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 © 2019, Korean Chemical Society

Copyright: 2019

Date received: 18 November 2018

Date accepted: 17 December 2018

Publication date (print): 20 April 2019

Volume: 63

Issue: 2

Pages: 85-93

Publisher ID: jkcs-63-85

DOI: 10.5012/jkcs.2019.63.2.85

Chalcones-Sulphonamide Hybrids: Synthesis, Characterization and Anticancer Evaluation

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 panel of chalcone-sulphonamide hybrids has been designed by tethering appropriate sulphonamide scaffold with substituted chalcones as a multi-target drug for anticancer screening. Chalcones were prepared by Claisen-Schmidt condensation reaction of a substituted aldehyde with para aminoacetophenone. All the synthesized compounds were evaluated against selected five cancer cell lines, MCF-7 (Breast cancer), DU-145 (Human prostate Carcinoma), HCT-15 (Colon cancer), NCIH-522 (stage 2, adenocarcinoma; non-small cell lung cancer) and HT-3 (Human cervical cancer). Most of the synthesized chalcone-sulphonamide hybrids showed amended cytotoxic activity against various cancer cell lines which may be attributed to the linkage of sulphonamide with chalcone skeleton. The synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR and HR-LCMS and spectral study assert the structures of synthesized sulphonamide-chalcone hybrids.

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INTRODUCTION▼

An affliction of cancer is raised world widely, with the changes in the living environment and also one of the most dominant causes of the morbidity and mortality. World-wide deaths related to cancer are estimated to elongate 12 million in the year 2015.1 Uncontrollable cell replication and rapid proliferation are the most important mechanism that causes cancer.2 During proliferation, microtubules or tubulins are most important molecular targets for cancer chemotherapeutic agents since they play a vital role and involve in cellular functions.3 The new generation of anticancer drugs affects the signals that promote or regulate cell cycle, growth factor, pathway affecting DNA repair and apoptosis.

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 are 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 chalcones are highly favorable to elicit numerous therapeutic activities.4-13 Previous literature revealed that the anticancer activity of chalcone might be due to molecular alteration such as tubulin inhibition, kinase inhibition, apoptosis, DNA and mitochondrial damage, inhibition of angiogenesis and also drug efflux protein activities.

Sulphonamides were found to possess many types of biologically interesting activities including antitumor activity. Many sulphonamide compounds exhibited their anticancer activity by inhibiting tubulin to form microtubule.14 The synthesized sulphonamides selectively inhibit proliferation, block the cell cycle and induce apoptosis in human cancer cells but not in normal cells.15,16 Chalcones containing a sulphonyl or sulphonamide group for cytotoxic effect on cells of many types of cancer. Anticancer activity of sulphonamide chalcone hybrid 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 anticancer activity.17

The anticancer activity of chalcone and sulphonamide set off medicinal chemistry researcher to synthesize novel sulphonamide-chalcone hybrids possessing such important properties and evaluate for their cytotoxic effect against various cancer cell lines in vitro.

EXPERIMENTAL▼

General Information

All the starting materials and solvents were purchased from SD Fine limited and Sigma-Aldrich and used without any further purification. Melting points were determined by the conventional method and then by electrocapillary apparatus and were uncorrected. All the synthesized compounds were monitored by thin layer chromatography (TLC) with precoated Aluminium sheets on silica gel (E-Merck) and the spots were visualized by the 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 1d−1f was synthesized as shown in Scheme 1. Commercially available sulphonamides were treated with chloroacetyl chloride and synthesized chalcones to provide the target sulphonamide-chalcone hybrids was depicted in Scheme 2. The structures of targeted compounds were characterized using spectral methods, and all spectral data corroborated the assumed structures.

Synthesis

General Procedure of Synthesis of Aminochalcone (1d−1f): The synthesis of chalcone derivatives was conducted according to the procedure reported in the reference by Claisen-Schmidt condensation reaction.18-20 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 Sulphonamide Chalcone (6a−8f): To a stirred solution of sulphonamide (2 mmol), chloroacetylchloride (2 mL) and try ethylamine (0.1 mL) in dry dimethylformamide at 0−5 ℃, aminochalcone 1d−1f (2 mmol) was added and stirred at room temperature for 3−4 hours by a magnetic stirrer. The stirred reaction mixture was then refluxed for 8−9 hours. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture on hot was poured to crushed ice afforded precipitates of chalcone-sulphonamide hybrids 3a−6f. Precipitates then washed with cold aqueous sodium carbonate and the crude product was recrystallized in acetone.

Characterization

The synthesis of chalcone derivatives 1d−1f was carried out by simple base catalyzed Claisen-Schmidt condensation21,22 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 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).

