Advanced
Synthesis, Characterization and Antimicrobial Activity of Bifunctional Sulfonamide-Amide Derivatives
Synthesis, Characterization and Antimicrobial Activity of Bifunctional Sulfonamide-Amide Derivatives
Journal of the Korean Chemical Society. 2013. Dec, 57(6): 731-737
Copyright © 2013, Korea Chemical Society
  • Received : July 10, 2013
  • Accepted : September 27, 2013
  • Published : December 20, 2013
Download
PDF
e-PUB
PubReader
PPT
Export by style
Article
Author
Metrics
Cited by
TagCloud
About the Authors
Babul Reddy A. Abbavaram
Hymavathi R.V. Reddyvari
Department of Bio-Chemistry, Sri Krishnadevaraya University, Anantapur-515055, A.P., India

Abstract
A convenient synthesis of bifunctional sulfonamide-amide derivatives was reported. Amide coupling of 4-methyl benzoic acid 1 followed by reaction with chlorosulfonic acid produce ethyl-4-(3-(chlorosulfonyl)-4-methylbenzoyl)piperazine- 1 -carboxylate 4 . The resulted compound on further treatment with various anilines produces the title sulfonamide-amide derivatives 5a−n . The configurations of these compounds were established by elemental analysis, IR, 1 H NMR, mass spectra, and by their preparation from the corresponding 4-methyl benzoic acid 1 and chlorosulfonic acid. All these new compounds demonstrate significant in vitro antibacterial and antifungal activities against all bacterial and fungal strains.
Keywords
INTRODUCTION
The development of simple and efficient methods for synthesis of bifunctional derivatives from readily available reagents is one of the major challenges in peptide chemistry. Among bifunctional derivatives, sulfonamide and amide bonds are represent the key functional group in peptides, polymers, many natural products and pharmaceuticals and most significant linkages in organic chemistry. 1 Molecules that are having both sulfonamide and amide functional groups are an important class of pharmaceutical compounds with a broad spectrum of biological activities. Some of these compounds reveal various types of biological properties such as histone deacetylase, 2 hepatitis C virus, 3 HIV-protease, 4 β-secretase (BACE1) inhibitors, 5 ανβ3 integrin, 6 glycine transporter 1(GlyT1), 7 matriptase, 8 and as a cholecystokinin type 2 receptor (CCK2R). 9 Moreover, bifunctional sulfonamide-amide compounds have played important role in synthetic chemistry to promising their in the field of biomedicinal chemistry. 10 Bifunctional sulfonamide-amide containing compounds have been synthesized via multistep approaches in the presence of expensive catalysts under sensitive conditions. 11 12 For instance, the sulfonamide derivatives are promisingly important in modern medicinal chemistry and agriculture. Many sulfonamide derivatives have been reported in the literature as antimicrobial, and antibiotic drugs, 13 14 anticonvulsants, and diuretics, 15 analgetics and antimigraine remedies. 15 Furthermore, a large variety of sulfonamide derivatives were reported to posses powerful inhibitors of proteases, 15 carbonic anhydrase, 16 COX-2, 17 caspase, 18 as well as osteogenic agents, 19 and antitumor drugs. 20 Some sulfonamides also exhibit a herbicidal activity. 21 Amide bond formation is one of the most important and regularly utilized reactions in organic synthesis. 22 23 These derivatives were associated with broad spectrum of biological activities including antituberculosis, 25 anticonvulsant, 26 analgesic-antiinflammatory, 27 insecticidal, 28 antifungal, 29 and antitumor, 30 properties. These outcome promoted us as part of my research respect to N -heterocycles, 31 and peptide chemistry, 32 we planned to synthesize the compounds that contain both amide and sulfonamide functional groups and evaluate for their antibacterial and antifungal activities.
EXPERIMENTAL
Melting points of synthesized compounds were determined in open capillary tubes on Mel-Temp apparatus and are uncorrected. Infrared spectra (νmax in cm −1 ) were recorded as KBr pellets on a Perkin-Elmer 283 double beam spectrophotometer. 1 H NMR spectra were recorded on an ABX 400 MHz spectrophotometer operating at 400 MHz, using DMSO- d 6 as solvent. The 1 H NMR chemical shifts were referenced to tetramethylsilane (TMS).
