-2017-0247

Keywords for this article

antibacterial; antimycobacterial; benzofuran; microwave irradiation; thiazole

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