(E)-2-((4-(3-(2,4-Dihydroxyphenyl)acryloyl)phenyl) amino)-N-(4-(N-(5-methylisoxazol-3-yl)sulfamoyl) phenyl) acetamide(6a): Red solid, mp 121−124 ℃ Yield 84.4%, Rf 0.62. FT-IR (ν, cm−1): 3741 (-OH), 3672 (-OH), 3649, 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): 8.48 (s, 1H, -OH), 8.49 (s, 1H, -OH), 7.95 (s, 1H, CONH-), 7.70 (s, 1H, -SO2NH-), 7.65 (d, 1Hβ -CH=CH-), 6.54 (d, 1Hα-CH=CH-), 6.02−7.93 (m, 10H, Ar-H), 6.01 (t, 1H, -NH-), 3.53 (s, 1H, CH=Cisoxazole), 2.88 (d, 2H, -CH2-), 2.73 (s, 3H, -CH3). 13C NMR (500 MHz, DMSO-d6, ppm): 195.17, 167.08, 153.09, 151.03, 144.34, 138.80, 130.54, 127.02, 126.00, 125.54, 122.95, 119.07, 119.07, 112.40, 40.80, 39.67, 39.46, 39.07, 38.83, 30.73, 25.82. HR-MS (ESI) Calculated for C27H24N4O7S [M+H+] 548.146, found 548.136. Molecular formula: Calculated C27H24N4O7S, found C27H24N4O7S.

(E)-2-((4-(3-(2,4-Dihydroxyphenyl)acryloyl)phenyl) amino)-N-(4-sulfamoylphenyl) acetamide (6b): Brick red solid, mp 118−120 ℃, 70.7%, Rf 0.66. FT-IR (ν, cm−13): 741 (-OH), 3672 (-OH), 3591, 3566, 3365, 3280 (2-NH, -NH2), 3101 (Ar C-H), 2974 (Aliphatic-CH), 1739 (-CONH-), 1678 (-CO), 1593 (-HC=CH-), 1456 (C-O), 1315, 1153(-SO2-), 952 (S-N), 833 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.10 (s, 1H, -OH), 7.95 (s, 1H, CONH-), 7.71 (s, 2H, -SO2NH2), 7.64 (d, 1Hβ -CH=CH-), 6.56 (d, 1Hα -CH=CH-), 6.02-7.86 (m, 10H, Ar-H), 6.54 (t, 1H, -NH-), 3.13 (s, 2H, -CH2-). 13C NMR (500 MHz, DMSO-d6, ppm): 195.34, 169.88, 162.48, 159.63, 153.67, 141.60, 138.61, 137.27, 130.64, 130.44, 127.07, 126.75, 119.09, 118.89, 112.57, 111.37, 60.91, 46.44, 42.85, 40.95, 40.02, 35.89, 30.87. HR-MS (ESI) Calculated for C23H21N3O6S [M+H+] 467.116, found 467.115. Molecular formula: Calculated C23H21N3O6S, found C23H21N3O6S.

(E)-2-((4-(3-(2,4-Dihydroxyphenyl)acryloyl)phenyl) amino)-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl) phenyl)acetamide (6c): Brickred solid, mp 130−133 ℃, Yield 74.5%, Rf 0.57. FT-IR (ν, cm−1): 3736 (-OH), 3597 (-OH), 3360, 3344, 3261 (3-NH-), 2929 (Ar C-H), 2846 (Aliphatic-CH), 1739 (-CONH-), 1651 (-CO), 1645 (-C=N), 1521 (-HC=CH-), 1400 (C-O), 1396, 1153 (-SO2-), 960 (S-N), 827 (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).13C NMR (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) Calculated for C29H27N5O6S [M+H+] 573.148, found 573.168. Molecular formula: Calculated C29H27N5O6S, found C29H27N5O6S.

(E)-N-(4-(N-Acetylsulfamoyl)phenyl)-2-((4-(3-(2,4-dihydroxyphenyl)acryloyl)phenyl) amino)acetamide (6d): Black solid, M.p 128−130 ℃, Yield 59.90%, Rf 0.56. FT-IR (ν, cm−1): 3741, 3672 (-OH), 3647, 3591, 3360 (3-NH-), 3000−3120 (Ar C-H), 2974 (Aliphatic-CH), 1734 (-CONH-), 1678 (-CO), 1591 (-HC=CH-), 1456 (C-O), 1363, 1153 (-SO2-), 952 (S-N), 829 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 8.10 (s, 1H, -OH), 7.95 (s, 1H, CONH-), 7.67 (d,1Hβ -CH=CH-), 7.64 (s, 1H, -SO2NH-) , 6.64 (d, 1Hα -CH=CH-), 6.04−7.95 (m, 10H, Ar-H), 6.54 (t, 1H, -NH-), 3.35 (d, 2H, -CH2-), 2.73 (s, 3H, -CH3). 13C NMR (500 MHz, DMSO-d6, ppm): 195.67, 162.94, 159.56, 154.09, 141.66, 138.80, 131.09, 129.06, 129.06, 125.02, 122.95, 119.08, 119.12, 113.02, 40.46, 39.67, 39.46, 39.07, 38.83, 36.34, 31.33, 26.33. HR-MS (ESI) Calculated for C25H23N3O7S [M+H+] 509.122, found 509.125. Molecular formula: Calculated C25H23N3O7S, found C25H23N3O7S.

