Journal Information

Journal ID (publisher-id): chemical

Title: Journal of the Korean Chemical Society

Translated Title (ko): 대한화학회지

ISSN (print): 1017-2548

ISSN (electronic): 2234-8530

Publisher: Korean Chemical Society대한화학회

Article Information

Copyright statement: Copyright © 2018, Korean Chemical Society

Copyright: 2018

Date received: 30 May 2018

Date accepted: 09 July 2018

Publication date (print): 20 October 2018

Volume: 62

Issue: 5

Pages: 377-385

Publisher ID: jkcs-62-377

DOI: 10.5012/jkcs.2018.62.5.377

Design, Synthesis and Biological Evaluation of Some Novel Chalcones-sulphonamide Hybrids

Mahammadali Khanusiya[*]

Zakirhusen Gadhawala

Department of Chemistry, The HNSB Ltd Science College, Himatnagar, Gujarat-India.

Author notes:

Correspondence to: [*] E-mail: khanusiya.mali@gmail.com

Abstract

A new class of Chalcone-Sulphonamide hybrids has been designed by condensing appropriate sulphonamide scaffold with substituted chalcones tethered by chloroacetyl chloride as a multi-target drug for therapeutic treatment. Chalcones were prepared by Claisen-Schmidt condensation of a substituted aldehyde with para aminoacetophenone. These Chalcone-Sulphonamide hybrids were screened by means of their antibacterial activity by NCCLS method. Among all these compounds, 5e and 5c displayed more potent growth inhibitory activity against Staphylococcus epidermidis and Pseudomonas aeruginosa bacteria respectively. Further, these hybrids were evaluated for their antifungal activity, among all hybrid 5a exhibited potent antifungal activity. The synthesized compounds were characterized by FT-IR, 1HNMR, 13CNMR and HR-LCMS and spectral study supports the structures of synthesized Chalcone-Sulphonamide hybrids.

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INTRODUCTION▼

Chalcone, an exceptional chemical template of two aromatic or heteroaryl rings joined by a three-carbon α, β-unsaturated carbonyl system, demonstrating a class of flavonoids. Flavonoids occur naturally in fruits and vegetables. The plant containing chalcone derivatives are traditionally deputed for therapeutic concern. Chalcones were availed for their multifarious biological activities and there is a number of reviews that had dealt with the pharmacological and chemical basis of the biological activities exhibited by chalcones. Literature reveals that natural and synthetic chalcone is highly favorable to elicit numerous therapeutic activities.1−10

The literature on chalcone elucidates the employment of three pointed strategies such as structural modification of both aryl rings, replacement of aryl rings with heteroaryl scaffold and molecular hybridization via conjugation with another potent pharmacophore for the betterment of biological properties. Diverse substitutions on both aryl rings of chalcone, depending upon their position, induce to enhance their biological activities. Replacing aromatic by heteroaryl in chalcone also influence pharmacological activity. Chemically chalcone hybrids are designed by linking chalcone derivative to another biologically potent scaffold such as sulphonamides, benzothiazoles; triazole, benzodiazepines, isoxazolines; imidazolones, indols, quinolines, coumarins etc have displayed promising biological activities.11

Sulphonamides are referred to compounds that have sulphonamide moiety (-SO2NH2) in its structure and were found to possess many types of biologically interesting activities including antitumor activity. Sulpha drugs are known to subscribe good antibacterial and antifungal activities. Sulphadiazine, sulfamerazine, and sulphadimidine are dominant sulpha drugs used in some acute bacterial infections, cerebrospinal meningitis and allergic infections.12 They consist of additive pharmaceutical drug involving several biological activities including antitumor,13 antibacterial,14 antifungal,15 anti-carbonic anhydrase,16 diuretic,17 hypoglycemic,18 antithyroid19 and anti HIV.20 Anticancer activity of sulphonamide chalcone hybrid (Fig. 1) has been reported in many types of cancers including pancreatic, hepatic and colon. Structural activity relationship analysis showed that chalcone containing sulphonamide group influences the biological activity.21

Figure1.

Chalcone-Sulphonamide hybrid.

jkcs-62-377-f001.tif

The biological activities of both pharmacophores motivate us to synthesize novel sulphonamide-chalcone hybrids possessing such important microbial properties. Various aldehydes were chosen to synthesize substituted chalcones and these chalcones were condensed with biologically potent sulpha drugs resulting into chalcone-sulphonamide hybrids.

EXPERIMENTAL▼

General Information

The starting materials and solvents were purchased from Sigma-Aldrich and SD Fine and used without further purification. Melting points were determined by the conventional method and then by electrocapillary apparatus and were uncorrected. All the synthesized compounds were inspected by thin layer chromatography (TLC) with precoated Aluminium sheets on silica gel (E-Merck) and the spots were visualized by UV lamp. The IR spectra of the compounds were recorded on Shimadzu FT-IR spectrometer. 1H NMR and 13C NMR spectra were recorded using a Bruker in DMSO at 500 MHz. IR, 1H NMR, and 13C NMR spectra were performed at Centre of Excellence Saurashtra University and High-Resolution Liquid Chromatography-Mass Spectra were performed at the SAIF Indian Institution of Technology. Aminochalcone compounds 1a-1c was synthesized as shown in Scheme 1. Commercially available sulphonamides 2a-2e were treated with chloroacetyl chloride to provide chlorosulfonyl acetamide depicted in Scheme 2. The general route for the synthesis of the target sulphonamide-chalcone hybrids was depicted in Scheme 3. The structures of targeted compounds were characterized using spectral methods, and all spectral data corroborated the assumed structures.