- Preparation of Ethyl-4-(4-methylbenzoyl)piperazine- 1-carboxylate (3)
To a ice-cold stirred solution of the 4-methyl benzoic acid 1 (2.0 g, 14.7 mmol) in dry CH 2 Cl 2 (50 mL) was added EDC (4.2 g, 22.0 mmol) followed by HOBT (2.7 g, 17.6 mmol) and then the resulting mixture was stirred vigorously for 30 min. Compound 2 (2.8 g, 17.6 mmol) was added slowly in the presence of triethylamine (1 eqv.) and the mixture stirred for 5 h. After completion of the reaction, the content was washed with water (10 mL × 3) and drying to concentration in vacuo yielded the crude product 3 as off-white solid ( Rf value : 0.5; Yield : 2.1 g (51%)). 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.32 (3H, t, J = 6.8 MHz, CH 3 −C), 2.32 (3H, s, CH 3 ), 2.71 (3H, s, CH 3 ), 3.21 (4H, t, J = 8.4 MHz, −CH2−N−CH2−), 3.75 (4H, t, J = 6.4 MHz, −CH 2 −N−CH 2 −), 4.20 (2H, q, C−CH 2 −O), 7.48 (2H, d, J = 4.8 MHz, Ar−H), 7.96 (2H, d, J = 4.4 MHz, Ar−H); IR (KBr) ν (cm −1 ): 1681 (C=O ester), 1703 (C=O amide); [M + ]: 276.33. Calcd. (%) for C 15 H 20 N 2 O 3 : C, 65.20; H, 7.31; N, 10.14. Found: C, 65.21; H, 7.34; N, 10.16.
- Preparation of Compound Ethyl-4-(3-(chlorosulfonyl)- 4-methylbenzoyl)piperazine-1-carboxylate (4)
To a stirred solution of chlorosulfonic acid (10 mL) was added to the compound 3 (1.0 g, 3.6 mmol) in portion wise and then the mixture was heated for 6 h at 100 ℃. The mixture was cooled, poured in to crushed ice and extracted with CH 2 Cl 2 . The extract was washed with ice water, dried over anhydrous Na 2 SO 4 and concentrated to yield compound 4 as brown oil ( Rf value : 0.4; Yield : 0.6 g (44%)). 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.38 (3H, t, CH 3 −C, J = 8.8 MHz), 2.32 (3H, s, CH 3 ), 2.77 (3H, s, CH 3 ), 3.26 (4H, t, J = 6.6 MHz, −CH 2 −N−CH 2 −), 3.78 (4H, t, J = 12.8 MHz, −CH 2 −N−CH 2 −), 4.22 (2H, q, C−CH 2 −O), 7.42 (1H, d, J = 8.0 MHz, Ar−H), 7.86 (1H, d, J = 12.4 MHz, Ar−H), 8.05 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 1685 (C=O ester), 1704 (C=O amide), 1357, 1170 (SO 2 ); [M + ]: 374.84. Calcd. (%) for C 15 H 19 ClN 2 O 5 S: C, 48.06; H, 5.11; Cl, 9.46; N, 7.47; S, 8.55. Found: C, 48.05; H, 5.15; Cl, 9.44; N, 7.46; S, 8.51.
- General Procedure for Synthesis of Compounds (5a−n)
To a solution of respective anilines (1.0 eq.) in CH 2 Cl 2 (15 mL) was added pyridine at 0 ℃ and the mixture stirred for 5 min. Compound 4 (1.0 eq.) in CH 2 Cl 2 (10 mL) was added and the mixture stirred at room temperature for 12− 48 h. The mixture was diluted with CH 2 Cl 2 (25 mL) and washed with diluted HCl and water. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated to obtain crude was subjected to column chromatography on silica gel to yield title compounds 5 .
- Preparation of Compound 3-(Chlorosulfonyl)-4-methylbenzoic Acid (6)
To a well-stirred solution of chlorosulfonic acid was added to the compound 1 (3.0 g, 22.0 mmol) in portion wise. The mixture was heated for 3 h at 100 ℃. The mixture was cooled, poured into crushed ice and extracted with CH 2 Cl 2 . The organic layer was washed with ice water, dried over anhydrous Na 2 SO 4 and concentrated to yield compound 6 as off white solid ( Rf value : 0.4; Yield : 3.0 g (58%)). 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 7.48 (1H, d, J = 5.6 MHz, Ar−H), 7.96 (1H, d, J = 6.4 MHz, Ar− H), 7.95 (1H, s, Ar−H); IR (KBr)ν (cm −1 ): 1681 (C=O acid), 1354, 1173 (SO 2 ); [M + ]: 233.66. Calcd. (%) for C 8 H 7 ClO 4 S: C, 40.95; H, 3.01; Cl, 15.11; S, 13.66. Found: C, 40.94; H, 3.03; Cl, 15.12; S, 13.66.
- General Procedure for Synthesis of Compounds (7a−n)
To a solution of anilines (1.2 eq.) in acetonitrile (15 mL) was added compound 5 (1.0 eq.) and the mixture stirred at room temperature for 16 h. The solid formed was filtered and washed with acetonitrile (5 mL). The filtrate was concentrated to afford residue was subjected to column chromatography on silica gel to yield compound 7 (Yield: 47−78%).