(E)-2-((4-(3-(2,4-Dihydroxyphenyl)acryloyl)phenyl) amino)-N-(4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl) acetamide (6e): Red Brick solid, mp 142−144 ℃, Yield 66.4%, Rf 0.60 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): 8.49 (s, 1H, -OH), 8.48 (s, 1H, CONH-), 7.76 (d, 1Hβ -CH=CH-), 7.65 (s, 1H, -SO2NH-), 6.65 (d, 1Hα -CH=CH-), 6.09−7.95 (m, 10H, Ar-H), 6.01 (1H, s, -CH=CH(pyrimidine)), 6.54 (t, 1H, -NH-), 3.35 (d, 2H, -CH2-). 13C NMR (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) Calculated for C27H23N5O6S [M+H+] 545.1363, found 545.1369. Molecular formula: Calculated C27H23N5O6S, found C27H23N5O6S.

(E)-N-(4-(N-(6-Chloropyridazin-3-yl)sulfamoyl)phenyl)-2-((4-(3-(2,4-dihydroxyphenyl)acryloyl)phenyl)amino) acetamide (6f): Red solid, mp 134−137 ℃, Yield 65%, 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), 1363, 1172 (-SO2-), 937 (S-N), 833 (C-S), 597.93 (C-Cl). 1H NMR (500 MHz, DMSO-d6, ppm): 8.20 (s, 1H, -OH), 7.95 (s, 1H, CONH-), 7.77 (d, 1Hβ, -CH=CH-), 7.65 (s, 1H, -SO2NH-), 6.54 (d, 1Hα -CH=CH-), 6.09−7.84 (m, 10H, Ar-H), 6.53 (1H, s, -CH=CH(pyrimidine)), 6.46 (t, 1H, -NH-), 3.40 (d, 2H, -CH2-). 13C NMR (500 MHz, DMSO-d6, ppm): 195.49, 195.26, 164.45, 162.51, 153.58, 152.59, 151.92, 141.10 140.36, 137.52, 134.23, 130.47, 129.86, 128.31, 126.97, 124.98, 119.02, 118.30, 112.63, 111.33, 108.78, 61.98, 60.25, 45.85, 40.40, 35.91, 30.90. HR-MS (ESI) Calculated for C27H22ClN5O6S [M+H+] 579.0912, found 579.0979. Molecular formula: Calculated C27H22ClN5O6S, found C27H22-ClN5O6S.

(E)-2-((4-(3-(4-Methoxyphenyl)acryloyl)phenyl)amino)-N-(4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl)acetamide (7a): Red solid, mp 116−118 ℃, Yield 76.2%, Rf 0.42. FT-IR (ν, cm−1): 3391, 3360, 3331(3-NH-), 3000−3100 (Ar C-H), 2974 (Aliphatic-CH), 1699 (-CO), 1629 (-C=N), 1595 (-HC=CH-), 1460 (C-O), 1336, 1166 (-SO2-), 979 (S-N), 819 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 7.95 (s, 1H, CONH-), 7.66 (d, 1Hβ -CH=CH-), 7.61 (s, 1H, -SO2NH-), 6.60 (d,1Hα -CH=CH-), 6.13−7.92 (m, Ar-H), 6.62 (t, 1H, -NH-), 3.36 (d, 2H, -CH2-), 2.73 (s, 3H, -OCH3). 13C NMR (500 MHz, DMSO-d6, ppm): 185.17, 162.08, 160.79, 153.67, 141.66, 130.94, 130.23, 127.75, 125.48, 125.54, 119.85, 112.40, 55.28, 40.80, 39.88, 39.67, 39.46, 39.04, 38.83, 35.74, 30.73. HR-MS (ESI) Calculated for C28H26N4O6S [M+H+] 546.1573, found 546.1354. Molecular formula: Calculated C28H26N4O6S, found C28H26N4O6S.