Scheme1.

Synthesis of aminochalcone.

jkcs-62-377-f002.tif
Scheme2.

Synthesis of chlorosulfonyl acetamide.

jkcs-62-377-f003.tif
Scheme3.

Synthesis of chalcone-sulphonamide hybrids.

jkcs-62-377-f004.tif

Synthesis

General procedure of synthesis of aminochalcone (1a-1c): The synthesis of chalcone derivatives [I] was conducted according to the procedure reported in the reference by Claisen-Schmidt condensation reaction.10−12 Acetophenone derivative (2.5 mmol) and substituted benzaldehydes (2.5 mmol) were dissolved in 30 ml methanol. To the solution, 10 ml NaOH (20%) solution was added dropwise and the reaction mixture was stirred for 1-2 hour at room temperature by a magnetic stirrer and kept for overnight. Subsequently, it was poured into ice water and neutralized. The solid precipitates were filtered off and recrystallized from methanol or ethyl acetate.

General procedure of synthesis of Intermediate (2a-2f): To a stirred solution of sulphonamide (2 mmol) in dimethylformamide at 0-5 ᵒC, chloro acetyl chloride (6 ml) was added dropwise and stirred at room temperature for 3-4 hours by a magnetic stirrer. The reaction mixture was neutralized with triethylamine then the precipitate was filtered, washed with cold water recrystallized from methanol.

General procedure of synthesis of sulphonamide chalcone (3a-5f): To a solution of aminochalcone 1a-1c (2 mmol) in Dimethylformamide, a solution of an intermediate 2a-2f (2 mmol) prepared in DMF was added. The stirred reaction mixture was then refluxed for 8-9 h. Upon completion, the reaction mixture was poured onto crushed ice. The precipitate was then washed with cold water and the crude product was recrystallized in acetone.

Characterization

The synthesis of chalcone derivatives (1a-1c) was carried out by simple base catalyzed Claisen-Schmidt condensation22,23 using 10% NaOH solution prepared in methanol between commercially available p-aminoacetophenone and substituted aromatic aldehydes. All the synthesized chalcone derivatives were evaluated by their spectral data (IR, 1HNMR, 13CNMR). IR spectra of chalcone derivatives showed the characteristic bands for carbonyl at 1650, CH=CH at 1590-1610 and for -OH at 3570-3395 cm-1. The 1HNMR spectra indicated broad singlet at 3.47-3.50 ppm appeared for -NH2 group, singlet of methoxy proton appeared about at 3.87 ppm and multiplets at 7.20-7.90 ppm for phenyl protons. For CO-CH=CH one doublet appears at 7.51-7.68 ppm and another doublet at 6.02-6.57 ppm respectively. The chlorosulphonamide derivatives 2a-2f were synthesized by treatment of chloroacetyl chloride with various sulpha drugs containing amino group in their structure in presence of triethylamine (Et3N).

3a: (E)-2-((4-(3-(4-Hydroxy-3-methylphenyl)acryloyl) phenyl)amino)-N-(4-(N-(5-methylisoxazol-3-yl) sulfamoyl) phenyl)acetamide

Yellow solid, Rf 0.52. FT-IR (ν, cm-1): 3741 (-OH), 3591, 3360,3331 (3-NH-), 3064-3100 (Ar C-H), 2974 (Aliphatic -CH), 1739 (-CONH-), 1678 (-CO), 1608 (-C=N ), 1591 (-HC=CH-), 1454 (C-O), 1398, 1157 (-SO2-) 952 (S-N), 833 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.20 (s, 1H, CONH-), 8.10 (s, 1H, -OH), 7.65 (d, 1Hβ -CH=CH-), 7.56 (s, 1H, -SO2NH-), 6.45 (d,1Hα -CH=CH-), 6.02-8.02 (m, 10H, Ar-H), 6.51 (t, 1H, -NH-), 4.63 (s, 1H, CH=Cisoxazole), 3.36 (d, 2H, -CH2-), 2.67 (s, 3H, -CH3), 2.27 (s, 3H, -OCH3). 13CNMR (500 MHz, DMSO-d6, ppm): 195.17, 167.08, 159.56, 154.09, 151.03, 141.66, 144.34, 138.80, 130.80, 127.02, 126.00, 125.54, 122.95, 119.07, 119.07, 112.40, 40.80, 39.67, 39.46, 39.07, 38.83, 27.03, 25.92, 12.11. HR-MS (ESI) Calcd for C28H26N4O6S [M+H+] 546.16, found 546.157.

