Synthesis, characterization, biological activities and molecular modeling of Schiff bases of benzene sulfonamides bearing curcumin scaffold

Mahmood Ahmed; Muhammad Abdul Qadir; Muhammad Imtiaz Shafiq; Muhammad Muddassar; Zahoor Qadir Samra; Abdul Hameed

doi:10.1016/j.arabjc.2016.11.017

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Original article

12 (

); 41-53

doi:

10.1016/j.arabjc.2016.11.017

Synthesis, characterization, biological activities and molecular modeling of Schiff bases of benzene sulfonamides bearing curcumin scaffold

Mahmood Ahmed^{^a,⁎}, Muhammad Abdul Qadir^{^a}, Muhammad Imtiaz Shafiq^{^b}, Muhammad Muddassar^{^c}, Zahoor Qadir Samra^{^b}, Abdul Hameed^{^d}

a Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan

b Institute of Biochemistry and Biotechnology, University of the Punjab, Lahore 54590, Pakistan

c Department of Biosciences, COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan

d H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan

⁎Corresponding author. mahmoodresearchscholar@gmail.com (Mahmood Ahmed)

Received: 2016-9-9, Accepted: 2016-11-28, Published: 2016-01-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Curcumin has shown large number of pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its various derivatives for diverse biological functions. In this study Schiff bases of benzenes sulfonamides bearing curcumin scaffold were synthesized to investigate their pharmacological effects. The structures of newly synthesized compounds were described by IR, ¹H NMR and ¹³C NMR spectral data. The anti-inflammatory and antinociceptive activities of new compounds were evaluated with indomethacin and diclofenac sodium in experimental animal models respectively. COX-2 enzyme inhibition was evaluated with synthesized compounds through in vitro cyclooxygenase assays. Inhibition assays result revealed that compound 3a was the most potent compound. Molecular docking studies were also performed to identify the plausible binding mode of this compound. Antibacterial and antifungal activities were evaluated with ciprofloxacin, nystatin and ketoconazole using disk diffusion method and minimum inhibitory concentration values were determined by 96-well plate assay method. Our studies showed that compound 3a has promising antibacterial and anti-inflammatory while 3c has better antifungal activity as compared to reference drugs. Similarly the combination of more potent compounds 3a and 3c with ciprofloxacin and nystatin respectively gave significant synergic effect.

Keywords

Schiff bases

Anti-inflammatory

Antinociceptive

Antibacterial

Antifungal

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1 Introduction

Curcuminoids are the major constituents of Curcuma longa L. (turmeric) and the yellow color of turmeric is by virtue of one of the major curcuminoids, curcumin which is used for centuries in several biological attributes due to its pharmacological safety (Amalraj et al., 2016). Chemically curcumin is diferuloylmethane which has been attracted extensively in biomedical research against various diseases. It exhibited wide range of biological activities such as antibacterial, antifungal, anti-inflammatory, antioxidant and cancer preventive properties (Liu et al., 2013; Sahu et al., 2016; Wei et al., 2012; Jha et al., 2015 ). Currently curcumin is acclaimed to be one of the most widely researched naturally occurring chemo preventive agents which is cytoprotective to healthy human cells. It has been tested in various disease models such as anti-amyloid β aggregation (Alzheimer’s disease), arthritis, and cancer as both treatment and preventive agent (Raghavan et al., 2015; Pröhl et al., 2016; Bayomi et al., 2015 ). In spite of important therapeutic application, limiting therapeutic utility concern is associated with curcumin because of its poor absorption and fast metabolism under physiological conditions (Lal et al., 2016). Much efforts have been attempted to improve pharmacokinetics and pharmacological properties of curcumin through its structure modification (Ferrari et al., 2011; Ohori et al., 2006). Active methylene and keto moiety are believed to be responsible for its rapid metabolism. In order to circumvent the problem of rapid metabolism and to improve its pharmacokinetics profile, we designed and synthesized the curcumin analogs/derivatives containing sulfonamides moiety having medicinally important five/six membered heterocyclic rings (Lal et al., 2013). Sulfonamides are important pharmacores which are extensively employed as antifolic agent by acting as competitive inhibitors of dihydropteroate synthase enzyme. These are structurally similar to p-aminobenzoic acid (PABA) which is cofactor for synthesis of folic acid by bacteria. So as an analog of PABA, sulfonamides can compete with it efficiently to prevent synthesis of proteins and nucleic acid which results the inhibition of various microorganisms (Qadir et al., 2015b,d,c,a ). Moreover, a sulfonamide is versatile moiety for its diverse pharmacological activities that include antibacterial, antifungal, anti-inflammatory and enzyme inhibition (Abbas et al., 2016; Firke and Bari, 2015; Mutahir et al., 2016; Khan et al., 2015 ). The newer antibacterial drugs with different mode of action and mechanism have become an emerging demand to overcome existing drugs resistant pathogens. So, in present work, sulfonamides were conjugated with curcumin via keto and enol linkage to form Schiff bases that could lead to better activity. Newly synthesized compounds were screened for in vitro antibacterial, antifungal and in vivo anti-inflammatory and antinociceptive activities. Moreover, sulfonamides in combination with trimethoprim have been extensively used for antibacterial enhancement efficacy via well-known synergistic effect (Zhang et al., 2015). Therefore, in present work, combination of strong active compound with ciprofloxacin (antibacterial drug) or nystatin (antifungal drug) was evaluated in vitro for synergistic effect.

2 Experimental

2.1

2.1 Chemistry

In present work, analytical grade chemicals obtained from Central Chemicals-Lahore originate to Merck (Germany) and Sigma Aldrich (USA) and were used without further purification to synthesize desired compounds. The spectral studies were performed on FTIR-ATR spectrometer (Bruker-USA) and NMR spectrometer (¹H NMR, 500 MHz and ¹³C NMR, 125 MHz, Bruker-USA). DMSO-d₆ was employed to obtain ¹H NMR, ¹³C NMR spectra while TLC Silica gel 60 F₂₅₄ (Merck, Darmstadt, Germany) was run to check the progress of reaction. Flash 2000 HT elemental analyzer (Thermo Scientific, UK) was used for concentration of hydrogen (H), carbon (C), nitrogen (N) and sulfur (S) of synthesized compounds (analysis procedure can be seen from supplementary file) while the melting point was measured by Gallenkamp apparatus.

2.2

2.2 General procedure of synthesis

In 100 mL flask, curcumin (1 mmol, 1 eq.) was dissolved in boiling ethanol then added respective sulfonamides (1 eq. for 3a-3f and 2 eq. for 4a-4f) and catalytic amount of glacial acetic acid. The reaction mixture was refluxed until the completion of reaction and progress of reaction were monitored by TLC (dichloromethane: methanol: ammonia in 75:25:1 ratio). From resulting mixture, solvent was evaporated by rotary evaporated to get solid product and purified by flash chromatography using eluent DCM/MeOH, 25:1. The elemental and spectral data of all synthetic compounds are presented below.

2.2.1

2.2.1 N-(3,4-dimethylisoxazol-5-yl)-4-({(1E,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)benzenesulfonamide (3a)

Bick red solid; Yield, 92.5%; M.P., 146–148 °C; R_f, 0.79; IR (ATR, υ cm⁻¹): 3483 (sulfonyl-NH), 3379 (phenolic-OH), 1626 (imine —CH⚌N—), 1345, 1152 (—NH—S⚌O) 1029 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 16.39 (1H, brs, OH), 10.47 (1H, s, NH), 9.65 (2H, s, ArOH), 7.53 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.34 (2H, d, J = 8.5 Hz, ArH_2″,6″), 7.31 (2H, d, J = 2 Hz, ArH_6,6′), 7.14 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.80 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH⚌CH_4,4′), 6.57 (2H, d, J = 9 Hz, ArH_3″,5″), 6.05 (1H, s, CH-OH), 3.82 (6H, s, (OMe)₂), 2.06 (3H, s, CH₃), 1.60 (3H, s, CH₃). ¹³C NMR (125 MHz, DMSO-d₆): 161.4, 153.4, 149.4, 148.1, 140.9, 128.8, 126.5, 123.3, 121.2, 115.8, 112.8, 111.4, 101.04, 55.8 (OCH₃ × 2), 10.4 (CH₃), 5.94 (CH₃). Anal. Calc. for C₃₂H₃₁N₃O₈S (FW = 617.67 g/mol): C, 62.2; H, 5.1; N, 6.8; S, 5.2%. Found: C, 62.1; H, 5.0; N, 6.9; S, 5.3%.