(E)-2-((4-(3-(4-Methoxyphenyl)acryloyl)phenyl)amino)-N-(4-sulfamoylphenyl) acetamide (7b): Yellow solid, mp 117−120 ℃, Yield 80.5%, Rf 0.67. FT-IR (ν, cm−1): 3510, 3505, 3350, 3240 (2-NH, -NH2), 3000−3100 (Ar C-H), 1728 (-CONH-), 1685 (-CO), 1593 (-HC=CH-), 1440 (C-O), 1334, 1163 (-SO2-), 977 (S-N), 817 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 7.95 (s, 1H, CONH-), 7.72 (d, 1Hβ-CH=CH-), 7.57 (s, 2H, -SO2NH2), 6.61 (d, 1Hα -CH=CH-), 6.13−7.93 (m, Ar-H), 6.63 (t, 1H, -NH-), 3.85 (s, 2H, -CH2-), 3.45 (s, 3H, -OCH3). 13C NMR (500 MHz, DMSO-d6, ppm): 191.30, 185.83, 169.73, 162.27, 160.79, 159.56, 153.67, 141.54, 141.31, 131.79, 130.23, 129.91, 128.46, 127.75, 126.67, 125.49, 121.15, 119.45, 118.74, 114.27, 112.66, 60.79, 54.94, 55.28, 40.81, 39.25, 38.83, 30.73. HR-MS (ESI) Calculated for C24H23N3O5S [M+H+] 465.1358, found 465.1153. Molecular formula: Calculated C24H23N3O5S, found C24H23N3O5S.

(E)-N-(4-(N-(4,6-Dimethylpyrimidin-2-yl)sulfamoyl) phenyl)-2-((4-(3-(4-methoxyphenyl)acryloyl)phenyl) amino) acetamide (7c): Light yellow solid, mp 109−111 ℃, Yield 62.0%, Rf 0.43. FT-IR (ν, cm−1): 3601, 3590, 3353 (3-NH-), 3000−3100 (Ar C-H), 2974, 2883 (Aliphatic-CH), 1747 (-CONH-), 1680 (-CO), 1649 (-C=N), 1595 (-HC=CH-), 1456 (C-O), 1396, 1165 (-SO2-), 977 (S-N), 819 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 7.93 (s, 1H, CONH-), 7.72 (d, 1Hβ -CH=CH-), 7.57 (s, 1H, -SO2NH-), 6.63 (d, 1Hα-CH=CH-), 6.13−7.91 (m, Ar-H), 6.13 (1H, s, -CH=CH(pyrimidine)), 6.61 (t, 1H, -NH-), 3.70 (d, 2H, -CH2-), 2.50 (s, 3H, -CH3), 3.37 (s, 3H, -OCH3), 2.31 (s, 3H, -CH3). 13C NMR (500 MHz, DMSO-d6, ppm): 187.69, 186.82, 167.79, 161.38, 160.92, 153.76, 143.61, 141.51, 131.05, 130.76, 129.92, 128.56, 127.83, 125.67, 119.98, 118.79, 114.49, 114.41, 113.89, 112.86, 55.37, 55.10, 47.83, 40.40, 40.03, 39.90, 39.07, 29.69, 23.18, 22.89. HR-MS (ESI) Calculated for C30H29N5O5S [M+H+] 571.1889, found 571.1909. Molecular formula: Calculated C30H29N5O5S, found C30H29N5O5S.

(E)-N-(4-(N-Acetylsulfamoyl)phenyl)-2-((4-(3-(4-methoxyphenyl) acryloyl)phenyl) amino)acetamide (7d): Yellow solid, mp 98−100 ℃, Yield 67.4%, Rf 0.56. FT-IR (ν, cm−1): 3568, 3360, 3246 (3-NH-), 3000-3100 (Ar C-H), 2839 (Aliphatic-CH), 1741 (-CONH-), 1674 (-CO), 1651 (-CN), 1595 (-HC=CH-), 1456 (C-O), 1338, 1166 (-SO2-), 1024 (S-N), 821 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 7.96 (s, 1H, CONH-), 7.86 (d, 1Hβ-CH=CH-), 7.58 (s, 1H, -SO2NH-), 6.62 (d, 1Hα -CH=CH-), 6.02−8.02 (m, 10H, Ar-H), 6.88 (t, 1H, -NH-), 3.70 (d, 2H, -CH2-), 3.39 (s, 3H, -CH3), 2.51 (s, 3H, -OCH3). 13C NMR (500 MHz, DMSO-d6, ppm): 197.17, 185.84, 162.27, 160.79, 153.67, 141.31, 130.94, 130.94, 129.72, 129.85, 127.75, 126.88, 125.00, 119.34, 118.61, 114.40, 113.77, 112.67, 111.32, 55.27, 54.99, 40.08, 39.46, 38.83, 35.74,30.72. HR-MS (ESI) Calculated for C26H25N3O6S [M+H+] 507.1464, found 507.1447. Molecular formula: Calculated C26H25N3O6S, found C26H25N3O6S.