3b: (E)-2-((4-(3-(4-Hydroxy-3-methylphenyl)acryloyl) phenyl)amino)-N-(4-sulfamoyl phenyl) acetamide

Brown solid, Rf 0.56. FT-IR (ν, cm-1): 3741 (-OH), 3591, 3566, 3365, 3280 (2-NH, -NH2), 3005 (Ar C-H), 2976 (Aliphatic -CH), 1734 (-CONH-), 1683 (-CO), 1639 (-C=N), 1595 (-HC=CH-), 1452 (C-O), 1311, 1149 (-SO2-), 962 (S-N), 829 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.20 (s,1H, CONH-), 8.10 (s, 1H, -OH), 7.65 (d,1Hβ -CH=CH-), 7.56 (s, 2H, -SO2NH2), 6.45 (d, 1Hα -CH=CH-), 6.02-8.02 (m, 10H, Ar-H), 6.51 (t, 1H, -NH-), 3.13 (s, 2H, -CH2-), 2.67 (s, 3H, -OCH3), 2.40 (s, 3H, -CH3).13CNMR (500 MHz, DMSO-d6, ppm): 195.17, 169.08, 159.56, 154.08, 141.66, 138.80, 130.54, 129.62, 127.02, 126.70, 125.54, 122.95, 117.17, 46.32, 40.09, 39.83, 39.09, 38.83, 27.03, 25.92. HR-MS (ESI) Calcd for C24H23N3O5S [M+H+] 465.135, found 465.136.

3c: (E)-N-(4-(N-(4,6-Dimethylpyrimidin-2-yl)sulfamoyl) phenyl)-2-((4-(3-(4-hydroxy-3-methylphenyl)acryloyl) phenyl)amino)acetamide

Brown solid, Rf 0.52. FT-IR (ν, cm-1): 3741 (-OH), 3591, 3360, 3253 (3-NH-), 3000-3100 (Ar C-H), 2974, 2883 (Aliphatic -CH), 1739 (-CONH-), 1678 (-CO), 1647 (-C=N), 1593 (-HC=CH-), 1456 (C-O), 1396, 1157 (-SO2-) 952 (S-N), 835 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.31 (s, 1H, CONH-), 8.30 (s, 1H, -OH), 7.65 (d, 1Hβ -CH=CH-), 7.56 (s, 1H, -SO2NH-), 6.55 (d, 1Hα -CH=CH-), 6.09-8.02 (m, 10H, Ar-H), 6.45 (1H, s, -CH=CH(pyrimidine)) 6.41 (t, 1H, -NH-), 3.36 (d, 2H, -CH2-), 2.56 (s, 3H, -CH3), 2.54 (s, 3H, -OCH3), 2.31 (s, 3H, -CH3). 13CNMR (500 MHz, DMSO-d6, ppm): 195.17, 167.08, 159.56, 154.09, 154.09 141.66, 138.80, 130.80, 129.24, 127.02,127.02, 126.00, 125.54, 122.95, 112.40, 119.02, 119.12, 114.40, 114.40, 40.80, 39.67, 39.46, 39.07, 38.83, 27.03, 12.11. HR-MS (ESI) Calcd for C30H29N5O5S [M+H+] 571.18, found 571.211.

3d: (E)-N-(4-(N-Acetylsulfamoyl)phenyl)-2-((4-(3-(4-hydroxy-3-methylphenyl)acryloyl) phenyl)amino)acetamide

Red solid, Rf 0.70. FT-IR (ν, cm-1): 3741 (-OH), 3568, 3360, 3246 (3-NH-), 3000 (Ar C-H), 2976, 2889 (Aliphatic -CH), 1734 (-CONH-), 1678 (-CO), 1647 (-C=N), 1597 (-HC=CH-), 1456 (C-O), 1363, 1155 (-SO2-), 958 (S-N), 839 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.20 (s, 1H, CONH-), 8.10 (s, 1H, -OH), 7.84 (d, 1Hβ -CH=CH-), 7.76 (s, 1H, -SO2NH-), 6.45 (d, 1Hα -CH=CH-), 6.02-8.02 (m, 10H, Ar-H), 6.51 (t, 1H, -NH-), 3.35 ( d, 2H, -CH2-), 2.67 (s, 3H, -CH3), 2.40 (s, 3H, -OCH3).13CNMR (500 MHz, DMSO-d6, ppm): 190.17, 170.20, 167.08, 159.56, 154.09, 141.66, 138.80, 130.80, 129.06, 129.06, 127.02, 122.95, 119.08, 119.12, 114.40, 44.80, 39.67, 39.46, 39.07, 38.83, 21.03, 16.11. HR-MS (ESI) Calcd for C26H25N3O6S [M+H+] 507.14, found 507.23.

3e: (E)-2-((4-(3-(4-Hydroxy-3-methylphenyl) acryloyl) phenyl)amino)-N-(4-(N-(pyrimidin-2-yl) sulfamoyl) phenyl)acetamide

Red Brick solid, Rf 0.41 FT-IR (ν, cm-1): 3743 (-OH), 3589, 3360, 3153 (3-NH-), 3000-3100 (Ar C-H), 2972, 2918 (Aliphatic -CH), 1738 (-CONH-), 1674 (-CO), 1649 (-C=N), 1590 (-HC=CH-), 1463(C-O), 1399, 1155 (-SO2-), 954 (S-N), 835 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.50 (s, 1H, CONH-), 8.20 (s, 1H, -OH), 7.77 (d, 1Hβ -CH=CH-), 7.65 (s, 1H, -SO2NH-), 6.54 (d, 1Hα -CH=CH-), 6.09-8.05 (m, 10H, Ar-H), 6.65 (1H, s, -CH=CH(pyrimidine)), 6.41 (t, 1H, -NH-), 3.35 (d, 2H, -CH2-), 2.38 (s, 3H, -OCH3). 13CNMR (500 MHz, DMSO-d6, ppm): 194.87, 167.08, 159.56, 154.09, 153.58, 138.80, 130.80, 129.24, 127.02, 124.78, 122.95, 112.40, 119.02, 119.12, 114.40, 114.40, 40.80, 39.67, 39.46, 39.25, 39.07, 38.83, 27.03, 25.11. HR-MS (ESI) Calcd for C28H25N5O5S [M+H+] 543.157, found 543.159.