2.2.2

2.2.2 4-({(1E,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide (3b)

Bick red solid; Yield, 86.7%; M.P., 142–144 °C; R_f, 0.86; IR (ATR, υ cm⁻¹): 3463 (sulfonyl-NH), 3355 (phenolic-OH), 1625 (imine —CH⚌N—), 1362, 1139 (—NH—S⚌O) 1027 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 16.39 (1H, brs, OH), 12.43 (1H, s, NH), 9.65 (2H, s, ArOH), 7.52 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.41 (2H, d, J = 8.5 Hz, ArH_2′',6′'), 7.31 (2H, d, J = 2 Hz, ArH_6,6′), 7.18 (1H, d, J = 4.5 Hz, CH⚌CH), 7.14 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.80 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH⚌CH_4,4′), 6.72 (1H, d, J = 4.5 Hz, CH⚌CH), 6.54 (2H, d, J = 9 Hz, ArH_3″,5″), 6.05 (1H, s, CH—OH), 3.82 (6H, s, (OCH₃)₂). ¹³C NMR (125 MHz, DMSO-d₆): 152.3, 149.4, 148.1, 140.9, 127.9, 126.5, 123.3, 121.2, 115.8, 112.6, 111.4, 107.6, 101.04, 55.8 (OCH₃ × 2). Anal. Calc. for C₃₀H₂₇N₃O₇S₂ (FW = 605.68 g/mol): C, 59.5; H, 4.5; N, 6.9; S, 10.6%. Found: C, 59.6; H, 4.4; N, 6.8; S, 10.7%.

2.2.3

2.2.3 4-({(1E,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)-N-(4-methylpyrimidin-2-yl)benzenesulfonamide (3c)

Bick red solid; Yield, 81.2%; M.P., 166–168 °C; R_f, 0.81; IR (ATR, υ cm⁻¹): 3480 (sulfonyl-NH), 3378 (phenolic-OH), 1624 (imine —CH⚌N—), 1326, 1148 (—NH—S⚌O) 1029 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 16.39 (1H, brs, OH), 10.47 (1H, s, NH), 9.65 (2H, s, ArOH), 8.29 (1H, d, J = 5 Hz, ArH), 7.62 (2H, d, J = 8.5 Hz, ArH_2″,6″), 7.53 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.31 (2H, d, J = 2 Hz, ArH_6,6′), 7.14 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.86 (1H, d, J = 5 Hz, ArH), 6.80 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH = CH_4,4′), 6.54 (2H, d, J = 8.5 Hz, ArH_3″,5″), 6.05 (1H, s, CH—OH), 3.82 (6H, s, (OCH₃)₂), 2.29 (3H, s, CH₃). ¹³C NMR (125 MHz, DMSO-d₆): 157.1, 153.04, 149.5, 148.1, 140.9, 130.2, 126.4, 123.3, 121.2, 115.8, 112.2, 111.4, 101.04, 55.8 (OCH₃ × 2), 23.5 (CH₃). Anal. Calc. for C₃₂H₃₀N₄O₇S (FW = 614.67 g/mol): C, 62.5; H, 4.9; N, 9.1; S, 5.2%. Found: C, 62.6; H, 4.8; N, 9.2; S, 5.3%.

2.2.4

2.2.4 4-({(1Z,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)-N-pyrimidin-2-ylbenzenesulfonamide (3d)

Bick red solid; Yield, 83.0%; M.P., 164–166 °C; R_f, 0.79; IR (ATR, υ cm⁻¹): 3483 (sulfonyl-NH), 3365 (phenolic-OH), 1623 (imine —CH⚌N—), 1351, 1149 (—NH—S⚌O) 1026 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 16.39 (1H, brs, OH), 10.47 (1H, s, NH), 9.65 (2H, s, ArOH), 8.29 (1H, d, J = 5 Hz, ArH), 7.62 (2H, d, J = 8.5 Hz, ArH_2″,6″), 7.53 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.31 (2H, d, J = 2 Hz, ArH_6,6′), 7.14 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.86 (1H, d, J = 5 Hz, ArH), 6.80 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH⚌CH_4,4′), 6.54 (2H, d, J = 8.5 Hz, ArH_3″,5″), 6.05 (1H, s, CH—OH), 3.82 (6H, s, (OCH₃)₂).

¹³C NMR (125 MHz, DMSO-d₆): 157.1, 153.04, 149.5, 148.1, 140.9, 130.2, 126.5, 123.3, 121.2, 115.8, 112.2, 111.4, 101.04, 55.8 (OCH₃ × 2). Anal. Calc. for C₃₁H₂₈N₄O₇S (FW = 600.64 g/mol): C, 62.0; H, 4.7; N, 9.3; S, 5.3%. Found: C, 62.1; H, 4.8; N, 9.2; S, 5.2%.

2.2.5

2.2.5 N-(5,6-dimethoxypyrimidin-4-yl)-4-({(1E,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)benzenesulfonamide (3e)

Brown solid; Yield, 82.3%; M.P., 146–148 °C; R_f, 0.86; IR (ATR, υ cm⁻¹): 3463 (sulfonyl-NH), 3375 (phenolic-OH), 1628 (imine —CH⚌N—), 1315, 1153 (—NH—S⚌O) 1030 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 16.39 (1H, brs, OH), 10.60 (1H, s, NH), 9.65 (2H, s, ArOH), 8.09 (1H, s, ArH), 7.62 (2H, d, J = 8.5 Hz, ArH_2″,6″), 7.53 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.31 (2H, d, J = 2 Hz, ArH_6,6′), 7.14 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.80 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH⚌CH_4,4′), 6.54 (2H, d, J = 8.5 Hz, ArH_3″,5″), 6.05 (1H, s, CH—OH), 3.87 (3H, s, OCH₃), 3.82 (6H, s, (OCH₃)₂), 3.65 (3H, s, OCH₃). ¹³C NMR (125 MHz, DMSO-d₆): 161.5, 153.1, 150.7, 149.4, 148.1, 140.9, 129.9, 126.9, 123.3, 121.2, 115.8, 112.3, 111.4, 101.04, 60.3 (OCH₃), 55.8 (OCH₃ × 2), 54.1 (OCH₃). Anal. Calc. for C₃₃H₃₂N₄O₉S (FW = 660.7 g/mol): C, 60.0; H, 4.9; N, 8.5; S, 4.9%. Found: C, 59.9; H, 5.0; N, 8.6; S, 4.8%.

2.2.6

2.2.6 N-{[4-({(1E,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)phenyl]sulfonyl}acetamide (3f)

Dark brown solid; Yield, 79.2%; M.P., 142–144 °C; R_f, 0.88; IR (ATR, υ cm⁻¹): 3378 (phenolic-OH), 2921 (amide-NH), 1626 (imine —CH⚌N—), 1366, 1141 (—NH—S⚌O) 1027 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 16.39 (1H, brs, OH), 11.61 (1H, s, NH), 9.65 (2H, s, ArOH), 7.53 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.50 (2H, d, J = 8.5 Hz, ArH_2″,6″), 7.31 (2H, d, J = 1.5 Hz, ArH_6,6′), 7.13 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.80 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH⚌CH_4,4′), 6.57 (2H, d, J = 9 Hz, ArH_3″,5″), 6.05 (1H, s, CH—OH), 3.82 (6H, s, (OCH₃)₂), 1.84 (3H, s, CH₃). ¹³C NMR (125 MHz, DMSO-d₆): 174.6 (CO), 149.5, 148.1, 140.8, 129.8, 126.5, 123.3, 121.2, 115.8, 112.4, 111.4, 101.04, 55.8 (OCH₃ × 2), 26.6 (CH₃). Anal. Calc. for C₂₉H₂₈N₂O₈S (FW = 564.61 g/mol): C, 61.7; H, 5.0; N, 5.0; S, 5.7%. Found: C, 61.8; H, 5.1; N, 5.0; S, 5.8%.

2.2.7

2.2.7 4,4′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]di(nitrilo)]bis[N-(3,4-dimethylisoxazol-5-yl)benzenesulfonamide] (4a)

Brown solid; Yield, 78%; M.P., 156–158 °C; R_f, 0.78; IR (ATR, υ cm⁻¹): 3484 (sulfonyl-NH), 3379 (phenolic-OH), 1626 (imine —CH⚌N—), 1345, 1152 (—NH—S⚌O) 1029 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 10.47 (2H, s, NH), 9.65 (2H, s, ArOH), 7.53 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.34 (4H, d, J = 8.5 Hz, ArH_2″,6″), 7.31 (2H, d, J = 2 Hz, ArH_6,6′), 7.14 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.80 (1H, d, J = 8 Hz, ArH), 6.75 (2H, d, J = 16 Hz, CH⚌CH_4,4′), 6.57 (4H, d, J = 9 Hz, ArH_3″,5″), 6.08 (2H, s, CH₂), 3.82 (6H, s, (OMe)₂), 2.06 (6H, s, (CH₃)₂), 1.60 (6H, s, (CH₃)₂). ¹³C NMR (125 MHz, DMSO-d₆): 161.4, 156.5, 153.4, 149.5, 148.2, 140.9, 128.8, 126.5, 124.7, 123.3, 121.2, 115.8, 112.8, 111.4, 101.06, 55.8 (OCH₃ × 2), 10.5 (CH₃ × 2), 5.96 (CH₃ × 2). Anal. Calc. for C₄₃H₄₂N₆O₁₀S₂ (FW = 866.96 g/mol): C, 59.8; H, 4.9; N, 9.7; S, 7.4%. Found: C, 59.7; H, 4.8; N, 9.8; S, 7.3%.