- General Procedure for Synthesis of Compound (5a−n)
To a solution of Compound (1.0 eq.) in CH 2 Cl 2 (15 mL) was added HOBT. H 2 O (1.2 eq.) at 0 ℃ and stirred for 5 min at the 0 ℃ temperature. Compound 2 (1.2 eq.) in CH 2 Cl 2 (10 mL) was added followed by the addition of EDC.HCl (1.5 eq.) portion wise. NEt 3 was added drop wise (to adjust pH ~8) and the mixture stirred at room temperature for another 2 h. The mixture was diluted with CH 2 Cl 2 (25 mL), washed with water, dried over anhydrous Na 2 SO 4 and concentrated to obtain residue was purified by column chromatography on silica gel to yield title compounds 5a−n .
- Ethyl-4-(4-methyl-3-(N-p-tolylsulfamoyl)benzoyl)piperazine- 1-carboxylate (5a)
Light brown solid; Yield: 68%, m.p. 186 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.38 (3H, t, J = 12.8 MHz, CH 3 −C), 2.54 (3H, s, CH 3 ), 2.87 (3H, s, CH 3 ), 3.15 (4H, t, J = 2.4 MHz, −CH 2 −N−CH 2 −), 3.86 (4H, t, J = 4.8 MHz, −CH 2 −N−CH 2 −), 4.26 (2H, q, C−CH 2 −O), 7.05 (2H, d, J = 6.0 MHz, Ar−H), 7.14 (2H, d, J = 6.4 MHz, Ar−H), 7.73 (1H, d, J = 2.8 MHz, Ar−H), 7.98 (1H, d, J = 4.4 MHz, Ar−H), 8.45 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3345 (NH), 1685 (C=O ester), 1708 (C=O amide), 1354, 1173 (SO 2 ); [M + ]: 445.21. Calcd. (%) for C 22 H 27 N 3 O 5 S: C, 59.32; H, 6.12; N, 9.43, S, 7.21. Found: C, 59.33; H, 6.14; N, 9.46, S, 7.20.
- Ethyl-4-(4-methyl-3-(N-m-tolylsulfamoyl)benzoyl)piperazine- 1-carboxylate (5b)
Light brown solid; Yield: 51%, m.p. 145−146 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.24 (3H, t, J = 8.8 MHz, CH 3 −C), 2.58 (3H, s, CH 3 ), 2.64 (3H, s, CH 3 ), 3.17 (4H, t, J = 4.4 MHz, −CH 2 −N−CH 2 −), 3.77 (4H, t, J = 4.8 MHz, −CH 2 −N−CH 2 −), 4.21 (2H, q, C−CH 2 −O), 7.01 (1H, d, J = 8.8 MHz, Ar−H), 7.18 (1H, t, J = 9.6 MHz Ar−H), 7.42 (1H, d, J = 2.8 MHz, Ar−H), 7.62 (1H, s, Ar−H), 7.83 (1H, d, J = 2.4 MHz, Ar−H), 8.01 (1H, d, J = 2.8 MHz, Ar−H), 8.42 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3348 (NH), 1689 (C=O ester), 1702 (C=O amide), 1351, 1157 (SO 2 ); [M + ]: 445.21. Calcd. (%) for C 22 H 27 N 3 O 5 S: C, 59.32; H, 6.12; N, 9.43, S, 7.21. Found: C, 59.31; H, 6.15; N, 9.43, S, 7.21.
- Ethyl-4-(3-(N-(4-methoxyphenyl)sulfamoyl)-4-methylbenzoyl) piperazine-1-carboxylate (5c)
Off white solid; Yield: 65%, m.p. 162−163 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.38 (3H, t, J = 1.6 MHz, CH 3 −C), 2.76 (3H, s, CH 3 ), 3.23 (4H, t, J = 4.4 MHz, −CH 2 − N−CH 2 −), 3.67 (3H, s, OCH 3 ), 3.82 (4H, t, J = 4.8 MHz, −CH 2 −N−CH 2 −), 4.21 (2H, q, C−CH 2 −O), 6.94 (2H, d, J = 7.1 MHz, Ar−H), 7.05 (2H, d, J = 7.2 MHz, Ar−H), 7.52 (1H, d, J = 8.8 MHz, Ar−H), 7.97 (1H, d, J = 4.0 MHz, Ar−H), 8.38 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3355 (NH), 1688 (C=O ester), 1703 (C=O amide), 1314, 1134 (SO 2 ); [M + ]: 461.52. Calcd. (%) for C 22 H 27 N 3 O 6 S: C, 57.27; H, 5.90; N, 9.10, S, 6.95. Found: C, 57.23; H, 5.92; N, 9.12, S, 6.95.