3f: (E)-N-(4-(N-(6-Chloropyridazin-3-yl)sulfamoyl) phenyl)-2-((4-(3-(4-hydroxy-3-methoxyphenyl) acryloyl) phenyl)amino) acetamide

Black solid, Rf 0.61 FT-IR (ν, cm-1): 3750 (-OH), 3585, 3356, 3143 (3-NH-), 3000-3100 (Ar C-H), 2972, 2918 (Aliphatic -CH), 1738 (-CONH-), 1674 (-CO), 1649 (-C=N ), 1590 (-HC=CH-), 1463 (C-O), 1399, 1155 (-SO2-), 954 (S-N), 835(C-S), 595(C-Cl). 1H NMR (500 MHz, DMSO-d6, ppm): 8.50 (s, 1H, CONH-), 8.20 (s, 1H, -OH), 7.77 (d, 1Hβ -CH=CH-), 7.65 (s, 1H, -SO2NH-), 6.54 (d, 1Hα -CH=CH-), 6.09-8.05 (m, 10H, Ar-H), 6.65 (1H, s, -CH=CH(pyrimidine)), 6.41 (t, 1H, -NH-), 3.35 (d, 2H, -CH2-), 2.38 (s, 3H, -OCH3). 13CNMR (500 MHz, DMSO-d6, ppm): 194.87, 167.08, 159.56, 154.09, 153.58, 146.52, 138.80, 130.80, 129.24, 127.02, 124.78, 122.95, 112.40, 119.02, 119.12, 114.40, 114.40, 40.80, 39.67, 39.46, 39.25, 39.07, 38.83, 27.03, 25.11. HR-MS (ESI) Calcd for C28H24ClN5O6S [M+H+] 593.118, found 593.113.

4a: (E)-2-((4-(3-(4-Hydroxy-3,5-dimethylphenyl)acryloyl)phenyl)amino)-N-(4-(N-(5-methylisoxazol-3-yl)sulfamoyl) phenyl)acetamide

Red solid, Rf 0.51. FT-IR (ν, cm-1): 3741 (-OH), 3566, 3360, 3331 (3-NH-), 3064-3100 (Ar C-H), 2974, 2883 (Aliphatic -CH), 1772 (-CONH-), 1678 (-CO), 1653 (-C=N), 1591 (-HC=CH-), 1456 (C-O), 1398, 1159 (-SO2-) 952 (S-N), 831 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.20 (s, 1H, CONH-), 8.10 (s, 1H, -OH), 7.65 (d, 1Hβ -CH=CH-), 7.56 (s, 1H, -SO2NH-), 6.45 (d, 1Hα -CH=CH-), 6.02-8.02 (m, 10H, Ar-H), 6.51 (t, 1H, -NH-), 4.63 (s, 1H, CH=C isoxazole), 3.36 (d, 2H, -CH2-), 2.67 (s, 3H, -CH3), 2.50 (s, 3H, -OCH3), 2.27 (s, 3H, -OCH3). 13CNMR (500 MHz, DMSO-d6, ppm): 195.17, 167.08, 159.56, 154.09, 151.03, 141.66, 144.34, 138.80, 130.80, 127.02, 126.00, 125.54, 122.95, 119.07, 119.07, 112.40, 40.80, 39.67, 39.46, 39.07, 38.83, 27.03, 25.92, 12.11, 12.03. HR-MS (ESI) Calcd for C29H28N4O6S [M+H+] 560.173, found 560.175.

4b: (E)-2-((4-(3-(4-Hydroxy-3,5-dimethylphenyl)acryloyl) phenyl)amino)-N-(4-sulfamoyl phenyl)acetamide

Pale yellow solid, Rf 0.69. FT-IR (ν, cm-1): 3741 (-OH), 3591, 3566, 3365, 3280 (2-NH, -NH2), 3005 (Ar C-H), 2976 (Aliphatic -CH), 1734 (-CONH-), 1683 (-CO), 1639 (-C=N), 1595 (-HC=CH-), 1452 (C-O), 1311, 1149 (-SO2-), 962 (S-N), 829 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.20 (s, 1H, CONH-), 8.10 (s, 1H, -OH), 7.65 (d, 1Hβ -CH=CH-), 7.56 (s, 2H, -SO2NH2), 6.45 (d, 1Hα -CH=CH-), 6.02-8.02 (m, 10H, Ar-H), 6.51 (t, 1H, -NH-), 3.13 (s, 2H, -CH2-), 2.67 (s, 3H, -CH3), 2.50 (s, 3H, -OCH3), 2.40 (s, 3H, -OCH3). 13CNMR (500 MHz, DMSO-d6, ppm): 195.17, 169.08, 159.56, 154.08, 141.66, 138.80, 130.54, 129.62, 127.02, 126.70, 125.54, 122.95, 117.17, 46.32, 40.09, 39.83, 39.09, 38.83, 27.03, 25.92, 12.54. HR-MS (ESI) Calcd for C25H25N3O7S [M+H+] 479.52, found 479.53.