2.2.8

2.2.8 4,4′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]di(nitrilo)]bis(N-1,3-thiazol-2-ylbenzenesulfonamide) (4b)

Brown solid; Yield, 76.3%; M.P., 162–164 °C; R_f, 0.82; IR (ATR, υ cm⁻¹): 3485 (sulfonyl-NH), 3318 (phenolic-OH), 1625 (imine —CH⚌N—), 1362, 1132 (—NH—S⚌O) 1030 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 12.37 (2H, s, NH), 9.65 (2H, s, ArOH), 7.52 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.41 (4H, d, J = 8.5 Hz, ArH_2″,6″), 7.31 (2H, d, J = 2 Hz, ArH_6,6′), 7.18 (2H, d, J = 4.5 Hz, CH⚌CH), 7.14 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.80 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH⚌CH_4,4′), 6.72 (2H, d, J = 4.5 Hz, CH⚌CH), 6.54 (4H, d, J = 8.5 Hz, ArH_3″,5″), 5.82 (1H, s, CH₂), 3.82 (6H, s, (OMe)₂). ¹³C NMR (125 MHz, DMSO-d₆): 152.4, 149.4, 148.1, 140.9, 127.9, 126.5, 123.3, 121.2, 115.8, 112.6, 111.4, 101.03, 79.2, 55.8 (OCH₃ × 2). Anal. Calc. for C₃₉H₃₄N₆O₈S₄ (FW = 842.99 g/mol): C, 55.6; H, 4.1; N, 9.9; S, 15.2%. Found: C, 55.6; H, 4.2; N, 9.8; S, 15.2%.

2.2.9

2.2.9 4,4′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]di(nitrilo)]bis[N-(4-methylpyrimidin-2-yl)benzenesulfonamide] (4c)

Brown solid; Yield, 75.2%; M.P., 175–177 °C; R_f, 0.81; IR (ATR, υ cm⁻¹): 3473 (sulfonyl-NH), 3378 (phenolic-OH), 1624 (imine —CH⚌N—), 1370, 1148 (—NH—S⚌O) 1030 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 11.08 (2H, s, NH), 9.65 (2H, s, ArOH), 8.29 (2H, d, J = 5 Hz, ArH), 7.62 (4H, d, J = 8.5 Hz, ArH_2″,6″), 7.53 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.31 (2H, d, J = 2 Hz, ArH_6,6′), 7.14 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.86 (2H, d, J = 5 Hz, ArH), 6.80 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH = CH_4,4′), 6.54 (4H, d, J = 8.5 Hz, ArH_3″,5″), 5.97 (2H, s, CH₂), 3.82 (6H, s, (OCH₃)₂), 2.29 (6H, s, (CH₃)₂). ¹³C NMR (125 MHz, DMSO-d₆): 149.4, 148.1, 140.9, 130.2, 126.5, 123.3, 121.2, 115.8, 112.2, 111.4, 101.03, 55.8 (OCH₃ × 2), 23.5 (CH₃ × 2). Anal. Calc. for C₄₃H₄₀N₈O₈S₂ (FW = 860.96 g/mol): C, 60.0; H, 4.7; N, 13.0; S, 7.5%. Found: C, 59.9; H, 4.8; N, 13.1; S, 7.4%.

2.2.10

2.2.10 4,4′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]di(nitrilo)]bis(N-pyrimidin-2-ylbenzenesulfonamide) (4d)

Brown solid; Yield, 74%; M.P., 172–174 °C; R_f, 0.74; IR (ATR, υ cm⁻¹): 3480 (sulfonyl-NH), 3376 (phenolic-OH), 1623 (imine —CH⚌N—), 1364, 1152 (—NH—S⚌O) 1026 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 11.08 (2H, s, NH), 9.65 (2H, s, ArOH), 8.29 (2H, d, J = 5 Hz, ArH), 7.62 (4H, d, J = 8.5 Hz, ArH_2″,6″), 7.53 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.31 (2H, d, J = 2 Hz, ArH_6,6′), 7.14 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.86 (2H, d, J = 5 Hz, ArH), 6.80 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH = CH_4,4′), 6.54 (4H, d, J = 8.5 Hz, ArH_3″,5″), 5.97 (2H, s, CH₂), 3.82 (6H, s, (OCH₃)₂).

¹³C NMR (125 MHz, DMSO-d₆): 149.4, 148.1, 140.9, 130.2, 126.5, 123.3, 121.2, 115.8, 112.2, 111.4, 101.03, 55.8 (OCH₃ × 2). Anal. Calc. for C₄₁H₃₆N₈O₈S₂ (FW = 832.91 g/mol): C, 59.1; H, 4.4; N, 13.5; S, 7.7%. Found: C, 59.1; H, 4.5; N, 13.4; S, 7.8%.

2.2.11

2.2.11 4,4′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]di(nitrilo)]bis[N-(5,6-dimethoxypyrimidin-4-yl)benzenesulfonamide] (4e)

Brown solid; Yield, 71.5%; M.P., 168–170 °C; R_f, 0.81; IR (ATR, υ cm⁻¹): 3463 (sulfonyl-NH), 3375 (phenolic-OH), 1624 (imine —CH⚌N—), 1373, 1153 (—NH—S⚌O) 1032 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 10.60 (2H, s, NH), 9.65 (2H, s, ArOH), 8.09 (2H, s, ArH), 7.62 (4H, d, J = 8.5 Hz, ArH_2″,6″), 7.53 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.31 (2H, d, J = 2 Hz, ArH_6,6′), 7.14 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.80 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH⚌CH_4,4′), 6.54 (4H, d, J = 8.5 Hz, ArH_3″,5″), 6.05 (2H, s, CH₂), 3.88 (6H, s, (OCH₃)₂), 3.82 (6H, s, (OCH₃)₂), 3.65 (6H, s, (OCH₃)₂). ¹³C NMR (125 MHz, DMSO-d₆): 161.5, 153.2, 150.7, 149.4, 148.1, 140.9, 129.9, 126.5, 123.3, 121.2, 115.8, 112.3, 111.4, 101.03, 60.3 (OCH₃ × 2), 55.8 (OCH₃ × 2), 54.1 (OCH₃ × 2). Anal. Calc. for C₄₅H₄₄N₈O₁₂S₂ (FW = 953.0 g/mol): C, 56.7; H, 4.7; N, 11.8; S, 6.7%. Found: C, 56.8; H, 4.8; N, 11.8; S, 6.8%.

2.2.12

2.2.12 N,N′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]bis(nitrilo-4,1-phenylenesulfonyl)]diacetamide (4f)

Dark brown solid; Yield, 71.6%; M.P., 170–172 °C; R_f, 0.84; IR (ATR, υ cm⁻¹): 3373 (phenolic-OH), 2924 (amide-NH), 1624 (imine —CH⚌N—), 1375, 1143 (—NH—S⚌O) 1026 (—S⚌O). ¹H NMR (500 MHz, DMSO-d₆): δ_H 11.60 (2H, s, NH), 9.65 (2H, s, ArOH), 7.50 (2H, d, J = 16 Hz, CH_3,3′⚌CH), 7.50 (4H, d, J = 8.5 Hz, ArH_2″,6″), 7.28 (2H, brs, ArH_6,6′), 7.13 (2H, dd, J = 2, 8 Hz, ArH_10,10′), 6.78 (1H, d, J = 8 Hz, ArH_9,9′), 6.75 (2H, d, J = 16 Hz, CH⚌CH_4,4′), 6.44 (2H, d, J = 8.5 Hz, ArH_3″,5″), 5.37 (2H, s, CH₂), 3.82 (6H, s, (OCH₃)₂), 1.59 (6H, s, (CH₃)₂). ¹³C NMR (125 MHz, DMSO-d₆): 174.6 (2CO), 150.3, 148.2, 140.9, 132.9, 128.4, 127.5, 126.3, 123.4, 121.1, 115.9, 112.6, 111.3, 101.04, 55.8 (OCH₃ × 2), 26.6 (CH₃ × 2). Anal. Calc. for C₃₇H₃₆N₄O₁₀S₂ (FW = 760.83 g/mol): C, 58.4; H, 4.8; N, 7.4; S, 8.4%. Found: C, 58.3; H, 4.9; N, 7.3; S, 8.5%.

2.3

2.3 Pharmacological activities

2.3.1

2.3.1 Experimental animals and acute toxicity study

Healthy Swiss albino mice (20–25 g) of either sex (Zangrando et al., 2015) were obtained from HEJ-Research Institute-Karachi, Pakistan and kept in animal house of Institute of Biochemistry and Biotechnology (IBB)-Lahore, Pakistan in cages (polypropylene) with sterilized rice husk as bedding material. They were fed standard rodent pellets and water ad libitum under standard condition of temperature (25 ± 2 °C, 12/12 h light/dark cycles) and relative humidity (55 ± 1%). Before the commencement of experiment, the animals were allowed to acclimatize to environment for 7 days. The protocol followed for animal experiments was approved by Compliance with ethical standards of IBB-Lahore (Document: IBBPU/09/2016) under the criteria established by National Academy of Sciences-USA and published by National Institute of Health (NIH-USA). For acute toxicity study, the mice were fasted for 12 h with free access to water. Initially, synthesized curcumin analogs administered orally at dose of 5 mg/kg body in DMSO weight and mortality was observed for 24 h. Then individually all animals were observed after 10 mg/kg oral administration for any behavioral and neurological changes such as salivation, tremors, diarrhea, lacrimation, sleep and feeding behavior as a sign of acute toxicity for 24 h.

