Journal of the Korean Chemical Society (대한화학회지)

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

Chalcones-Sulphonamide Hybrids: Synthesis, Characterization and Anticancer Evaluation

  • Received : 2018.11.18
  • Accepted : 2018.12.17
  • Published : 2019.04.20
Download PDF
⟨ Previous Next ⟩

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, $^{13}C$ NMR and HR-LCMS and spectral study assert the structures of synthesized sulphonamide-chalcone hybrids.

Keywords

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 anti-cancer 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.

JCGMDC_2019_v63n2_85_f0001.png 이미지

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

JCGMDC_2019_v63n2_85_f0002.png 이미지

Scheme 2. Synthesis of targeted Chalcone-sulphonamide hybrids 6a−8f. Reagent and condition: c. DMF, chloroacetylchloride, triethylamine, 0−5℃. d. Reflux, 8−9 h.

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 (2.5mmol) 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 (0.1mL) 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, 1H NMR, 13C NMR). 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 1H NMR 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 oC 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). 13 C 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 oC, 70.7%, Rf 0.66. FT-IR (ν, cm−1 ): 3741 (-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 (500MHz, 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 130−133oC, 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 (Ali-phatic-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 (500MHz, 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: Cal-culated 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 oC, 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) acet-amide (6e): Red Brick solid, mp 142−144 oC, 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 oC, 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)acet-amide (7a): Red solid, mp 116−118 oC, 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 oC, 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 oC, 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-methoxy-phenyl)acryloyl)phenyl) amino)acetamide (7d): Yellow solid, mp 98−100 oC, 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 (-C-N), 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 oC, 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 (500MHz, 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 oC, 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 oC, 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). 1 H 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 oC, 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). 1 H 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 oC, 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 oC, 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 oC, 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). 13C NMR (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 oC, Yield 62.6%, Rf 0.70. 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) Calcu-lated 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).

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 1 H 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 1734−1739cm−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 44.54ppm for methylene, 56.79ppm for methoxy, 167.97ppm for amide carbonyl and 190.97ppm 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.

Table 1. Structures and % yield of chalcone-sulphonamide hybrids

JCGMDC_2019_v63n2_85_t0003.png 이미지

Table 1. (continued)

JCGMDC_2019_v63n2_85_t0004.png 이미지

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.

Table 2. Percentage cell inhibition by chalcone-sulphonamide hybrids 6a−8f against various cancer cell lines​​​​​​​

JCGMDC_2019_v63n2_85_t0002.png 이미지

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.