4c: (E)-N-(4-(N-(4,6-Dimethylpyrimidin-2-yl) sulfamoyl)phenyl)-2-((4-(3-(4-hydroxy-3,5-dimethyl phenyl) acryloyl)phenyl)amino)acetamide

Black solid, Rf 0.57. FT-IR (ν, cm-1): 3741 (-OH), 3591, 3560, 3329 (3-NH-), 3000 (Ar C-H), 2974, 2883 (Aliphatic -CH), 1739 (-CONH-), 1678 (-CO), 1645 (-C=N), 1593 (-HC=CH-), 1456 (C-O), 1396, 1157 (-SO2-) 952 (S-N), 835 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.31 (s, 1H, CONH-), 8.30 (s, 1H, -OH), 7.65 (d, 1Hβ -CH=CH-), 7.56 (s, 1H, -SO2NH-), 6.55 (d, 1Hα -CH=CH-), 6.09-8.02 (m, 10H, Ar-H), 6.45 (1H, s, -CH=CH(pyrimidine)) 6.41 (t, 1H, -NH-), 3.36 (d, 2H, -CH2-), 2.56 (s, 3H, -CH3), 2.54 (s, 3H, -OCH3), 2.31 (s, 3H, -OCH3).13CNMR (500 MHz, DMSO-d6, ppm): 195.17, 167.08, 159.56, 154.09, 154.09 141.66, 138.80, 130.80, 129.24, 127.02, 127.02, 126.00, 125.54, 122.95, 112.40, 119.02, 119.12, 114.40, 114.40, 40.80, 39.67, 39.46, 39.07, 38.83, 27.03, 12.78, 12.10 HR-MS (ESI) Calcd for C31H31N5O7S [M+H+] 585.20, found 585.201.

4d: (E)-N-(4-(N-Acetylsulfamoyl)phenyl)-2-((4-(3-(4-hydroxy-3,5-dimethylphenyl)acryloyl)phenyl)amino) acetamide

Brown solid, Rf 0.80. FT-IR (ν, cm-1): 3741 (-OH), 3591, 3360, 3255 (3-NH-), 3000-3100 (Ar C-H), 2974, 2883 (Aliphatic -CH), 1734 (-CONH-), 1678 (-CO), 1653 (-C=N), 1591 (-HC=CH-), 1456(C-O), 1363, 1153 (-SO2-), 952 (S-N), 829 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.20 (s, 1H, CONH-), 8.10 (s, 1H, -OH), 7.84 (d, 1Hβ -CH=CH-), 7.76 (s, 1H, -SO2NH-), 6.45 (d, 1Hα -CH=CH-), 6.02-8.02 (m, 10H, Ar-H), 6.51 (t, 1H, -NH-), 3.35 (d, 2H, -CH2-), 2.67 (s, 3H, -CH3), 2.50 (s, 3H, -OCH3), 2.40 (s, 3H, -OCH3). 13CNMR (500 MHz, DMSO-d6, ppm): 190.17, 170.20, 167.08, 159.56, 154.09, 141.66, 138.80, 130.80, 129.06, 129.06, 127.02, 122.95, 119.08, 119.12, 114.40, 44.80, 39.67, 39.46, 39.07, 38.83, 21.03, 16.11, 12.23. HR-MS (ESI) Calcd for C27H27N3O6S [M+H+] 521.16, found 521.25.

4e: (E)-2-((4-(3-(4-Hydroxy-3,5-dimethylphenyl)acryloyl) phenyl)amino)-N-(4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl) acetamide

Red solid, Rf 0.61 FT-IR (ν, cm-1): 3743 (-OH), 3649, 3564, 3358 (3-NH-), 3000-3100 (Ar C-H), 2974, (Aliphatic -CH), 1738 (-CONH-), 1674 (-CO), 1687 (-C=N), 1587 (-HC=CH-), 1463 (C-O), 1363, 1153 (-SO2-), 950 (S-N), 829 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.50 (s, 1H, CONH-), 8.20 (s, 1H, -OH), 7.77 (d, 1Hβ -CH=CH-), 7.65 (s, 1H, -SO2NH-), 6.54 (d, 1Hα -CH=CH-), 6.09-8.05 (m, 10H, Ar-H), 6.65 (1H, s, -CH=CH(pyrimidine)), 6.41 (t, 1H, -NH-), 3.35 (d, 2H, -CH2-), 2.50 (s, 3H, -CH3), 2.38 (s, 3H, -OCH3). 13CNMR (500 MHz, DMSO-d6, ppm): 194.87, 167.08, 159.56, 154.09, 153.58, 138.80, 130.80, 129.24, 127.02, 124.78, 122.95, 112.40, 119.02, 119.12, 114.40, 114.40, 40.80, 39.67, 39.46, 39.25, 39.07, 38.83, 27.03, 25.81, 16.12. HR-MS (ESI) Calcd for C29H27N5O5S [M+H+] 557.173, found 557.173.