2.3.2

2.3.2 Anti-inflammatory activity assay: carrageenan induced hind paw edema

Anti-inflammatory activity was assessed by induction of acute inflammation by carrageenan in mice as described earlier (Bhowmick et al., 2014; Zangrando et al., 2015; Rauf et al., 2014 ). Briefly, 15 groups of mice were established and each group contains 6 mice. The mice were fasted 16 h before experiment but water was allowed ad libitum. The paw thickness of each mouse was measured with the help of vernier caliper (Mitutoyo, Japan) at 0 h time. The test substances (Curcumin and curcumin analogs, 10 mg/kg body weight), standard drug (Indomethacin 10 mg/kg body weight) and control (0.9% saline 10 mL/kg body weight) were administered intraperitoneally 1 h before injection of phlogistic agent (Carrageenan 0.1 mL, 1% in 0.9% saline). Carrageenan was injected subcutaneously into sub plantar tissue of right hind paw of each mouse to induce acute inflammation. The thickness (mm) of right hind paw was measured at 1st, 2nd and 3rd h after carrageenan injection. The anti-inflammatory activity was calculated by percentage inhibition of edema using the following formula: $Percentage inhibition of inflammation = \frac{{(C_{t} - C_{0})}_{control} - {(C_{t} - C_{0})}_{treated}}{{(C_{t} - C_{0})}_{control}} \times 100$ where C_t is right hind paw thickness at time for both treated and control group while C_o is thickness before carrageenan injection.

2.3.3

2.3.3 Cyclooxygenase-2 inhibitory activity

Cyclooxygenase-2 (COX-2) inhibition assay was performed by kit method (Item No. 760151, Cayman Chemical Company, USA). Briefly, 100% initial activity well contained assay buffer (150 μL), heme (10 μL) and COX-2 enzyme solution (10 μL). Inhibitory well contained assay buffer (110 μL), heme (10 μL) and COX-2 enzyme solution (10 μL) and sample (40 μL, 10 μM). Then plate was shaken carefully for 10 s. and incubated at 25 °C for 5 min. After the incubation colorimetric substrate (20 μL) was added to each well and reaction was initiated by arachidonic acid (20 μL). Again plate was shaken for 10 s. and incubated at 25 °C for 5 min. Absorbance of each well at 590 nm was noted by micro plate reader LT-4500 (Labtech International Ltd, UK) and COX-2 inhibition (%) was calculated by the following formula (Bandgar et al., 2014): $% COX- 2 inhibition = 1 - \frac{T}{C} \times 100$ where, T is absorbance of inhibitory well and C is absorbance of 100% initial activity without inhibitor.

2.3.4

2.3.4 Antinociceptive activity assay: acetic acid induced writhing

Anti-nociceptive activity was assessed by induction of acetic acid writhing in mice as described earlier (Bhowmick et al., 2014; Zangrando et al., 2015; Rauf et al., 2014 ). Briefly, 14 groups of mice were established and each group contains 6 mice. The mice were fasted 16 h before experiment but water was allowed ad libitum. The test substances (Curcumin analogs, 10 mg/kg body weight), standard drug (Diclofenac sodium 10 mg/kg body weight) and control (0.9% saline 10 mL/kg body weight) were administered intraperitoneally 1 h before injection of acetic acid (0.2 mL, 1% in 0.9% saline). After injection of acetic acid, each mouse put in big glass cylinder and total number of writhing episodes (turning of trunk, extension of hind legs and constriction of abdomen) was counted after 5 min and continued for period of 20 min. Antinociceptive activity was assessed by calculating percentage inhibition of writhing count of treated group from the mean writhing count of control group using the following formula: $Percentage antinociceptive activity = \frac{T_{c} - T_{t}}{T_{c}} \times 100$ where T_c is writhing count of control group while T_t is writhing count of treated group

2.3.5

2.3.5 Bacterial and fungal strains

Six bacterial strains, two gram positive, viz. Staphylococcus aureus ATCC 25923, Methicillin resistant staphylococcus aureus N315, and four gram negative, viz. Salmonella enterica ATCC 14028, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumonia ATCC 13882 were obtained from Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan, while six indigenous pathogenic fungal isolates have Accession No. Aspergillus niger 1109, Aspergillus flavus 1110, Fusarium oxysporum 1175, Fusarium solani 1199, Alternaria alternata 1200, and Penicillium digitatum 1160 were obtained from Institute of Agricultural Sciences, University of the Punjab, Lahore, Pakistan. The bacterial and fungal cultures were revived from the respective fresh isolates and maintained on tryptic soy agar (TSA) and potato dextrose agar (PDA) respectively slants at +4 °C until use.

2.3.6

2.3.6 Antibacterial assay

Disk diffusion method was used to evaluate the antibacterial susceptibility of synthesized curcumin derivatives. Three gradients concentrations (4 mg/mL, 2 mg/mL, and 1 mg/mL) of curcumin derivatives as well as standard reference drug (ciprofloxacin) were used and concentrations were made in acetone which has no activity against the test microorganisms. 5 μL of each concentration was soaked on sterile 6 mm Whatman filter paper No. 1 disk and dried for 30 min under laminar flow. 100 μL microbial suspension of 0.5 McFarland nephelometry standard (10⁸ cells/mL) was spread over the TSA media (20 mL in each petri plate) with the help of sterilized glass spreader to ensure the even growth of microorganism. The soaked disks were placed aseptically with the help of sterile forceps at equal distances over the inoculated plates. The plates were incubated at 37 ± 1 °C for 24 h and distinct zone was visualized surrounding the disks. The zones of inhibition (mm) were measured using digital vernier caliper (Starrett 799A-6/150, USA), evaluated the antibacterial activities and all studies were performed in triplicates. Minimum inhibitory concentration (MIC) value was calculated by using two fold serial dilution technique and concentration range 2000–1.95 μg/mL was used for MIC determination. 150 μL tryptic soy broth and 50 μL of bacterial suspension was added to each serially diluted concentration in 96-well plate then incubated at 37 ± 1 °C. After 24 h of incubation the optical density of mixture in 96-well plate was recorded at 600 nm using a microplate reader (BioRad, USA). The lowest concentration of the derivative that prevented the development of visible growth (OD₆₀₀ less than 0.05) is considered to be the MIC value (Dhorajiya et al., 2014; Aslam et al., 2016; Sharma et al., 2015 ).

2.3.7

2.3.7 Antifungal assay

Disk diffusion method was also used for antifungal susceptibility of synthesized curcumin derivatives with same three gradient concentrations in acetone as mentioned above but nystatin and ketoconazole were used as reference drug. 200 μL spore suspension of 1.5 × 10⁵ cells/mL (OD: 0.2 at 530 nm) was spread over the PDA media (20 mL in each petri plate). The soaked disks were placed aseptically with the help of sterile forceps at equal distances over the inoculated plates. The plates were incubated at 28 ± 1 °C for 48 h and distinct zone was visualized surrounding the disks. The zones of inhibition (mm) were measured and evaluated the antifungal activities. MIC value was also calculated by using two fold serial dilution technique for same range of concentration as in antibacterial assay using 96-well plate assay. 150 μL potato dextrose broth and 50 μL of spore suspension was added to each serially diluted concentration then incubated at 28 ± 1 °C. After 48 h of incubation the optical density of mixture in 96-well plate was recorded at 530 nm using a microplate reader (BioRad, USA). The lowest concentration of the derivative that prevented the development of visible growth (OD₅₃₀ less than 0.05) is considered to be the MIC value (Lal et al., 2013; Xie et al., 2015).

2.3.8

2.3.8 Percentage activity and fractional inhibitory concentration index

Percentage activity index (% AI) was determined by formula as given in equation-A, with respect to reference drugs such as ciprofloxacin for antibacterial and nystatin for antifungal studies. Fractional inhibitory concentration (FIC) index was determined by combination studies (equation-B), FIC index value ⩽ 1 represents the synergistic effect, FIC index value > 1 and < 2 represents the additive interaction while FIC index > 2 represents the antagonistic effect (Jain and Mishra, 2016; Zhang et al., 2015):

(A)

% AI = \frac{Zone of inhibition of synthetic derivative}{Zone of inhibition of reference drug} \times 100

(B)

FIC index = \frac{MIC of compound A in mixture}{MIC of compound A alone} + \frac{MIC of compound B in mixture}{MIC of compound B alone}

2.3.9

2.3.9 Statistical analysis

Statistical analysis was performed on SPSS version 15 (SPSS Inc., Chicago, IL, USA) for Windows; analysis of variance (ANOVA) was performed for significant difference (p < 0.05) with post hoc multiple comparisons for anti-inflammatory results obtained after 3 h.