Acknowledgments

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

References

  1. Fadeyi, O. O.; Adamson, S. T.; Myles, E. L.; Okoro, C. O. Bioorg. Med. Chem. Lett. 2008, 18, 4172. https://doi.org/10.1016/j.bmcl.2008.05.078
  2. Hiss, D. C.; Gabriels, G. A. Expert Opin. Drug Discov. 2009, 4, 799. https://doi.org/10.1517/17460440903052559
  3. Valiron, O.; Caudron, N.; Job, D. Cell Mol. Life Sci. 2001, 58, 2069. https://doi.org/10.1007/PL00000837
  4. Colliste, C. B.; Bail, L.; Trouillas, P.; Pouget, C.; Habrioux, G.; et al. Anticancer Res. 2001, 21, 3949.
  5. Ngameni, B.; Kuete, V.; Ambassa, P.; Justine, K.; Marlyse, M. L. et al. Med. Chem. 2013, 3, 233. https://doi.org/10.2174/157340607780620671
  6. Chandrabose, K.; Narayana, S. K.; Narayana, M.; Sakhtivel, R.; Uma, V.; Elungavan, M.; Devrajan, K.; Piyush, T. et al. Recent Pat. Anticancer Drug Discov. 2015, 10(1), 97.
  7. Chimenti, F.; Fioravanti, R.; Blasco, A.; Chimenti, P.; Secci, D.; Rossi, F. et al. J. Med. Chem. 2009, 52, 2818. https://doi.org/10.1021/jm801590u
  8. Kamal, A.; Prabhakar, S.; Ramaiah, M.; Venkat Reddy P.; Ratna Reddy, C.; Malla Reddy, A.; Shankaraiha, N.; Lakshmi Narayan Reddy, T.; Pushpvalli, S.; Pal Bhadra M. Eur. J. Med. Chem. 2011, 46, 3820. https://doi.org/10.1016/j.ejmech.2011.05.050
  9. Narender, T.; Venkateswarlu, K.; Vishnu Nayak, B.; Sarkar, S. Tetrahedron Lett. 2011, 52, 5794. https://doi.org/10.1016/j.tetlet.2011.08.120
  10. Rajakumar, P.; Raja, S. Tetrahedron Lett. 2008, 49, 6539. https://doi.org/10.1016/j.tetlet.2008.09.005
  11. Suvitha, S.; Siddig Ibrahim, A.; Mohammed Ali, M.; Mohan, S. Molecules 2012, 17, 6179. https://doi.org/10.3390/molecules17066179
  12. Ratchanok, P.; Amporn, S.; Prasit, M.; Chanin, N.; Supaluk, P.; Somsak, R.; Virapong, P. Eur. J. Med. Chem. 2014, 85, 65. https://doi.org/10.1016/j.ejmech.2014.07.087
  13. Iqbal, H.; Prabhakar, V.; Sangita, A.; Chandrika, B.; Balasubramanium, R. Med. Chem. Res. 2014, 23, 4383. https://doi.org/10.1007/s00044-014-1007-z
  14. Takagi, M.; Honmura, T.; Watanabe, S.; Yamaguchi, R.; Nogawa, M.; Nishimura, I.; Katoh, F.; Matsuda, M.; Hidaka, H. Invest. New Drug. 2013, 21, 387. https://doi.org/10.1023/A:1026282716250
  15. Supuran, C. T.; Casini, A.; Scozzafava, A. Med. Res. Rev. 2003, 23, 535. https://doi.org/10.1002/med.10047
  16. Mak, N. K.; Kok, T. W.; Wong, R. N. S. et al. J. Biomed. Sci. 2003, 10, 418. https://doi.org/10.1007/BF02256433
  17. Das, M.; Manna, K. J. Toxicology 2016, 1.
  18. Fathalla, O. A.; Zaghary, W. A.; Radwan, H. H.; Awad, S. M.; Mohamed, S. M. Archives of Pharma. Res. 2002, 23, 258. https://doi.org/10.1007/BF02976623
  19. Sapuran, C. T.; Scozzafava, A.; Casini, A. Med. Res. Rev. 2003, 23, 146. https://doi.org/10.1002/med.10025
  20. Supuran, C. T.; Scozzafava, A. Immunol. Endocr. Metab. Agents Med. Chem. 2001, 1, 61. https://doi.org/10.2174/1568013013359131
  21. Maren, T. H. Annu. Rev. Pharmacol. Toxicol. 1976, 16, 309. https://doi.org/10.1146/annurev.pa.16.040176.001521
  22. Chun, W. M.; Marzieh, Y.; Noorsaddah, A. R.; Kung, Y. B; Pichika, M. R. Eur. J. Med. Chem. 2014, 77, 378. https://doi.org/10.1016/j.ejmech.2014.03.002
  23. Hamada, N. M. M; Abdo, N. Y. M. Molecules 2015, 20, 10468. https://doi.org/10.3390/molecules200610468
  24. Asha, V. C.; Ratnadeep, S. J.; Priyanka, G. M.; Charansingh, H. G. J. Korean Chem. Soc. 2011, 55, 776. https://doi.org/10.5012/jkcs.2011.55.5.776
  25. Shankaraiah, N.; Siraj, K. P.; Nekkanti, S.; Shrinivasulu, V.; Sharma, P.; Senawar, K. R.; Satish, M.; Vishnuvardhan M. V. P. S.; Ramakrishnan, S.; Jadala, C.; Nagesh, N.; Kamal, A. Bioorg. Chem. 2015, 59, 130. https://doi.org/10.1016/j.bioorg.2015.02.007
  26. Nielsen, S. F.; Boesen, T.; Larsen, M.; Schonnig, K.; Kromann, H. Bioorg. Med. Chem. 2004, 12, 3047. https://doi.org/10.1016/j.bmc.2004.03.071