4f: (E)-N-(4-(N-(6-Chloropyridazin-3-yl)sulfamoyl)phenyl)-2-((4-(3-(4-hydroxy-3,5-dimethoxyphenyl)acryloyl) phenyl) amino)acetamide

Brown solid, Rf 0.65 FT-IR (ν, cm-1): 3745 (-OH), 3638, 3560, 3355 (3-NH-), 3000-3100 (Ar C-H), 2974, (Aliphatic -CH), 1738 (-CONH-), 1674 (-CO), 1687 (-C=N), 1587 (-HC=CH-), 1463 (C-O), 1363, 1153 (-SO2-), 950 (S-N), 829 (C-S), 590.22 (C-Cl). 1H NMR (500 MHz, DMSO-d6, ppm): 8.50 (s, 1H, CONH-), 8.20 (s, 1H, -OH), 7.77 (d, 1Hβ -CH=CH-), 7.65 (s, 1H, -SO2NH-), 6.54 (d, 1Hα -CH=CH-), 6.09-8.05 (m, 10H, Ar-H), 6.65 (1H, s, -CH=CH(pyrimidine)), 6.41 (t, 1H, -NH-), 3.35 (d, 2H, -CH2-), 2.50 (s, 3H, -CH3), 2.38 (s, 3H, -OCH3). 13CNMR (500 MHz, DMSO-d6, ppm): 194.87, 167.08, 159.56, 154.09, 153.58, 144.56, 138.80, 130.80, 129.24, 127.02, 124.78, 122.95, 112.40, 119.02, 119.12, 114.40, 114.40, 40.80, 39.67, 39.46, 39.25, 39.07, 38.83, 27.03, 25.81,16.12. HR-MS (ESI) Calcd for C29H26 ClN5O7S [M+H+] 623.140, found 623.124.

5a: (E)-2-((4-(3-(2-Hydroxyphenyl)acryloyl)phenyl) amino)-N-(4-(N-(5-methylisoxazol-3-yl) sulfamoyl)phenyl) acetamide

Red solid, Rf 0.68. FT-IR (ν, cm-1): 3741 (-OH), 3672, 3568, 3360 (3-NH-), 3064-3100 (Ar C-H), 2974, 2883 (Aliphatic -CH), 1734 (-CONH-), 1678 (-CO), 1608 (-C=N), 1593 (-HC=CH-), 1454 (C-O), 1396, 1153 (-SO2-) 954 (S-N), 831 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.20 (s, 1H, CONH-), 8.10 (s, 1H, -OH), 7.65 (d, 1Hβ -CH=CH-), 7.56 (s, 1H, -SO2NH-), 6.45 (d, 1Hα -CH=CH-), 6.02-8.02 (m, 10H, Ar-H), 6.51 (t, 1H, -NH-), 4.63 (s, 1H, CH=C isoxazole), 3.36 (d, 2H, -CH2-), 2.67 (s, 3H, -CH3). 13CNMR (500 MHz, DMSO-d6, ppm): 195.17, 167.08, 159.56, 154.09, 151.03, 141.66, 144.34, 138.80, 130.80, 127.02, 126.00, 125.54, 122.95, 119.07, 119.07, 112.40, 40.80, 39.67, 39.46, 39.07, 38.83, 27.03, 25.92. HR-MS (ESI) Calcd for C27H24N4O6S [M+H+] 532.14, found 532.14.

5b: (E)-2-((4-(3-(2-Hydroxyphenyl)acryloyl)phenyl)amino)-N-(4-sulfamoylphenyl) acetamide

Red solid, Rf 0.56. FT-IR (ν, cm-1): 3741 (-OH), 3591, 3566, 3365, 3280 (2-NH, -NH2), 3005 (Ar C-H), 2976 (Aliphatic -CH), 1734 (-CONH-), 1683 (-CO), 1639 (-C=N), 1595 (-HC=CH-), 1452 (C-O), 1311, 1149 (-SO2-), 962 (S-N), 829 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.20 (s, 1H, CONH-), 8.10 (s, 1H, -OH), 7.65 (d, 1Hβ -CH=CH-), 7.56 (s, 2H, -SO2NH2), 6.45 (d, 1Hα -CH=CH-), 6.02-8.02(m, 10H, Ar-H), 6.51 (t, 1H, -NH-), 3.13 (s, 2H, -CH2-). 13CNMR (500 MHz, DMSO-d6, ppm): 195.17, 169.08, 159.56, 154.08, 141.66, 138.80, 130.54, 129.62, 127.02, 126.70, 125.54, 122.95, 117.17, 46.32, 40.09, 39.83, 39.09, 38.83, 29.03. HR-MS (ESI) Calcd for C23H21N3O5S [M+H+] 451.120, found 451.117.

5c: (E)-N-(4-(N-(4,6-Dimethylpyrimidin-2-yl)sulfamoyl)phenyl)-2-((4-(3-(2-hydroxy phenyl)acryloyl) phenyl) amino)acetamide

Red solid, Rf 0.77. FT-IR (ν, cm-1): 3741 (-OH), 3672, 3591, 3360 (3-NH-), 3000-3100 (Ar C-H), 2974, 2883 (Aliphatic -CH), 1739 (-CONH-), 1678 (-CO), 1645 (-C=N), 1593 (-HC=CH-), 1454 (C-O), 1396, 1155 (-SO2-), 954 (S-N), 835 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.31 (s, 1H, CONH-), 8.30 (s, 1H, -OH), 7.65 (d, 1Hβ -CH=CH-), 7.56 (s, 1H, -SO2NH-), 6.55 (d, 1Hα -CH=CH-), 6.09-8.02 (m, 10H, Ar-H), 6.45 (1H, s, -CH=CH(pyrimidine)), 6.41 (t, 1H, -NH-), 3.36 (d, 2H, -CH2-), 2.56 (s, 3H, -CH3), 2.31 (s, 3H, -CH3). 13CNMR (500 MHz, DMSO-d6, ppm): 195.17, 167.08, 159.56, 154.09, 154.09 141.66, 138.80, 130.80, 129.24, 127.02, 127.02, 126.00, 125.54, 122.95, 112.40, 119.02, 119.12, 114.40, 114.40, 40.80, 39.67, 39.46, 39.07, 38.83, 27.03. HR-MS (ESI) Calcd for C29H27N5O5S [M+H+] 557.62, found 557.62.