(E)-2-((4-(3-(4-Methoxyphenyl)acryloyl)phenyl)amino)-N-(4-(N-(pyrimidin-2-yl) sulfamoyl)phenyl)acetamide (7e): Red solid, mp 124−125 ℃, Yield 69.0%, Rf 0.58. FT-IR (ν, cm−1): 3360, 3340, 3228 (3-NH-), 3000−3100 (Ar C-H), 2918 (Aliphatic-CH), 1738 (-CONH-), 1665 (-CO), 1508 (-C=N), 1593 (-HC=CH-), 1421 (C-O), 1338, 1155 (-SO2-), 981 (S-N), 819 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 7.94 (s, 1H, CONH-), 7.79 (d, 1Hβ -CH=CH-), 7.62 (s, 1H, -SO2NH-), 6.64 (d, 1Hα -CH=CH-), 6.14−7.94 (m, Ar-H), 6.14 (1H, s, -CH=CH(pyrimidine)), 3.39 ( d, 2H, -CH2-), 2.88 (s, 3H, -OCH3). 13C NMR (500 MHz, DMSO-d6, ppm): 185.84, 162.27, 160.79, 153.67, 141.32,130.95, 130.23, 128.45, 127.75, 125.50, 119.85, 118.60, 114.27, 113.77, 112.67, 55.27, 54.98, 41.17, 40.08, 39.87, 39.66, 39.04, 38.83, 35.74, 30.72. HR-MS (ESI) Calculated for C28H25N5O5S [M+H+] 543.1576, found 543.1527. Molecular formula: Calculated C28H25N5O5S, found C28H25N5O5S.

(E)-N-(4-(N-(6-Chloropyridazin-3-yl)sulfamoyl)phenyl)-2-((4-(3-(4-methoxyphenyl)acryloyl)phenyl)amino) acetamide (7f): Yellow solid, mp 133−135 ℃, Yield 67.1%, Rf 0.72. FT-IR (ν, cm−1): 3385, 3356, 3143 (3-NH-), 3000−3100 (Ar C-H), 1747 (-CONH-), 1700 (-CO), 1647 (-C=N ), 1593 (-HC=CH-), 1460 (C-O), 1338, 1165 (-SO2-), 979 (S-N), 817 (C-S), 563 (C-Cl). 1H NMR (500 MHz, DMSO-d6, ppm): 7.96 (s, 1H, CONH-), 7.75 (d, 1Hβ -CH=CH-), 7.61 (s, 1H, -SO2NH-), 6.67 (d, 1Hα -CH=CH-), 6.17−7.96 (m, Ar-H), 6.90 (1H, s, -CH=CH(pyrimidine)), 6.17 (t, 1H, -NH-), 3.72 (d, 2H, -CH2-), 2.52 (s, 3H, -OCH3). 13C NMR (500 MHz, DMSO-d6, ppm): 191.25, 185.86, 162.27, 161.29, 160.79, 158.21, 153.69, 143.47, 141.34, 132.02, 131.78, 130.23, 129.90, 128.47, 127.36, 125.52, 121.15, 119.85, 118.62, 114.00, 113.75, 112.49, 111.34, 55.62, 54.96, 52.09, 45.29, 41.92, 40.07, 39.24, 38.82, 35.73, 30.71. HR-MS (ESI) Calculated for C28H24ClN5O5S [M+H+] 577.1187, found 577.1089. Molecular formula: Calculated C28H24ClN5O5S, found C28H24ClN5O5S.

(E)-2-((4-(3-(3,4-Dimethoxyphenyl)acryloyl)phenyl) amino)-N-(4-(N-(5-methylisoxazol-3-yl)sulfamoyl) phenyl)acetamide (8a): Red solid, mp 140−141 ℃, Yield 80.5%, Rf 0.55. FT-IR (ν, cm−1): 3450, 3490, 3331 (3-NH-), 3000−3100 (Ar C-H), 1701 (-CO), 1649 (-C=N), 1591 (-HC=CH-), 1456 (C-O), 1336, 1172 (-SO2-), 979 (S-N), 833 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 7.96 (s, 1H, CONH-), 7.61 (d, 1Hβ -CH=CH-), 7.50 (s, 1H, -SO2NH-), 6.63 (d, 1Hα -CH=CH-), 6.14−7.94 (m, Ar-H), 6.14 (t, 1H, -NH-), 3.81 (d, 2H, -CH2-), 2.73 (s, 3H, -OCH3), 2.71 (s, 3H, -OCH3). 13C NMR (500 MHz, DMSO-d6, ppm): 206.90, 187.75, 186.26, 171.09, 162.53, 160.35, 159.26, 153.82, 151.35, 150.89, 149.13, 144.21, 131.18, 130.20, 129.57, 128.12, 125.78, 123.93, 120.12, 119.62, 118.85, 112.93, 110.64, 96.62, 62.02, 60.94, 55.81, 48.15, 45.91, 40.03, 39.92, 35.90, 32.16, 30.90. MS (ESI) Calculated for C29H28N4O7S [M+H+] 576.62, found 576.10.