- Ethyl-4-(3-(N-(3-methoxyphenyl)sulfamoyl)-4-methylbenzoyl) piperazine-1-carboxylate (5d)
Off white solid; Yield: 68%, m.p. 186−187 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.35 (3H, t, J = 3.6 MHz, CH 3 −C), 2.72 (3H, s, CH 3 ), 3.18 (4H, t, J = 4.8 MHz, −CH 2 − N−CH 2 −), 3.64(3H, s, OCH 3 ), 3.78 (4H, t, J = 4.4 MHz, −CH 2 − N−CH 2 −), 4.23 (2H, q, C−CH 2 −O), 6.95 (1H, d, J = 4.8 MHz, Ar−H), 7.09 (1H, t, J = 7.2 MHz, Ar−H), 7.34 (1H, d, J = 7.2 MHz, Ar−H), 7.55 (1H, s, Ar−H), 7.86 (1H, d, J = 2.8 MHz, Ar−H), 7.99 (1H, d, J = 7.6 MHz, Ar−H), 8.35 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3344 (NH), 1685 (C=O ester), 1703 (C=O amide), 1357, 1154 (SO 2 ); [M + ]: 461.52. Calcd. (%) for C 22 H 27 N 3 O 6 S: C, 57.27; H, 5.90; N, 9.10, S, 6.95. Found: C, 57.24; H, 5.91; N, 9.12, S, 6.93.
- Ethyl-4-(3-(N-(4-chlorophenyl)sulfamoyl)-4-methylbenzoyl) piperazine-1-carboxylate (5e)
White solid; Yield: 91%, m.p. 154 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.33 (3H, t, J = 2.8 MHz, CH 3 − C), 2.78 (3H, s, CH 3 ), 3.23 (4H, t, J = 4.4 MHz, −CH 2 −N− CH 2 −), 3.83 (4H, t, J = 4.0 MHz, −CH 2 −N−CH 2 −), 4.22 (2H, q, C−CH 2 −O), 7.08 (2H, d, J = 7.2 MHz, Ar−H), 7.16 (2H, d, J = 7.2 MHz, Ar−H), 7.55 (1H, d, J = 7.6 MHz, Ar−H), 7.94 (1H, d, J = 6.4 MHz, Ar−H), 8.35 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3352 (NH), 1687 (C=O ester), 1704 (C=O amide), 1312, 1134 (SO 2 ); [M + ]: 465.11. Calcd. (%) for C 21 H 24 ClN 3 O 5 S: C, 54.13; H, 5.19; Cl, 7.61; N, 9.02, S, 6.88. Found: C, 54.13; H, 5.12; Cl, 7.63; N, 9.03, S, 6.85.
- Ethyl-4-(3-(N-(3-chlorophenyl)sulfamoyl)-4-methylbenzoyl) piperazine-1-carboxylate (5f)
White solid; Yield: 82%, m.p. 162−165 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.34 (3H, t, J = 2.4 MHz, CH 3 −C), 2.77 (3H, s, CH 3 ), 3.19 (4H, t, J = 4.0 MHz, −CH 2 − N−CH 2 −), 3.78 (4H, t, J = 4.8 MHz, −CH 2 −N−CH 2 −), 4.21 (2H, q, C−CH 2 −O), 7.05 (1H, d, J = 6.4 MHz, Ar−H), 7.18 (1H, t, J = 7.2 MHz, Ar−H), 7.35 (1H, d, J = 7.6 MHz, Ar−H), 7.58 (1H, s, Ar−H), 7.83 (1H, d, J = 7.2 MHz, Ar−H), 7.92 (1H, d, J = 6.4 MHz, Ar−H), 8.31 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3344 (NH), 1687 (C=O ester), 1701 (C=O amide), 1352, 1157 (SO 2 ); [M + ]: 465.11. Calcd. (%) for C 21 H 24 ClN 3 O 5 S: C, 54.13; H, 5.19; Cl, 7.61; N, 9.02, S, 6.88. Found: C, 54.14; H, 5.19; Cl, 7.62; N, 9.03, S, 6.88.
- Ethyl-4-(3-(N-(4-fluorophenyl)sulfamoyl)-4-methylbenzoyl) piperazine-1-carboxylate (5g)
White solid; Yield: 77%, m.p. 123−124 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.28 (3H, t, J = 4.0 MHz, CH 3 −C), 2.71 (3H, s, CH 3 ), 3.19 (4H, t, J = 4.8 MHz, −CH 2 − N−CH 2 −), 3.81 (4H, t, J = 4.4 MHz, −CH 2 −N−CH 2 −), 4.20 (2H, q, C−CH 2 −O), 7.07 (2H, d, J = 7.2 MHz, Ar−H), 7.18 (2H, d, J = 7.1 MHz, Ar−H), 7.54 (1H, d, J = 7.6 MHz, Ar−H), 7.93 (1H, d, J = 6.2 MHz, Ar−H), 8.31 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3353 (NH), 1688 (C=O ester), 1701 (C=O amide), 1345, 1136 (SO 2 ); [M + ]: 449.51. Calcd. (%) for C 21 H 24 FN 3 O 5 S: C, 56.11; H, 5.39; F, 4.23; N, 9.35, S, 7.13. Found: C, 56.13; H, 5.40; F, 4.23; N, 9.36, S, 7.15.