5d: (E)-N-(4-(N-Acetylsulfamoyl)phenyl)-2-((4-(3-(2-hydroxyphenyl)acryloyl)phenyl) amino)acetamide

Red solid, Rf 0.70. FT-IR (ν, cm-1): 3741 (-OH), 3672, 3568, 3360 (3-NH-), 3000-3100 (Ar C-H), 2972 (Aliphatic -CH), 1739 (-CONH-), 1678 (-CO), 1647 (-C=N), 1593 (-HC=CH-), 1456 (C-O), 1396, 1155 (-SO2-), 952 (S-N), 835 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.20 (s, 1H, CONH-), 8.10 (s, 1H, -OH), 7.84 (d, 1Hβ -CH=CH-), 7.76 (s, 1H, -SO2NH-), 6.45 (d, 1Hα -CH=CH-), 6.02-8.02 (m, 10H, Ar-H), 6.51 (t, 1H, -NH-), 3.35 (d, 2H, -CH2-), 2.40 (s, 3H, -CH3). 13CNMR (500 MHz, DMSO-d6, ppm): 190.17, 170.20, 167.08, 159.56, 154.09, 141.66, 138.80, 130.80, 129.06, 129.06, 127.02, 122.95, 119.08, 119.12, 114.40, 44.80, 39.67, 39.46, 39.07, 38.83, 29.03. HR-MS (ESI) Calcd for C25H23N3O6S [M+H+] 493.13, found 493.18.

5e: (E)-2-((4-(3-(2-Hydroxyphenyl)acryloyl)phenyl)amino)-N-(4-(N-(pyrimidin-2-yl) sulfamoyl)phenyl)acetamide

Red Brick solid, Rf 0.53 FT-IR (ν, cm-1): 3743 (-OH), 3672, 3589, 3358 (3-NH-), 3000-3100 (Ar C-H), 2972 (Aliphatic -CH), 1739 (-CONH-), 1678 (-CO), 1649 (-C=N), 1593 (-HC=CH-), 1456 (C-O), 1369, 1157 (-SO2-), 952 (S-N), 833 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.50 (s, 1H, CONH-), 8.20 (s, 1H, -OH), 7.77 (d, 1Hβ -CH=CH-), 7.65 (s, 1H, -SO2NH-), 6.54 (d, 1Hα -CH=CH-), 6.09-8.05 (m, 10H, Ar-H), 6.65 (1H, s, -CH=CH(pyrimidine)), 6.41 (t, 1H, -NH-), 3.41 (d, 2H, -CH2-). 13CNMR (500 MHz, DMSO-d6, ppm): 194.87, 167.08, 159.56, 154.09, 153.58, 138.80, 130.80, 129.24, 127.02, 124.78, 122.95, 112.40, 119.02, 119.12, 114.40, 114.40, 40.80, 39.67, 39.46, 39.25, 39.07, 38.83, 29.03. HR-MS (ESI) Calcd for C27H23N5O5S [M+H+] 529.14, found 529.21.

5f: (E)-N-(4-(N-(6-Chloropyridazin-3-yl)sulfamoyl)phenyl)-2-((4-(3-(2-hydroxyphenyl) acryloyl)phenyl)amino) acetamide

Red Brick solid, Rf 0.60 FT-IR (ν, cm-1): 3745 (-OH), 3670, 3578, 3358 (3-NH-), 3000-3100 (Ar C-H), 2972 (Aliphatic -CH), 1739 (-CONH-), 1678 (-CO), 1649 (-C=N), 1593 (-HC=CH-), 1456 (C-O), 1369, 1157 (-SO2-), 952 (S-N), 833 (C-S), 597.93 (C-Cl). 1H NMR (500 MHz, DMSO-d6, ppm): 8.50 (s, 1H, CONH-), 8.20 (s, 1H, -OH), 7.77 (d, 1Hβ -CH=CH-), 7.65 (s, 1H, -SO2NH-), 6.54 (d,1Hα -CH=CH-), 6.09-8.05 (m, 10H, Ar-H), 6.65 (1H, s, -CH= CH(pyrimidine)), 6.41 (t, 1H, -NH-), 3.41 (d, 2H, -CH2-). 13CNMR (500 MHz, DMSO-d6, ppm): 194.87, 167.08, 159.56, 154.09, 153.58, 146.36, 138.80, 130.80, 129.24, 127.02, 124.78, 122.95, 112.40, 119.02, 119.12, 114.40, 114.40, 40.80, 39.67, 39.46, 39.25, 39.07, 38.83, 29.03. HR-MS (ESI) Calcd for C27H22ClN5O5S [M+H+] 563.098, found 563.103.