(E)-2-((4-(3-(3,4-Dimethoxyphenyl)acryloyl)phenyl) amino)-N-(4-sulfamoylphenyl) acetamide (8b): Yellow solid, mp 127−129 ℃, Yield 88.0%, Rf 0.57. FT-IR (ν, cm−1): 3410, 3375, 3305, 3240 (2-NH, -NH2), 3000−3100 (Ar C-H), 1741 (-CONH-), 1627 (-CO), 1591 (-HC=CH-), 1456 (C-O), 1338, 1136 (-SO2-), 977 (S-N), 833 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 7.97 (s, 1H, CONH-), 7.67 (d, 1Hβ-CH=CH-), 7.53 (s, 2H, -SO2NH2), 6.041 (d, 1Hα -CH=CH-), 6.04−7.97 (m, Ar-H), 3.95 (s, 2H, -CH2-), 3.35 (s, 3H, -OCH3), 2.89 (s, 3H, -OCH3). 13C NMR (500 MHz, DMSO-d6, ppm): 191.30, 185.83, 162.27, 153.68, 151.16, 150.67, 148.94, 141.86, 130.99, 129.88, 127.95, 127.53, 125.50, 123.27, 119.90, 112.64, 111.45, 110.37, 55.66, 55.50, 40.08, 39.87, 39.04, 38.83, 35.74, 30.65, 29.56. MS (ESI) Calculated for C25H25N3O6S [M+H+] 495.54, found 494.40.

(E)-2-((4-(3-(3,4-Dimethoxyphenyl)acryloyl)phenyl) amino)-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl) phenyl)acetamide (8c): Red solid, M.p 155−156 ℃, Yield 66.0%, Rf 0.63. FT-IR (ν, cm−1): 3401, 3390, 3353 (3-NH-), 3000−3100 (Ar C-H), 2883 (Aliphatic-CH), 1701 (-CONH-), 1681 (-CO), 1649 (-C=N), 1593 (-HC=CH-), 1456 (C-O), 1365, 1136 (-SO2-), 977 (S-N), 833 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 7.95 (s, 1H, CONH-), 7.75 (d, 1Hβ-CH=CH-), 7.56 (s, 1H, -SO2NH-), 6.62 (d, 1Hα -CH=CH-), 6.14−7.93 (m, Ar-H), 6.98 (1H, s, -CH=CH(pyrimidine)), 6.62 (t, 1H, -NH-), 3.82 (d, 2H, -CH2-), 3.37 (s, 3H, -CH3), 2.80 (s, 3H, -OCH3), 2.50 (s, 3H, -OCH3). 13C NMR (500 MHz, DMSO-d6, ppm): 185.82, 162.27, 153.67, 150.67, 148.94, 141.30, 130.94, 129.88, 127.53, 127.95, 125.50, 123.37, 119.90, 119.39, 112.65, 111.45, 110.37, 55.66, 40.08, 39.88, 39.67, 39.46, 39.04, 38.83, 35.74, 30.65, 29.64. MS (ESI): Calculated for C31H31N5O6S [M+H+] 601.67, found 601.1.

(E)-N-(4-(N-Acetylsulfamoyl)phenyl)-2-((4-(3-(3,4-dimethoxyphenyl)acryloyl)phenyl) amino)acetamide (8d): Red solid, mp 158−160 ℃, Yield 71.0%, Rf 0.59. FT-IR (ν, cm−1): 3568, 3360, 3246 (3-NH-), 3000−3100 (Ar C-H), 2839 (Aliphatic-CH), 1745 (-CONH-), 1681 (-CO), 1647 (-C-N), 1595 (-HC=CH-), 1456 (C-O), 1338, 1157 (-SO2-), 1020 (S-N), 835 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 7.87 (s, 1H, CONH-), 7.77 (d, 1Hβ -CH=CH-), 7.58 (s, 1H, -SO2NH-), 6.62 (d, 1Hα -CH=CH-), 6.13−7.82 (m, Ar-H), 6.98 (t, 1H, -NH-), 3.81 (d, 2H, -CH2-), 3.37 (s, 3H, -CH3), 2.88 (s, 3H, -OCH3), 2.73 (s, 3H, -OCH3). 13C NMR (500 MHz, DMSO-d6, ppm): 185.84, 162.27, 153.67, 150.67, 148.94, 141.86, 130.99, 129.88, 129.76, 128.90, 127.75, 125.50, 123.27, 119.34, 118.61, 112.67, 111.45, 110.30, 55.50, 40.08, 39.87, 38.83, 35.74, 30.72, 29.56, 23.25. MS (ESI): Calculated for C27H27N3O7S [M+H+] 537.58, found 537.2.