- Ethyl-4-(3-(N-(3-fluorophenyl)sulfamoyl)-4-methylbenzoyl) piperazine-1-carboxylate (5h)
White solid; Yield: 78%, m.p. 194−196 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.31 (3H, t, J = 4.4 MHz, CH 3 −C), 2.72 (3H, s, CH 3 ), 3.14 (4H, t, J = 4.8 MHz, −CH 2 − N−CH 2 −), 3.73 (4H, t, J = 4.0 MHz, −CH 2 −N−CH 2 −), 4.20 (2H, q, C−CH 2 −O), 7.05 (1H, d, J = 7.2 MHz, Ar−H), 7.18 (1H, t, J = 6.8 MHz, Ar−H), 7.31 (1H, d, J = 7.2 MHz, Ar−H), 7.59 (1H, s, Ar−H), 7.84 (1H, d, J = 6.4 MHz, Ar−H), 7.99 (1H, d, J = 6.8 MHz, Ar−H), 8.31 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3344 (NH), 1687 (C=O ester), 1701 (C=O amide), 1352, 1157 (SO 2 ); [M + ]: 449.51. Calcd. (%) for C 21 H 24 FN 3 O 5 S: C, 56.11; H, 5.39; F, 4.23; N, 9.35, S, 7.13. Found: C, 56.13; H, 5.40; F, 4.23; N, 9.36, S, 7.15.
- Ethyl-4-(4-methyl-3-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)- 4-methylbenzoyl)piperazine-1-carboxylate (5i)
White solid; Yield: 54%, m.p. 169−171 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.33 (3H, t, J = 4.0 MHz, CH 3 −C), 2.77 (3H, s, CH 3 ), 3.23 (4H, t, J = 4.2 MHz, −CH 2 − N−CH 2 −), 3.86 (4H, t, J = 4.4 MHz, −CH 2 −N−CH 2 −), 4.26 (2H, q, C−CH 2 −O), 7.12 (2H, d, J = 4.8 MHz, Ar−H), 7.34 (2H, d, J = 7.1 MHz, Ar−H), 7.58 (1H, d, J = 6.8 MHz, Ar− H), 7.99 (1H, d, J = 6.4 MHz, Ar−H), 8.34 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3353 (NH), 1685 (C=O ester), 1701 (C=O amide), 1334, 1142 (SO 2 ); [M + ]: 499.21. Calcd. (%) for C 22 H 24 F 3 N 3 O 5 S: C, 52.90; H, 4.84; F, 11.41; N, 8.41, S, 6.42. Found: C, 52.91; H, 4.84; F, 11.43; N, 8.41, S, 6.42.
- Ethyl-4-(4-methyl-3-(N-(3-(trifluoromethyl)phenyl)sulfamoyl)- 4-methylbenzoyl)piperazine-1-carboxylate (5j)
White solid; Yield: 59%, m.p. 175−177 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.34 (3H, t, J = 12.8 MHz, CH 3 − C), 2.79 (3H, s, CH 3 ), 3.19 (4H, t, J = 4.8 MHz, −CH 2 −N− CH 2 −), 3.72 (4H, t, J = 4.0 MHz, −CH 2 −N−CH 2 −), 4.23 (2H, q, C−CH 2 −O), 7.08 (1H, d, J = 4.4 MHz, Ar−H), 7.19 (1H, t, J = 7.2 MHz, Ar−H), 7.39 (1H, d, J = 7.6 MHz, Ar−H), 7.62 (1H, s, Ar−H), 7.80 (1H, d, J = 6.4 MHz, Ar−H), 7.99 (1H, d, J = 8.4 MHz, Ar−H), 8.33 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3342 (NH), 1688 (C=O ester), 1703 (C=O amide), 1356, 1153 (SO 2 ); [M + ]: 499.21. Calcd. (%) for C 22 H 24 F 3 N 3 O 5 S: C, 52.90; H, 4.84; F, 11.41; N, 8.41, S, 6.42. Found: C, 52.92; H, 4.84; F, 11.43; N, 8.42, S, 6.43.