2.3.10

2.3.10 Molecular modeling studies

For molecular modeling studies, compounds were sketched and energy minimized using the Maestro molecular modeling tool. Two hundred conforms for each molecule were generated using the Open Eye Software OMEGA tool (Hawkins et al., 2010). Cycloxygenase-2 crystal structure (4PH9) was downloaded from protein data bank and heteroatoms were removed and hydrogen atoms were added using the Schrodinger molecular modeling software (Orlando et al., 2015). The docked complex structure of protein and small molecules was energy minimized using the AMBER10 force field to relax it up to 1 Å deviation from native structure to remove steric clashes.

3 Results and discussion

3.1

3.1 Chemistry

The target curcumin derivatives containing sulfonamide moiety were prepared by interaction of curcumin with sulfa drugs such as sulfafurazole, sulfathiazole, sulfamerazine, sulfadiazine, sulfadoxine and sulfacetamide. The sulfonamide molecules have been attached to ketonic and enolic group using ethanol as solvent and acetic acid as catalyst. The mono (3a-3f) and bis (4a-4f) Schiff bases were resulted in good yield (71.6–92.5%). Synthetic route and structure of curcumin derivatives containing sulfonamides are depicted in Scheme 1. All the synthesized compounds were characterized by performing IR, ¹H NMR and ¹³C NMR spectral studies. In IR spectra, a broad absorption band at 3463–3483 cm⁻¹ indicates the presence of —NH moiety of sulfonamides in 3a-3e and 4a-4e compounds while absorption bands 2921, 2924 cm⁻¹ correspond to —NH of acetamide in compounds 3f and 4f respectively. A strong absorption band in 1148–1153 cm⁻¹ (symmetrical), 1315–1362 cm⁻¹ (unsymmetrical) region for compounds 3a-3f while 1132–1170 cm⁻¹ (symmetrical), 1345–1375 cm⁻¹ (unsymmetrical) region for 4a-4f compounds confirms the presence of —NH—S⚌O group. Moreover, characteristics of sulfoxide absorption band appeared in region 1026–1032 cm⁻¹ for all synthetic compounds. In ¹H NMR spectra, compounds 3a-3f exhibited broad singlet at δ 16.39 ppm assigned to proton of enol which confirmed that the imine formed first by replacing the carbonyl while in compounds 4a-4f this signal disappeared. The peaks for —NH proton of —SO₂NH— group appeared at δ 10.47–12.43 ppm confirmed the formation of sulfonamides. The compounds 3f and 4f gave singlet at δ 2.49–2.48 ppm assigned to proton of —CH₃ linked to amide moiety. In addition, all the other aliphatic and aromatic protons appeared in appropriate values of chemical shifts and integrals as explained in experimental section. In ¹³C NMR spectra, characteristics peaks at δ 149–162 ppm assigned to imine carbon (—C⚌N—) while carbonyl carbon in compounds 3f and 4f exhibits the signal at δ 174.6 ppm. The signals for methoxy carbon in all the compounds were appeared at δ 55.8–60.3 ppm. So, ¹³C NMR spectral analyses were consistent with assigned structure of all compounds.

Synthetic route of curcumin derivatives.

3.2

3.2 In vivo anti-inflammatory activity

In the literature, it has been reported that curcumin inhibits the inflammation in carrageenan induced edema in rats (Manjunatha and Srinivasan, 2006). Response of living tissues to injury which involves tissue breakdown/repair, cell migration, various chemical mediators such as leukotriene B4, serotonin, histamine, bradykinin, prostaglandins, interleukins-1 beta (IL-1b), IL-6, TNF-α, enzyme activators like protease, lysosomes and chemotactic agents has been reported in development of inflammatory disease (Saravanan et al., 2016). In the present study, the anti-inflammatory activity of synthesized compounds was evaluated by carrageenan induced paw edema in experimental animal models which is globally recognized and is believed to be biphasic. Early phase (1–2 h) is predominantly a non-phagocytic edema followed by a late phase (up to 4 h) with increased edema formation. Early phase of this model is attributed to release of bradykinin, histamine, serotonin and increased synthesis of prostaglandins in damaged tissue surroundings. The late phase is sustained by prostaglandins release and mediated by leukotrienes, bradykinin and polymorphonuclear cells (Zangrando et al., 2015; Rauf et al., 2014; Abdel-Sayed et al., 2016 ). The anti-inflammatory data (Table 1) indicate that carrageenan induced edema is significantly inhibited by tested compounds in late phase. Among the screened compounds (3a-3f, 4a-4f), compound 3a with isoxazole moiety exhibited greater anti-inflammatory activity by inhibition 82% of induced edema which is comparable to standard drug indomethacin (84.4% inhibition). Moreover, anti-inflammatory activity (72.6–82% inhibition) of curcumin derivatives is greater than curcumin (71.5% inhibition), and mono Schiff bases have greater inhibitory effect than bis Schiff bases. Thus our findings suggest a possible inhibition of cyclooxygenase enzymes that promote prostaglandin synthesis by our synthetic compounds and their effect is similar to non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin.

Table 1 Anti-inflammatory and antinociceptive activities of curcumin derivatives.

Treatment	Anti-inflammatory activity				Antinociceptive activity		% inhibition
	Paw edema in mm (mean ± SEM), n = 6, (% inhibition)				Total writhing count (mean ± SEM), n = 6	% inhibition	COX-2 at 10 μM
	0 h	1 h	2 h	3 h	Total writhing count (mean ± SEM), n = 6	% inhibition	COX-2 at 10 μM
3a	1.73 ± 0.04 (−)	2.67 ± 0.12 (11.3)	2.53 ± 0.09 (43.9)	2.26 ± 0.11 (82.0)^e	19.1 ± 1.8	66.8	71.3
3b	1.75 ± 0.05 (−)	2.61 ± 0.09 (18.9)	2.57 ± 0.11 (39.6)	2.37 ± 0.08 (75.0)^f	29.1 ± 2.4	49.4	49.7
3c	1.74 ± 0.08 (−)	2.56 ± 0.14 (22.6)	2.51 ± 0.08 (44.6)	2.26 ± 0.12 (79.7)^g	23.3 ± 2.2	59.5	51.2
3d	1.74 ± 0.08 (−)	2.56 ± 0.14 (22.6)	2.51 ± 0.08 (44.6)	2.36 ± 0.12 (75.8)^h	24.1 ± 2.2	58.1	41.3
3e	1.73 ± 0.05 (−)	2.65 ± 0.11 (13.2)	2.58 ± 0.12 (38.8)	2.38 ± 0.09 (74.6)ⁱ	28.4 ± 2.8	50.6	38.4
3f	1.75 ± 0.06 (−)	2.60 ± 0.13 (19.8)	2.53 ± 0.11 (43.9)	2.41 ± 0.12 (74.2)^J	28.6 ± 2.9	50.3	36.4
4a	1.78 ± 0.01 (−)	2.59 ± 0.11 (20.7)	2.51 ± 0.08 (47.5)	2.45 ± 0.11 (73.8)^k	34.5 ± 1.2	40.0	27.3
4b	1.76 ± 0.04 (−)	2.66 ± 0.05 (15.1)	2.58 ± 0.11 (41.0)	2.46 ± 0.08 (72.6)^l	31.4 ± 3.3	45.4	26.8
4c	1.75 ± 0.05 (−)	2.67 ± 0.07 (13.2)	2.49 ± 0.14 (46.8)	2.37 ± 0.09 (75.8)^m,h	29.4 ± 1.1	48.9	25.6
4d	1.75 ± 0.05 (−)	2.67 ± 0.07 (13.2)	2.49 ± 0.14 (46.8)	2.42 ± 0.09 (73.8)^n,k	29.9 ± 1.1	48.0	24.4
4e	1.73 ± 0.04 (−)	2.57 ± 0.1 (20.7)	2.49 ± 0.15 (45.3)	2.35 ± 0.12 (75.8)^o,h	28.5 ± 2.5	50.4	21.2
4f	1.76 ± 0.08 (−)	2.47 ± 0.11 (30.2)	2.43 ± 0.12 (51.8)	2.37 ± 0.11 (76.2)^p	25.8 ± 2.2	55.1	21.4
Curcumin	1.79 ± 0.04 (−)	2.61 ± 0.13 (22.6)	2.54 ± 0.04 (46.0)	2.52 ± 0.11 (71.5)^q	–	–	19.1
Standard drug^a,b,c	1.74 ± 0.05 (−)	2.67 ± 0.14 (12.3)	2.42 ± 0.12 (51.1)	2.14 ± 0.09 (84.4)^r	18.9 ± 1.9	67.1	76.5
Control^d	1.75 ± 0.04 (−)	2.81 ± 0.11 (−)	3.14 ± 0.12 (−)	4.31 ± 0.11 (−)	57.5 ± 2.2	–	–

Significantly different values are represented by different letters (e–r) using one way ANOVA at p < 0.05.