(E)-2-((4-(3-(3,4-Dimethoxyphenyl)acryloyl)phenyl) amino)-N-(4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl) acetamide (8e): Red-orange solid, mp 152−154 ℃, Yield 68.0%, Rf 0.66. FT-IR (ν, cm−1): 3348, 3340, 3244 (3-NH-), 3000−3100 (Ar C-H), 2929 (Aliphatic-CH), 1738 (-CONH-), 1631 (-CO), 1506 (-C=N), 1593 (-HC=CH-), 1438 (C-O), 1338, 1155 (-SO2-), 977 (S-N), 831 (C-S). 1H NMR (500 MHz, DMSO-d6, ppm): 7.98 (s, 1H, CONH-), 7.79 (d, 1Hβ-CH=CH-), 7.63 (s, 1H, -SO2NH-), 6.64 (d, 1Hα -CH=CH-), 6.15−7.96 (m, Ar-H), 6.15 (1H, s, -CH=CH(pyrimidine)), 3.73 (d, 2H, -CH2-), 2.88 (s, 3H, -OCH3), 2.73 (s, 3H, -OCH3). 13CNMR (500MHz, DMSO-d6, ppm): 185.87, 162.26, 153.68, 151.17, 150.48, 148.74, 144.01, 141.88, 131.0, 130.75, 129.88, 128.45, 127.54, 125.50, 123.84, 119.85, 118.60, 112.66, 111.45, 110.39, 55.27, 54.98, 40.07, 39.66, 39.04, 38.83, 35.72, 30.72, 29.56. MS (ESI): Calculated for C29H27N5O6S [M+H+] 573.61, found 573.2.

(E)-N-(4-(N-(6-Chloropyridazin-3-yl)sulfamoyl)phenyl)-2-((4-(3-(3,4-dimethoxyphenyl)acryloyl)phenyl)amino) acetamide (8f): Light yellow solid, mp 146−148 ℃, Yield 62.6%, Rf0.70. FT-IR (ν, cm−1): 3739, 3556, 3354 (3-NH-), 3000−3100 (Ar C-H), 2918 (Aliphatic-CH), 1747 (-CONH-), 1700 (-CO), 1647 (-C=N), 1587 (-HC=CH-), 1408 (C-O), 1309, 1138 (-SO2-), 975 (S-N), 827 (C-S), 599 (C-Cl). 1H NMR (500 MHz, DMSO-d6, ppm): 7.95 (s, 1H, CONH-), 7.77 (d, 1Hβ -CH=CH-), 7.65 (s, 1H, -SO2NH-), 6.61 (d, 1Hα-CH=CH-), 6.17−7.84 (m, Ar-H), 6.56 (1H, s, -CH=CH(pyrimidine)), 6.46 (t, 1H, -NH-), 3.40 (d, 2H, -CH2-), 2.89 (s, 3H, -OCH3), 2.73 (s, 3H, -OCH3). 13C NMR (500 MHz, DMSO-d6, ppm): 185.87, 164.34, 162.27, 153.68, 151.77, 150.67, 148.93, 141.34, 140.15, 137.36, 134.08, 131.08, 128.15, 127.95, 126.87, 125.53, 123.27, 119.90, 118.12, 112.67, 111.43, 110.35, 55.65, 45.58, 40.05, 39.84, 30.71, 29.56. MS (ESI) Calculated for C29H26ClN5O6S [M+H+] 608.06, found 609.0.

RESULTS AND DISCUSSION▼

Chemistry

The synthetic outline utilized for the synthesis of the targeted chalcone-sulphonamides hybrids are depicted in Scheme 1 and Scheme 2. Hydroxy and methoxy introduction on the benzene ring of chalcone scaffold could play a significant role in displaying remarkable cytotoxic effect.23,24 Base-catalyzed Claisen-Schmidt condensation between commercially available 4-aminoacetophenone and substituted aromatic aldehydes gave chalcones 1d−1f in good yield (Scheme 1).

Scheme1.

Synthesis of chalcone compounds 1d-1f. Reagent and condition: a. 20% NaOH, CH3OH, 25-30 ℃, overnight. b. 25% HCl, ethyl acetate.

jkcs-63-85-f001.tif
Scheme2.

Synthesis of targeted Chalcone-sulphonamide hybrids 6a-8f. Reagent and condition: c. DMF, chloroacetylchloride, triethylamine, 0-5 ℃. d. Reflux, 8-9 h.

jkcs-63-85-f002.tif

The structural investigation to synthesized compounds was based on their spectroscopic (IR, NMR, MS) data. IR spectrum of compound 1a revealed characteristic strong intensity bands at 3340, 3219 cm−1, for carbonyl at 1647−1680, -CH=CH- at 1590-1610 and for -OH at 3570−3395 cm−1. The 1H NMR spectra of compounds 1d−1f displayed downfield doublets at 8.06 and 7.5 ppm assigned for CH=CO and CH=CH respectively. Broad singlet in upfield at 3.47−3.50 ppm appeared for -NH2 group and singlet of methoxy proton in 1d and 1f appeared about at 3.87 ppm.