- Ethyl-4-(4-methyl-3-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)- 4-methylbenzoyl)piperazine-1-carboxylate (5k)
White solid; Yield: 61%, m.p. 140−143 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.28 (3H, t, J = 4.0 MHz, CH 3 −C), 2.64 (3H, s, CH 3 ), 3.16 (4H, t, J = 4.4 MHz, −CH 2 − N−CH 2 −), 3.72 (4H, t, J = 4.0 MHz, −CH 2 −N−CH 2 −), 4.24 (2H, q, C−CH 2 −O), 7.09 (1H, d, J = 7.1 MHz, Ar−H), 7.20 (1H, t, J = 7.1 MHz, Ar−H), 7.31 (1H, t, J = 7.3 MHz, Ar−H), 7.48 (1H, d, J = 6.4 MHz, Ar−H), 7.82 (1H, d, J = 8.4 MHz, Ar−H), 7.99 (1H, d, J = 7.6 MHz, Ar−H), 8.34 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3346 (NH), 1684 (C=O ester), 1705 (C=O amide), 1357, 1163 (SO 2 ); [M + ]: 499.21. Calcd. (%) for C 22 H 24 F 3 N 3 O 5 S: C, 52.90; H, 4.84; F, 11.41; N, 8.41, S, 6.42. Found: C, 52.90; H, 4.84; F, 11.43; N, 8.42, S, 6.41.
- Ethyl-4-(4-methyl-3-(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)- 4-methylbenzoyl)piperazine-1-carboxylate (5l)
White solid; Yield: 68%, m.p. 186−187 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.35 (3H, t, J = 4.0 MHz, CH 3 −C), 2.78 (3H, s, CH 3 ), 3.35 (4H, t, J = 4.8 MHz, −CH 2 − N−CH 2 −), 3.87 (4H, t, J = 4.4 MHz, −CH 2 −N−CH 2 −), 4.25 (2H, q, C−CH 2 −O), 6.78 (2H, d, J = 7.2 MHz, Ar−H), 6.99 (2H, d, J = 6.4 MHz, Ar−H), 7.58 (1H, d, J = 4.8 MHz, Ar−H), 7.92 (1H, d, J = 6.8 MHz, Ar−H), 8.30 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3352 (NH), 1687 (C=O ester), 1704 (C=O amide), 1348, 1137 (SO 2 ); [M + ]: 515.12. Calcd. (%) for C 22 H 24 F 3 N 3 O 6 S: C, 51.25; H, 4.69; F, 11.06; N, 8.15, S, 6.22. Found: C, 51.23; H, 4.70; F, 11.05; N, 8.16, S, 6.23.
- Ethyl-4-(4-methyl-3-(N-(3-(trifluoromethoxy)phenyl)sulfamoyl)- 4-methylbenzoyl)piperazine-1-carboxylate (5m)
White solid; Yield: 72%, m.p. 175−176 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.32 (3H, t, J = 4.4 MHz, CH 3 −C), 2.73 (3H, s, CH 3 ), 3.17 (4H, t, J = 4.0 MHz, −CH 2 − N−CH 2 −), 3.78 (4H, t, J = 4.0 MHz, −CH 2 −N−CH 2 −), 4.26 (2H, q, C−CH 2 −O), 6.78 (1H, d, J = 6.4 MHz, Ar−H), 6.95 (1H, t, J = 7.1 MHz, Ar−H), 7.05 (1H, d, J = 7.6 MHz, Ar−H), 7.25 (1H, s, Ar−H), 7.83 (1H, d, J = 4.8 MHz, Ar−H), 8.02 (1H, d, J = 7.2 MHz, Ar−H), 8.33 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3348 (NH), 1685 (C=O ester), 1703 (C=O amide), 1354, 1156 (SO 2 ); [M + ]: 515.12. Calcd. (%) for C 22 H 24 F 3 N 3 O 6 S: C, 51.25; H, 4.69; F, 11.06; N, 8.15, S, 6.22. Found: C, 51.24; H, 4.73; F, 11.05; N, 8.13, S, 6.22.
- Ethyl-4-(4-methyl-3-(N-(2-(trifluoromethoxy)phenyl)sulfamoyl)- 4-methylbenzoyl)piperazine-1-carboxylate (5n)
White solid; Yield: 648%, m.p. 138−140 ℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 1.32 (3H, t, J = 12.8 MHz, CH 3 −C), 2.70 (3H, s, CH 3 ), 3.18 (4H, t, J = 4.4 MHz, −CH 2 − N−CH 2 −), 3.73 (4H, t, J = 4.8 MHz, −CH 2 −N−CH 2 −), 4.24 (2H, q, C−CH 2 −O), 6.86 (1H, d, J = 4.0 MHz, Ar−H), 6.97 (1H, t, J = 7.1 MHz, Ar−H), 7.11 (1H, t, J = 7.3 MHz, Ar−H), 7.34 (1H, d, J = 6.4 MHz, Ar−H), 7.82 (1H, d, J = 7.2 MHz, Ar−H), 7.99 (1H, d, J = 8.0 MHz, Ar−H), 8.34 (1H, s, Ar−H); IR (KBr) ν (cm −1 ): 3342 (NH), 1684 (C=O ester), 1703 (C=O amide), 1356, 1162 (SO 2 ); [M + ]: 515.12. Calcd. (%) for C 22 H 24 F 3 N 3 O 6 S: C, 51.25; H, 4.69; F, 11.06; N, 8.15, S, 6.22. Found: C, 51.25; H, 4.71; F, 11.06; N, 8.16, S, 6.23.