RESULTS AND DISCUSSION▼

Chemistry

Chalcone 1a-1c then condensed with chlorosulphonamide derivatives 2a-2f in dimethylformamide with a few drops of Et3N afforded Chalcone-Sulphonamide hybrids 3a-5f (Scheme 3). The key reaction involved the formation of a C-N bond between the nitrogen of chalcone and carbon of sulphonamide derivatives. Structures of all obtained hybrids 3a-5f were further supported by IR, NMR, and HRMS. IR spectra of 3a-5f displayed -NH- absorption band at 3330-3360 cm-1 and stretching band of amide carbonyl at 1734-1739 cm-1. The disappearance of broad singlet in 1HNMR of 3a-5f implied the absence of free -NH2 group of chalcone moiety and led to the formation of a C-N bond between two pharmacophores. In the 1HNMR spectra, methylene protons present between -NH- and -CO- appeared as a doublet at 3.36 ppm. 13CNMR spectrum of 3a revealed different characteristic signals at 44.54 ppm for methylene, 56.79 for methoxy, 167.97 for amide carbonyl and 190.97 for vinyl carbonyl also supported to the proposed structure. The hybrid 3a showed molecular ion (M+H+) peak at 546.157 corresponding to the molecular formula of C28H26N4O6S.

Antimicrobial activity

Chemically synthesized all chalcone-sulphonamide hybrids 3a-5f were screened for their antibacterial activity against P.aeruginosa (Gram-negative), S.epidermidis (Gram-positive) strains and also for their antifungal activity against Candida albicans. Table 2 lists the IC50 values of the hybrids against respective test microorganisms and also shows Selectivity ratios. Selectivity ratios of compounds were calculated using following formula.

Selectivity ratio = IC 50  value of reference drug IC 50 value of synthesized compound

The selectivity ratios of chalcone-sulphonamide are shown in Table 2. Arbitrarily IC50 value of a synthesized compound against test organism was less than the IC50 values of reference drug and selectivity ratio ≥1 were used to identify promising compounds. Results of gram-positive organism inhibition study indicate followings compounds were found to be lid among others when it was compared IC50 value obtained by Streptomycin (8.625 µM/ml) with standard drug inhibitory value. 4f > 5e > 4d. Similarly, results for gram-negative microorganism, most effective compounds were arranged in the following an order when it was compared IC50 value obtained by Streptomycin (6.230 µM/ml) with standard drug inhibitory value 4c > 3e > 5c. Fluconazole and test compounds were tested against Candida albicans in dose-dependent manner. The table showed that comparative lower IC50 value was found with compounds 5a against Candida albicans.

Table1.

Structures and % yield of chalcone-sulphonamide hybrids

jkcs-62-377-t001.tif
Table2.

Percentage cell inhibition by compounds against S.epidermidis (gram-positive bacteria), P.aeruginosa (gram-negative bacteria) and Candida albicans fungi strain

Entry Staphylococcus epidermidis Pseudomonas aeruginosa Candida albicans
IC50 µM/ml Selectivity Ratio IC50 µM/ml Selectivity Ratio IC50 µM/ml Selectivity Ratio
3a >100.0 <0.100 41.73 0.149 21.30 0.484
3b 20.24 0.426 20.24 0.308 >100 <0.100
3c 32.40 0.266 22.95 0.272 100.0 0.1000
3d 20.71 0.416 14.52 0.432 16.34 0.630
3e 42.22 0.204 5.940 1.050 >100 <0.100
3f >100.0 <0.100 11.50 0.542 16.69 0.617
4a 41.94 0.206 15.94 0.392 >100.0 <0.100
4b 22.89 0.377 89.32 <0.100 13.07 0.788
4c 14.01 0.616 2.523 2.470 >100.0 <0.100
4d 7.580 1.150 >100.0 <0.100 25.73 0.400
4e 16.19 0.533 >100.0 <0.100 >100.0 <0.100
4f 2.568 3.369 40.30 0.155 25.93 0.397
5a 21.88 0.394 75.19 <0.100 9.320 1.110
5b >100 <0.100 18.71 0.333 75.36 0.139
5c 69.72 0.124 6.050 1.040 27.11 0.380
5d 67.08 0.128 >100.0 <0.100 76.88 0.134
5e 7.440 1.160 >100.0 <0.100 >100.0 <0.100
5f 26.62 0.324 11.18 0.558 38.09 0.270

*STD = Streptomycin for bacterial strains and fluconazole for fungal strain

CONCLUSION▼

Chalcone-Sulphonamide hybrids have been synthesized by conjugating sulphadrugs with substituted chalcones with the objectives of the multi-target drug for therapeutic treatment. Antibacterial and antifungal activities of these hybrids revealed that 4d, 4f, and 5e displayed a significant activity against Staphylococcus epidermidis and compounds, 3e, 4c and 5c showed more potent growth inhibitory activity against Pseudomonas aeruginosa bacteria strains. While only 5a is more potent antifungal agent towards Candida albicans fungi. Further studies on the application of this method for the synthesis of highly potent biologically active chalcones are underway. We may conclude that the sulphonamide pharmacophore possessing pyrimidine scaffold is associated with enhanced antibacterial activity and gave more potent compounds. This study may provide valuable information for further investigation as therapeutic agents.

Acknowledgements▼

The publication cost of this paper was supported by the Korean Chemical Society.

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