^a Indomethacin for anti-inflammatory assay.

^b Diclofenac sodium for antinoceptive assay.

^c Celecoxib for COX-2 inhibition assay.

^d 0.9% saline.

3.3

3.3 Cyclooxygenase-2 inhibitory activity

All the tested compounds were tested for inhibitory activity against ovine COX-2 employing screening assay kit. The % inhibition values calculated in triplicate and average inhibitory value of each compound is presented in Table 1. Standard selective COX-2 inhibitor, Celecoxib, was used as reference drug. Results demonstrated that compound 3a exhibited 71.3% inhibition that is comparable with reference drug (76.5% inhibition). Mono Schiff bases (3a-3f) relatively have higher inhibitory activities than bis Schiff bases (4a-4f).

3.4

3.4 Molecular docking studies

The inflammatory response is mainly stimulated by the prostaglandins lipids compounds, which are generated by the action of cyclooxygenase enzymes (Dubois et al., 1998). Since the role of curcumin to bind with cyclooxygenase-2 (COX-2) enzyme in the inhibition of keratinocyte cell line “HaCaT” inflammation has been explored (Cho et al., 2005), its molecular docking studies were also performed in COX-2 protein (Maldonado-Rojas and Olivero-Verbel, 2011). Similarly we also docked our most potent compounds in the active site of human COX-2 enzyme to envisage the binding modes. Different COX-2 enzyme crystal structures have been deposited in protein databank, and we selected a recently deposited crystal structure of Mus musculus COX-2 enzyme (PDB ID = 4PH9). The structure has been solved at 1.81 Å resolution and no atom/residue is missing in the active site of the protein. Manual docking simulations followed by energy minimization of the protein-ligand complex structure revealed that most active compound possessed good binding mode with promising interactions with the side chains of the protein (Figs. 1 and 2). Compound 3a has satiated well in the active site of the protein, the —OH and —OCH₃ bearing head phenyl ring of the modified curcumin placed inside the hydrophobic binding site channel (Kurumbail et al., 1996) containing Leu-353, Ser-354, Tyr-356 and Val-523 of the COX-2 enzyme and sulfonamide bearing tail group is exposed toward the solvent site as shown in Fig. 1. The head phenyl ring of compound 3a occupied the same position, where one of co-crystal ligands in COX-2 enzyme is present (Fig. 1). Similarly it has reasonable van der Waals interactions with the most of the hydrophobic residues present in the active site (Fig. 2).

Plausible binding mode of the compound-3a (yellow color sticks) in the active site of the COX-2 (red and green) enzyme with co-crystal ligand (magenta color stick).

Residues in the active site of COX-2 protein interacting with compound-3a.

3.5

3.5 Antinociceptive activity

Acetic acid induced writhing responses were established to evaluate the antinociceptive activity of curcumin derivatives. Both peripheral and central nociception actions are produced by intraperitoneally administration of acetic acid. Injection of acetic acid attributed to significant release of endogeneous mediators such as prostaglandins, bradykinins, pro-inflammatory cytokines and substance P. Local peritoneal receptor could be attributed to abdominal writhing (pain) which is symbolized by abdominal muscle contraction accompanied by extension of forelimbs and body elongation (Hasnain et al., 2012; Uddin et al., 2014). Among the tested compounds (3a-3f, 4a-4f), compound 3a has more prevention of writhing episodes (Table 1) than any other compound and showed the antinociceptive activity up to 66.8% which is comparable to diclofenac sodium (67.1% inhibition). Thus it could be assumed that synthetic curcumin derivatives interfered with the release of peripherally acting endogeneous substances responsible for pain sensation. Moreover, the mode of action of synthetic curcumin derivatives is similar to NSAID and analgesic such as diclofenac sodium.

3.6

3.6 Antibacterial activity

Newly synthesized curcumin derivatives were screened for their antibacterial activity using disk diffusion method for inhibition zone measurement and MIC of each compound was calculated by 96-well plate method by measuring OD at 600 nm using two fold serial method by following CLSI guidelines (Cockerill et al., 2010). Synthesized compounds were screened against four gram negative bacteria including Salmonella enterica ATCC 14028, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumonia ATCC 13882 and two gram positive bacteria like Staphylococcus aureus ATCC 25923, Methicillin resistant staphylococcus aureus N315. Ciprofloxacin was also screened against respective bacteria as control drug. Curcumin and sulfa drugs used in synthesize of curcumin derivatives were also screened for their antibacterial activity. AI of each synthetic compound was also measured as compared to standard drug ciprofloxacin. Combination studies (FIC index) were performed using micro-dilution check board method and FIC index calculation method is described in experimental section. Zone of inhibition, MIC, % AI and FIC index values are presented in Tables 2 and 3. The data (Table 2) showed that compounds 3a, 3b, 4a and 4b with isoxazole and thiazole moieties have appreciable antibacterial activity against both the gram positive and gram negative bacteria. Compound 3b with thiazole ring has highest zone of inhibition (23.0 mm) against S. aureus with AI value 69.1% when compared with ciprofloxacin and has MIC 15.63 μg/mL. Compounds 3c-3e and 4c-4e with 1,3-diazine moiety have AI value ranged between 52.2 and 53.1% against gram positive S. aureus and MRSA and bit better activity against gram negative E. coli, P. aeruginosa, K. pneumonia and S. enterica. Compounds 3f and 4f with acetamide moiety are more potent against gram positive than gram negative bacteria with MIC 15.63 and 31.25 μg/mL (Table 3) respectively. Sulfa drugs used in present study did not show any activity against both types of bacteria while curcumin showed mild activity with diameter of zone of inhibition ranges between 10 and 14.3 mm for highest concentration (4 mg/mL). While curcumin derivatives showed activity against all bacterial strains which is might be due to the synergic effect of sulfonamide moiety and curcumin scaffold. Sulfonamides inhibited the synthesis of dihydropteroate synthase enzyme while curcumin inhibited the bacterial surface protein sortase A and prevent the cell adhesion to fibronectin (Qadir et al., 2015b,a,d,c; Basniwal et al., 2011; Park et al., 2005 ). So curcumin derivatives could anchor to the bacterial cell wall to disrupt the membrane structures and then penetrate inside the cell to breakdown the structure of cell organelles.

Table 2 Antibacterial data as zone of inhibition for curcumin derivatives at three gradient concentrations.

Compound	Gram (+) bacteria		Gram (−) bacteria
Compound	S. aureus	MRSA	E. coli	P. aeruginosa	K. pneumonia	S. enterica
3a	22.7, 18.7, 13.0	21.3, 17.3, 11.7	22.0, 17.3, 13.0	21.3, 16.3, 11.3	22.0, 18.0, 13.0	21.0, 16.0, 12.0
3b	23.0, 17.0, 12.6	20.6, 15.7, 11.7	22.0, 17.0, 12.6	21.0, 16.0, 12.0	18.0, 15.0, 11.0	17.7, 13.0, 9.7
3c	17.7, 13.7, 9.3	16.7, 12.7, 8.7	21.0, 13.7, 9.3	20.0, 13.0, 8.3	18.0, 14.7, 9.0	22.0, 15.0, 11.0
3d	17.7, 13.7, 9.3	16.7, 12.7, 8.7	21.0, 13.7, 9.3	20.0, 13.0, 8.3	18.0, 14.7, 9.0	22.0, 15.0, 11.0
3e	17.7, 13.7, 8.6	16.7, 11.3, 7.7	18.0, 12.3, 8.6	18.0, 12.0, 8.0	18.6, 14.7, 8.7	20.0, 14.0, 10.0
3f	22.3, 18.0, 12.3	21.3, 17.3, 11.7	22.0, 17.7, 12.3	21.0, 16.3, 12.0	18.6, 14.0, 9.7	16.7, 12.0, 9.0
4a	22.7, 17.0, 12.3	21.0, 16.0, 11.3	22.0, 17.0, 12.3	21.0, 16.0, 12.0	17.7, 13.0, 9.0	16.7, 12.0, 9.3
4b	20.7, 16.0, 11.0	20.0, 15.3, 10.7	20.0, 15.3, 11.0	19.0, 15.0, 10.0	17.7, 13.0, 9.0	16.7, 11.3, 8.7
4c	17.7, 12.7, 8.6	17.0, 11.3, 8.3	21.0, 14.3, 8.6	20.0, 14.0, 8.0	17.7, 13.6, 8.0	22.0, 17.0, 14.0
4d	17.7, 12.7, 8.6	17.0, 11.3, 8.3	21.0, 14.3, 8.6	20.0, 14.0, 8.0	17.7, 13.6, 8.0	22.0, 17.0, 14.0
4e	17.7, 11.7, 8.6	17.7, 11.3, 8.3	17.0, 11.3, 8.6	16.0, 11.0, 8.0	22.0, 16.0, 12.0	22.0, 17.7, 14.0
4f	22.7, 18.0, 12.6	21.0, 17.3, 11.7	19.0, 12.3, 9.6	17.7, 12.0, 9.0	16.0, 12.0, 9.0	17.7, 13.0, 9.7
Sulfafurazole	–, –, –	–, –, –	–, –, –	–, –, –	–, –, –	11, –, –
Sulfathiazole	–, –, –	–, –, –	–, –, –	–, –, –	–, –, –	–, –, –
Sulfamerazine	–, –, –	–, –, –	–, –, –	–, –, –	–, –, –	9, –, –
Sulfadiazine	–, –, –	–, –, –	–, –, –	–, –, –	–, –, –	9, –, –
Sulfadoxine	–, –, –	–, –, –	–, –, –	–, –, –	9, –, –	–, –, –
Sulfacetamide	–, –, –	–, –, –	–, –, –	–, –, –	–, –, –	–, –, –
Curcumin	14.3, 10.0, –	11.0, 9.0, –	14.3, 10.0, –	14.3, 10.0, –	12.0, 8.0, –	10.0, 8.0, –
^aCiprofloxacin	33.3, 30.3, 28.3	32.0, 29.3, 27.6	35.3, 31.0, 29.0	34.0, 31.0, 29.0	32.0, 30.0, 29.7	34, 31.7, 30.3