RESULTS AND DISCUSSION
Bifunctional sulfonamide-amide derivaties ( 5a−n ) were synthesized by expedient synthetic route is outlined in 1 . The compound 3 was obtained by the reaction of 4-methylbenzoic acid ( 1 ) with ethylpiperazine-1-carboxylate ( 2 ) by a standard amide (Et 3 N-HOBT-EDC) coupling procedure, 33 which was consequently converted into ethyl-4-(3-(chlorosulfonyl)-4-methylbenzoyl)piperazine- 1-carboxylate ( 4 ), by adding chlorosulfonic acid. This compound was permitted to react with various anilines in CH 2 Cl 2 to afford the title compounds 5a−n . The completion of the reaction was monitored by TLC (hexane-ethyl acetate, 70:30). Under these conditions, several anilines were effectively and quantitatively coupled with 4-methyl benzoic acid proving the efficiency of this method. Simple workup, along with the good yields of the products and also the mild reaction conditions pramoted us to apply this method for the synthesis of bifunctional sulfonamide-amide derivaties ( 5a−n ). All synthesized compounds were deduced from their elemental analyses, IR, 1 H NMR and Mass spectral data.
PPT Slide
Lager Image
Ra = 4-CH3C6H4, b = 3-CH3C6H4, c = 4-OCH3C6H4, d = 3-OCH3C6H4, e = 4-ClC6H4, f = 3-ClC6H4, g= 4-FC6H4, h = 3-FC6H4, i = 4-CF3C6H4, j = 3-CF3C6H4, k = 2-CF3C6H4, l = 4-OCF3C6H4, m = 3-OCF3C6H4, n = 2-OCF3C6H4.
Characteristic IR absorption bands were observed for (NH), (C=O) and (SO 2 ) at 3345, 1735, 1354 and 1145 cm −1 , respectively. The aromatic hydrogens resonated at d 6.78− 8.45. The structure was further confirmed by mass spectral studies.
The title compounds 5a−n was further confirmed by the treatment of 4-methylbenzoic acid with chlorosulfonic acid to yielded sulfonyl chloride 6 . Reaction of 6 with varies anilines under standard conditions to give 7a−n and finally the 7a−n converted into sulfonamide-amide derivatives with ethylpiperazin-1-carboxylate ( 2 ) ( 2 ).
PPT Slide
Lager Image
ANTIBACTERIAL ACTIVITY
The sulfonamide and amide derivatives known to be more potent antimicrobial agents. 10 23 24 All the compounds synthesized in the current study (5a through 5n ) were, therefore, screened for their antibacterial activity with respect to human pathogenic bacteria such as Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Streptococcus faecalis , and Propionibacterium acnes . The minimum inhibition concentration was determined using the dilution method. 34 DMF was used as a blank and ciprofloxacin as standard, and the results are presented in 1 . An examination of the data expose that all the compounds showed antibacterial activity ranging from 0.14 to 6.74 μg/mL −1 . Of the compounds 5d to 5f and 5l to 5n exhibited potent antimicrobial activity followed the order: 5n > 5m > 5l > 5e > 5f > 5d . The results clearly indicate that the existence of methoxy/chloro/trifluoromethoxy group at the phenyl ring enhances the antimicrobial activity.
ANTIFUNGAL ACTIVITY
The compounds 5a−n were screened also for their antifungal activity ( 1 ) against Candida albicans and Aspergillus niger using fungicide fuuconazole in DMF as the standard. 35 All the compounds exhibited diffident to high-antifungal activity when compared with that of the reference compound. Most of the compounds exerted high activity against the tested fungi.
In vitro antimicrobial activity of compounds5a−n
PPT Slide
Lager Image
In vitro antimicrobial activity of compounds 5a−n
CONCLUSIONS
We have synthesized original derivatives of bifunctional sulfonamide-amide analogues by predictable methods. Among the synthesized compounds, almost all compounds showed good activity against bacteria and fungi and emerged as potential molecules for advance development.
Acknowledgements
The publication cost of this paper was supported by the Korean Chemical Society.