The further approach was drawn to design and synthesize novel chalcone-sulphonamide hybrids which are found an imperial class of anticancer agents.25,26 Thus, the treatment of chalcone 1d−1f with sulphonamide in DMF yielded the desired hybrids 6a−8f (Scheme 2). The key reaction complied is the formation of a C-N bond between the nitrogen of chalcone and carbon of sulphonamide derivatives. Structures of all the synthesized hybrids 6a−8f are further supported by IR, NMR, and HRMS. IR spectra of 6a−8f displayed -NH- absorption band at 3330−3360 cm−1 and stretching band of amide carbonyl at 1734−1739 cm−1. The broad singlet in 1H NMR of 6a−8f has disappeared which implies the absence of free -NH2 group of chalcone moiety and further resulted in the formation of a C-N bond between two pharmacophores. In the 1H NMR spectra, methylene protons present between -NH- and -CO- appear as a doublet at 3.36 ppm. 13C NMR spectrum of 6a revealed different characteristic signals at 44.54 ppm for methylene, 56.79 ppm for methoxy, 167.97 ppm for amide carbonyl and 190.97 ppm for vinyl carbonyl also reinforce the proposed structure. High-resolution mass spectroscopy reveals that hybrid 6a showed molecular ion (M+H+) peak at 546.157 corresponding to the molecular formula of C28H26N4O6S.

Anticancer Activity

Chemically synthesized all chalcone-sulphonamide hybrids 6a−8f were screened for their anticancer activity against MCF-7(Breast cancer), DU-145(Human prostate Carcinoma), HCT-15 (Colon cancer), NCIH-522 (stage 2, adenocarcinoma; non-small cell lung cancer) and HT-3 (Human cervical cancer) cell lines. Table 2 list the IC50 values of the hybrids against respective cell lines. IC50 values of all synthesized compound against test organism were compared to standard doxorubicin drug.

Table1.

Structures and % yield of chalcone-sulphonamide hybrids

jkcs-63-85-t001.tif
Table2.

Percentage cell inhibition by chalcone-sulphonamide hybrids 6a−8f against various cancer cell lines

Hybrids IC50(μM/ml)
MCF-7 HCT-15 DU-145 NCIH-522 HT-3
6a >100 55.20 14.40 6.53 54.36
6b >100 51.92 99.05 11.81 17.90
6c 68.52 53.70 22.50 10.08 14.48
6d 36.53 49.57 24.82 >100 17.89
6e >100 16.24 19.26 12.49 116.4
6f 3.774 15.09 16.90 18.87 12.10
7a 19.75 19.48 1.952 13.72 8.626
7b 24.61 8.061 83.56 7.951 30.33
7c >100 77.33 62.70 43.09 8.889
7d 71.33 12.80 8.565 88.03 >100
7e >100 84.45 5.451 20.26 6.334
7f 25.71 89.34 >100 >100 2.708
8a 3.579 1.599 59.74 >100 7.179
8b 12.43 1.937 94.08 26.84 5.755
8c 6.209 >100 >100 14.39 21.42
8d 1.514 67.32 11.48 32.21 15.04
8e >100 13.21 4.892 18.82 >100
8f 7.94 43.01 11.00 23.47 6.70
Doxorubicin 12.19 8.772 4.152 7.784 3.740

The result of anticancer activity revealed that most of the synthesized chalcone-sulphonamide hybrids exhibited significant in-vitro cytotoxicity. It was found that compounds 6f, 8a, 8b, 8c, 8d and 8f showed more potent activity against human breast cancer line MCF-7 compared to Doxorubicin reference drug. 7b, 8a and 8b exhibited promising anticancer activity against HCT-15 cancer cell line. While compound 7a, 7e and 8e showed higher activity than Doxorubicin against human prostate cancer cells DU-145. Compounds 6a and 7b exhibited significant activity against human lung cancer cells NCIH-522. Against HT-3 cancer cell lines hybrids 7f and 8b are found to be potent. Generally, the anticancer activity shown by 6a, 7a and 8a may attribute to isoxazole heterocycle present. In compounds 6f, 7e, 7f, 8c, 8e and 8f anticancer potency may be due to the presence of pyridine heterocycles while in 7b, 8b and 8d cytotoxicity may attribute to the linkage of chalcone moiety to sulphonamide scaffold.

CONCLUSION▼

Sulphonamide-chalcone hybrids have been synthesized by conjugating sulphonamide pharmacophore with substituted chalcones as anticancer agents. A panel of chalcone-sulphonamide derivatives was synthesized, characterized and evaluated for their potential in vitro anticancer activity against various human cancer cell lines. Among all the compounds, 6a, 6f, 7a, 7b, 7e, 7f, 8a, 8b, 8c, 8d, 8e and 8f show a significant cytotoxicity against various cancer cell lines than doxorubicin. From the SAR (Structural Activity Relationship) we may conclude that the introduction of oxazole or pyrimidine scaffold is associated with enhanced anticancer activity and gave more potent compounds. This study may provide valuable information for further investigation as anticancer agents.

Acknowledgements▼

Authors are grateful to the Korean Chemical Society as the publication cost of this paper was supported by the Korean Chemical Society.

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