^a Control drug, zone of inhibition was measured in mm, gradient concentration of 4 mg/mL, 2 mg/mL, and 1 mg/mL was used, S. aureus = Staphylococcus aureus, MRSA = Methicillin resistant staphylococcus aureus, E. coli = Escherichia coli, P. aeruginosa = Pseudomonas aeruginosa, K. pneumonia = Klebsiella pneumonia, S. enterica = Salmonella enterica.

Table 3 Antibacterial data as MIC and AI for curcumin derivatives.

Compound	Gram (+) bacteria				Gram (−) bacteria
	S. aureus		MRSA		E. coli		P. aeruginosa		K. pneumonia		S. enterica
	MIC	AI	MIC	AI	MIC	AI	MIC	AI	MIC	AI	MIC	AI
3a	15.63	68.2	31.25	66.6	15.63	62.3	15.63	62.6	15.63	68.8	31.25	61.8
3b	15.63	69.1	31.25	64.4	15.63	62.3	31.25	61.8	250	56.3	500	52.1
3c	250	53.2	500	52.2	31.25	59.5	62.5	58.8	250	56.3	15.63	64.7
3d	250	53.2	500	52.2	31.25	59.5	62.5	58.8	250	56.3	15.63	64.7
3e	250	53.2	500	52.2	250	51.0	250	52.9	250	58.1	62.5	58.8
3f	15.63	67.0	31.25	66.6	15.63	62.3	31.25	61.8	250	58.1	1000	49.1
4a	15.63	68.2	31.25	65.6	31.25	62.3	31.25	61.8	500	55.3	1000	49.1
4b	62.5	62.2	62.5	62.5	62.5	56.7	125	55.9	500	55.3	1000	49.1
4c	250	53.2	500	53.1	62.5	59.5	125	58.8	500	55.3	15.63	64.7
4d	250	53.2	500	53.1	62.5	59.5	125	58.8	500	55.3	15.63	64.7
4e	250	53.2	500	55.3	500	48.2	1000	47.1	31.25	68.8	15.63	64.7
4f	15.63	68.2	31.25	65.6	125	53.8	250	52.1	1000	50.0	250	52.1
Sulfafurazole	–	–	–	–	>1000	–	>1000	–	–	–	–	32.4
Sulfathiazole	–	–	–	–	>1000	–	>1000	–	–	–	–	–
Sulfamerazine	–	–	–	–	>1000	–	>1000	–	–	–	–	26.5
Sulfadiazine	–	–	–	–	>1000	–	>1000	–	–	–	–	26.5
Sulfadoxine	–	–	–	–	>1000	–	>1000	–	–	28.1	–	–
Sulfacetamide	–	–	–	–	>1000	–	>1000	–	–	–	–	–
Curcumin	>500	42.9	>1000	34.4	>500	40.5	>1000	42.1	>1000	37.5	>1000	29.4
^aCiprofloxacin	1.95	100	1.95	100	0.98	100	0.98	100	1.95	100	0.98	100

^a Control drug, AI = activity index in percentage, MIC = minimum inhibitory concentrations in μg/mL.

3.7

3.7 Antifungal activity

Antifungal activity revealed that almost all the curcumin derivatives showed poor activity against the Aspergillus species (A. niger, A. flavus), A. alternata and P. digitatum. However all the compounds have appreciable activity against the F. solani as compared to ketoconazole. Table 4 lists the diameter of zone of inhibition of all tested compounds at three gradient concentrations. Compound 3c is 2–4-fold more potent than nystatin and ketoconazole respectively against F. oxysporum with MIC value 15.63 μg/mL. Compounds 3a-3d are 2–4-fold more active than antifungal drugs nystatin and ketoconazole against F. oxysporum with MIC value ranged between 15.63 and 31.25 μg/mL (Table 5).

Table 4 Antifungal data as zone of inhibition for curcumin derivatives at three gradient concentrations.

Compound	Fungal strains
Compound	A. niger	A. flavus	F. solani	F. oxysporum	A. alternata	P. digitatum
3a	10.0, 8.0, 7.0	10.0, 8.0, 6.0^*	11.0, 8.0, 6.0^*	16.0, 13.0, 11.0	15.0, 12.0, 11.0	12, 10, 9.0
3b	10.0, 8.0, 6.0^*	10.0, 8.0, 6.0^*	10.0, 6.0^, 6.0^	16.0, 13.0, 11.0	14.0, 11.0, 9.0	13.0, 11.0, 9.0
3c	12, 10, 9.0	12.0, 9.0, 7.0	13.0, 11.0, 9.0	18.0, 16.0, 13.0	16.0, 13.0, 11.0	16.0, 13.0, 11.0
3d	12, 10, 9.0	11.0, 8.0, 7.0	10.0, 6.0^, 6.0^	16.0, 13.0, 11.0	14.0, 11.0, 9.0	14.0, 11.0, 9.0
3e	11.0, 8.0, 7.0	11.0, 8.0, 7.0	11.0, 9.0, 8.0	12, 10, 9.0	12, 10, 9.0	14.0, 11.0, 9.0
3f	10.0, 8.0, 6.0^*	10.0, 8.0, 6.0^*	10.0, 6.0^, 6.0^	10.0, 8.0, 7.0	11.0, 9.0, 8.0	11.0, 8.0, 7.0
4a	12.0, 10.0, 9.0	10.0, 8.0, 6.0^*	10.0, 6.0^, 6.0^	10.0, 8.0, 7.0	11.0, 9.0, 7.0	13.0, 11.0, 10.0
4b	10.0, 8.0, 6.0^*	10.0, 8.0, 6.0^*	10.0, 6.0^, 6.0^	12, 10, 9.0	12, 10, 9.0	13.0, 11.0, 10.0
4c	12, 10, 9.0	12.0, 9.0, 7.0	10.0, 8.0, 7.0	12, 10, 9.0	15.0, 12.0, 11.0	14.0, 11.0, 9.0
4d	12, 10, 9.0	11.0, 8.0, 7.0	10.0, 6.0^, 6.0^	12, 10, 9.0	15.0, 12.0, 11.0	14.0, 11.0, 9.0
4e	8.0,7.0, 6.0^*	10.0, 8.0, 6.0^*	10.0, 6.0^, 6.0^	11.0, 9.0, 8.0	10.0, 8.0, 6.0^*	14.0, 11.0, 9.0
4f	11.0, 9.0, 7.0	10.0, 8.0, 6.0^*	10.0, 6.0^, 6.0^	11.0, 9.0, 8.0	10.0, 8.0, 6.0^*	13.0, 11.0, 10.0
Curcumin	11.0, 9.0, 7.0	9.0, 8.0, 6.0^*	10.0, 6.0^, 6.0^	10.0, 8.0, 7.0	11.0, 8.0, 7.0	10.0, 8.0, 7.0
^aNystatin	25.0, 22.0, 20.0	25.0, 22.0, 20.0	15.0, 13.0, 11.0	11.0, 9.0, 8.0	23.0, 21.0, 18.0	24.0, 21.0, 18.0
^bKetoconazole	12.0, 10.0, 9.0	19.0, 16.0, 12.0	10.0, 8.0, 7.0	10.0, 8.0, 7.0	23.0, 21.0, 18.0	25.0, 22.0, 20.0

^* No inhibition zone, ^a,bcontrol drug, zone of inhibition was measured in mm, gradient concentration of 4 mg/mL, 2 mg/mL, and 1 mg/mL was used, A. niger = Aspergillus niger, A. flavus = Aspergillus flavus, F. solani = Fusarium solani, F. oxysporum = Fusarium oxysporum, A. alternata = Alternaria alternata, P. digitatum = Penicillium digitatum.

Table 5 Antifungal data as MIC and AI for curcumin derivatives.