References
Smil D. , Leit S. , Ajamian A. , Allan M. , Chantigny Y. A. , Déziel R. , Therrien E. , Wahhab A. , Manku S. 2007 WO 07/143822 International Patent
Ekhato1 I. V. , Liao Y. , Plesescu M. 2004 J. Labelled Compd. Radiopharm. 47 821 -    DOI : 10.1002/jlcr.870
Stachel S. J. 2004 J. Med. Chem. 47 6447 -    DOI : 10.1021/jm049379g
Elliot D. 2009 Bioorg. Med. Chem. Lett. 19 4832 -    DOI : 10.1016/j.bmcl.2009.06.041
Zhao Z. 2009 Bioorg. Med. Chem. Lett. 19 1488 -    DOI : 10.1016/j.bmcl.2008.12.115
Steinmetzer T. 2006 J. Med. Chem. 49 4116 -    DOI : 10.1021/jm051272l
Pippel M. , Allison B. D. , Phuong V. K. , Li L. , Morton M. F. , Prendergast C. , Wu X. , Shankley N. P. , Rabinowitz M. H. 2009 Bioorg. Med. Chem. Lett. 19 6376 -    DOI : 10.1016/j.bmcl.2009.09.065
Murray P. J. , Kay C. , Scicinski J. J. , McKeown S. , Watson S. P. , Car R. A. E. 1999 Tetrahedron Lett. 40 5609 -    DOI : 10.1016/S0040-4039(99)01042-4
Sammes P. G. 1990 In Comprehensive Medicinal Chemistry; Hansch, C., Sammes, P. G., Taylor, J. B., Eds.; Chapter 7.1. Pergamon Press Oxford, UK
Connor E. E. 1998 Sulfonamide Antibiotics Prim. Care Update OB/GYNS 5 32 -    DOI : 10.1016/S1068-607X(97)00121-2
Kleemann A. , Engel J. , Kutscher B. , Reichert D. 1999 Pharmaceutical Substance: Syntheses, Patents, Applications, Stuttgart Guide 2nd ed Oxford Press Thieme
Wilkinson B. L. , Bornaghi L. F. , Houston T. A. , Innocenti A. , Vullo C. , Supuran C. T. , Poulsen S. A. 2007 J. Med. Chem. 50 1651 -    DOI : 10.1021/jm061320h
Almansa C. 2004 J. Med. Chem. 47 5579 -    DOI : 10.1021/jm040844j
Chu W. , Rothfuss J. , d'Avignon A. , Zeng C. , Zhou D. , Hotchkiss R. S. , Mach R. H. 2007 J. Med. Chem. 50 3751 -    DOI : 10.1021/jm070506t
Gopalsamy A. 2008 J. Med. Chem. 51 7670 -    DOI : 10.1021/jm801069w
Yates M. H. , Kallman N. J. , Ley C. P. , Wei J. N. 2009 Org. Process Res. Dev. 13 255 -    DOI : 10.1021/op800210x
Cloudsdale I. S. , Anderson R. J. , Chinn H. R. , Craig G. W. , Deng L. , Herberich-Patton P. N. , Pomes J. C. Herbicidal Sulfonylamides: Synthesis and Chemistry of Agrochemicals IV ACS Symposium Series 584 37 -
Pattabiraman V. R. , Bode J. W. 2011 Nature 480 471 -    DOI : 10.1038/nature10702
Soule J.-F. , Miyamura H. , Kobayashi S. 2011 J. Am. Chem. Soc. 133 18550 -    DOI : 10.1021/ja2080086
Yamaguchi K. , Kobayashi H. , Oishi T. , Mizuno N. 2011 Angew. Chem. Int. Ed. 51 544 -
Allen C. L. , Chhatwal A. R. , Williams J. M. J. 2012 Chem. Commun. 48 666 -    DOI : 10.1039/c1cc15210f
Hassan Z. , Suroor A. K. 2012 Eu. J. Med. Chem. 58 206 -    DOI : 10.1016/j.ejmech.2012.10.002
Uludag M. O. , Caliskan Ergun B. , Alkani D. A. , Ercani N. , Ozkan G. , Banoglu E. 2011 Turk. J. Chem. 35 427 -
Bao-Lei W. 2013 J. Agric. Food Chem. 61 5483 -    DOI : 10.1021/jf4012467
Graybill T. L. , Ross M. J. , Gauvin B. R. , Gregory J. S. , Harris A. L. , Ator M. A. , Rinker J. M. , Dolle R. E. 1992 Bioorg. Med. Chem. Lett. 1375 -
Inceler N. , Yilmaz A. , Baytas S. N. 2013 Med. Chem. Res. 22 3109 -    DOI : 10.1007/s00044-012-0317-2
Banerji B. , Mallesham B. , Kiran Kumar S. , Kunwar A. C. , Iqbal J. 2002 Tetrahedron Lett. 43 6479 -    DOI : 10.1016/S0040-4039(02)01239-X
Frakels R. , Sonnenwirth A. C. 1970 Clinical Laboratory Method and Diagnosis 7th ed. Cv Mosby Company Germany
1953 British Pharmacopoeia Pharmaceutical Press London