Compound	Fungal strains
	A. niger		A. flavus		F. solani		F. oxysporum		A. alternata		P. digitatum
	MIC	AI	MIC	AI	MIC	AI	MIC	AI	MIC	AI	MIC	AI
3a	>500	40	>500	40	125	73.3	31.25	145.5	125	65.2	500	50.0
3b	>500	40	>500	40	125	66.7	31.25	145.5	125	60.9	500	54.2
3c	250	48	250	48	62.5	86.7	15.63	163.6	62.5	69.6	62.5	66.7
3d	250	48	>500	44	125	66.7	31.25	145.5	125	60.9	125	58.3
3e	>500	44	>500	44	62.5	73.3	125	109.1	500	52.2	125	58.3
3f	>500	40	>500	40	125	66.7	125	90.9	>500	47.8	>500	45.8
4a	250	48	>500	40	125	66.7	125	90.9	>500	47.8	500	54.2
4b	>500	40	>500	40	125	66.7	125	109.1	500	52.2	500	54.2
4c	250	48	250	48	125	66.7	125	109.1	125	65.2	500	58.3
4d	250	48	>500	44	125	66.7	125	109.1	125	65.2	500	58.3
4e	>1000	32	>500	40	125	66.7	125	100	>500	43.5	500	58.3
4f	>500	44	>500	40	125	66.7	125	100	>500	43.5	500	54.2
Curcumin	>500	44	>1000	36	125	66.7	125	90.9	>500	47.8	>500	41.7
^aNystatin	31.25	100	15.63	100	31.25	100	62.5	100	31.25	100	31.25	100
^bKetoconazole	125	100	62.5	100	125	100	125	100	31.25	100	31.25	100

^a,b Control drug, AI = activity index in percentage, MIC = minimum inhibitory concentrations in μg/mL.

3.8

3.8 Synergic effect

Synergic effect, is depicted in Table 6 and combination of strong acting sulfonamide 3a with ciprofloxacin showed a broad antibacterial spectrum with less dosage. Moreover, FIC index was less than 1 which described that combination system had good synergic effect. Notably, combination of ciprofloxacin (0.12 μg/mL) with compound 3a (7.8 μg/mL) inhibits growth of MRSA, which was 8-fold more potent than alone ciprofloxacin itself. In addition, the combination of antifungal drug nystatin with more potent compound 3c was used against all fungal strains for synergic affect evaluation as described in Table 6. In combination system, the compound 3c gave good activity against all fungal strains with MIC value ranged between 7.81 and 62.5 μg/mL. Moreover, FIC index was less than 1 which described that combination system had good synergic effect. In particular, combination system displayed high activity with less dosage against all tested fungal strains. This effect might be attributed to different mechanisms of action for these compounds toward tested fungal strains.

Table 6 Combination effect of compound 3a with antibacterial drug ciprofloxacin and compound 3c with antifungal drug nystatin.

Bacteria	Compounds	MIC	FIC index	Effect	Fungi	Compounds	MIC	FIC index	Effect
S. aureus	Ciprofloxacin	0.24				Nystatin	15.63
S. aureus	3a	3.91	0.37	Synergistic	A. niger	3c	62.5	0.75	Synergistic
MRSA	Ciprofloxacin	0.49				Nystatin	7.81
MRSA	3a	7.81	0.50	Synergistic	A. flavus	3c	62.5	0.75	Synergistic
E. coli	Ciprofloxacin	0.12				Nystatin	15.63
E. coli	3a	3.91	0.37	Synergistic	F. solani	3c	31.25	1.0	Synergistic
P. aeruginosa	Ciprofloxacin	0.24				Nystatin	15.63
P. aeruginosa	3a	3.91	0.50	Synergistic	F. oxysporum	3c	7.81	0.75	Synergistic
K. pneumonia	Ciprofloxacin	0.24				Nystatin	7.81
K. pneumonia	3a	7.81	0.62	Synergistic	A. alternata	3c	15.63	0.50	Synergistic
S. enterica	Ciprofloxacin	0.24				Nystatin	7.81
S. enterica	3a	7.81	0.37	Synergistic	P. digitatum			0.50	Synergistic

MIC = minimum inhibitory concentrations in μg/mL.

4 Conclusion

In this study, twelve Schiff bases having curcumin scaffold with sulfonamide moiety were synthesized successfully and their structures were confirmed by IR, ¹H NMR and ¹³C NMR. All the compounds were assayed for anti-inflammatory, antinociceptive activities in experimental animal models as well as against the panel of 12 microorganisms belonging to gram positive, gram negative and fungi types. Among the tested compounds, compound 3a with isoxazole moiety exhibited highest anti-inflammatory and antinociceptive activities compared to standard drugs like indomethacin and diclofenac sodium. Similarly in vitro assays showed high percentage inhibition of the compound 3a against COX-2 enzyme. Docking experiments predicted the plausible binding mode in the active site of enzyme with reasonable good interactions. Similarly in this series compound 3c gave best antifungal (F. oxysporum) activity compared to nystatin (MIC = 15.63 μg/mL). Moreover, combination of more potent compound 3a with antibacterial drug ciprofloxacin and 3c with antifungal drug nystatin showed notably enhanced antimicrobial efficiency than using the individual drugs themselves. Importantly, combination of ciprofloxacin (0.12 μg/mL) with compound 3a (7.8 μg/mL) inhibits growth of MRSA, which was 8-fold more potent than ciprofloxacin itself.

Compliance with ethical standards

Ethical approval: This article contains studies with animals performed by the authors and ethical approval with document is provided in experimental section.

Acknowledgment

We are thankful to Higher Education Commission (HEC), Pakistan, for providing financial support of this project.

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Appendix A

Supplementary material

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2016.11.017.

Appendix A

Supplementary material

Supplementary data 1

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Introduction

Experimental

Chemistry
General procedure of synthesis
Pharmacological activities

Results and discussion

Chemistry
In vivo anti-inflammatory activity
Cyclooxygenase-2 inhibitory activity
Molecular docking studies
Antinociceptive activity
Antibacterial activity
Antifungal activity
Synergic effect

Conclusion

Compliance with ethical standards

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Synthesis, characterization, biological activities and molecular modeling of Schiff bases of benzene sulfonamides bearing curcumin scaffold

Abstract

Keywords

Schiff bases

Anti-inflammatory

Antinociceptive

Antibacterial

Antifungal

1 Introduction

2 Experimental

2.1 Chemistry

2.2 General procedure of synthesis

2.2.1 N-(3,4-dimethylisoxazol-5-yl)-4-({(1E,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)benzenesulfonamide (3a)

2.2.2 4-({(1E,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide (3b)

2.2.3 4-({(1E,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)-N-(4-methylpyrimidin-2-yl)benzenesulfonamide (3c)

2.2.4 4-({(1Z,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)-N-pyrimidin-2-ylbenzenesulfonamide (3d)

2.2.5 N-(5,6-dimethoxypyrimidin-4-yl)-4-({(1E,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)benzenesulfonamide (3e)

2.2.6 N-{[4-({(1E,2Z,4E)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1-[(E)-2-(4-hydroxy-3-methoxyphenyl)vinyl]penta-2,4-dien-1-ylidene}amino)phenyl]sulfonyl}acetamide (3f)

2.2.7 4,4′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]di(nitrilo)]bis[N-(3,4-dimethylisoxazol-5-yl)benzenesulfonamide] (4a)

2.2.8 4,4′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]di(nitrilo)]bis(N-1,3-thiazol-2-ylbenzenesulfonamide) (4b)

2.2.9 4,4′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]di(nitrilo)]bis[N-(4-methylpyrimidin-2-yl)benzenesulfonamide] (4c)

2.2.10 4,4′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]di(nitrilo)]bis(N-pyrimidin-2-ylbenzenesulfonamide) (4d)

2.2.11 4,4′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]di(nitrilo)]bis[N-(5,6-dimethoxypyrimidin-4-yl)benzenesulfonamide] (4e)

2.2.12 N,N′-[[(1E,3Z,5Z,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-diylidene]bis(nitrilo-4,1-phenylenesulfonyl)]diacetamide (4f)

2.3 Pharmacological activities

2.3.1 Experimental animals and acute toxicity study

2.3.2 Anti-inflammatory activity assay: carrageenan induced hind paw edema

2.3.3 Cyclooxygenase-2 inhibitory activity

2.3.4 Antinociceptive activity assay: acetic acid induced writhing

2.3.5 Bacterial and fungal strains

2.3.6 Antibacterial assay

2.3.7 Antifungal assay

2.3.8 Percentage activity and fractional inhibitory concentration index

2.3.9 Statistical analysis

2.3.10 Molecular modeling studies

3 Results and discussion

3.1 Chemistry

3.2 In vivo anti-inflammatory activity

3.3 Cyclooxygenase-2 inhibitory activity

3.4 Molecular docking studies

3.5 Antinociceptive activity

3.6 Antibacterial activity

3.7 Antifungal activity

3.8 Synergic effect

4 Conclusion

Compliance with ethical standards

Acknowledgment

References

Appendix A

Supplementary material

Appendix A

Supplementary material

Supplementary data 1

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