Three series of substituted sydnone sulfonamide derivatives were synthesized wherein 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone (5) was linked by a sulfonamide linkage with various thiazole, benzothiazole and quinazoline groups. The structures of the compounds were confirmed by IR and NMR spectroscopy and elemental analysis. The synthesized compounds were evaluated for their antibacterial, antifungal, antiproliferative and anti-HIV activities. Anti-HIV activity was determined against human immunodeficiency virus HIV-1 (III-B) and HIV-2 (ROD) in MT-4 cells. Inhibition of cytomegalovirus and varicella-zoster virus (VZV) replication was measured in human embryonic lung (HEL) cells.
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Introduction
Thiazole, benzothiazole and quinazoline are among the most versatile heterocyclic groups which play an important role in synthetic and pharmaceutical chemistry [1–5]. Sydnones are interesting series of mesoionic heterocycles having vast range of various biological and synthetic applications [6–8]. The hydrogen atom at C4 of sydnone ring underwent substitution with a variety of electrophiles [9]. Consequently, the synthesis of these sydnones comprising sulfonamide linkage is of continuing interest and a prerequisite for the development of new drugs in the field. Combination of sydnone ring with thiazole, benzothiazole and quinazolines by sulfonamide linkage at C4 might lead to the creation of further efficient compounds. The present article reports the synthesis of new sydnone sulfonamides and determination of their antibacterial, antifungal, antiproliferative, and anti-HIV activity.
Experimental Chemical Part
Melting points were determined by the open capillary method and are uncorrected. Elemental analyses were carried out on a Heraeus Carlo Erba 1180 CHN analyzer. All compounds were analyzed satisfactorily for C, H, and Ncontent. The infrared (IR) spectra were scanned on a Thermo Scientific Nicolet iS10 FT-IR spectrometer. NMR spectra were recorded on Brucker Avance II NMR spectrometer. Chemical shifts (δ) refer to internal tetramethylsilane (TMS). Thin layer chromatography (TLC) was performed on E-Merck pre-coated 60 F254 plates and the spots were rendered visible by exposing the plates to UV light.
Results and Discussion
In our previous work, we have synthesized several sydnone derivatives and evaluated their antibacterial activity [10]. To continue our efforts in this area, the present article describes the synthesis of sydnone sulfonamide derivatives and their antibacterial, antifungal, anti-HIV, and anticancer activity against some important species.
3-(4-Methylphenyl)sydnone (4) has been synthesized using a four-step procedure starting from 4-methylaniline according to Fig. 1 by undergoing esterification, hydrolysis, nitrosation and cyclization [11]. The mechanism of sydnone ring formation is depicted in Fig. 1.
Mechanism of formation of a sydnone ring.
Compound 4 undergoes chlorosulfonation to get sulfonylchloride derivative which, when treated with different thiazole, benzothiazole and quinazoline derivatives, yields the corresponding sulfonamide derivatives (13 – 15).
The structures of newly synthesized compounds were confirmed by IR and NMR spectroscopy. The IR spectra of the newly synthesized compounds show bands near 1750 cm−1 for C=O group of sydnone ring. The absorption bands between 1392 – 1349 and 1177 – 1170 cm−1 represent the characteristic SO2asym and SO2sym vibrations, respectively. The C-S-C and C-N bonds of thiazole and benzothiazole show bands near 690 – 734 and 1628 – 1663 cm−1, respectively, whereas C-N and C=O bonds of quinazoline show absorption between 1590 – 1612 and 1660 – 1674 cm−1, respectively. Furthermore, 1H NMR spectra of compounds 13 – 15 show confirmatory signals near δ = 10.00 ppm for sulfonamide linkage, and 13C NMR spectra show verification signals for carbonyl carbon of sydnone ring near δ = 168 ppm. The compounds showed modest activity against bacteria and fungi and no specific activity against CMV, VZV or HIV.
General Procedure for the Synthesis of 3-(4-Methylphenyl)-4-(chlorosulfonyl)sydnones (5)
Chlorosulfonic acid (0.66 mL, 0.01 mol) was added dropwise into the mixture of 3-(4-methylphenyl)sydnone (1.76 g, 0.01 mol) and catalytic amount of phosphorous pentoxide (P2O5) over 30 min with constant stirring at 0 – 5 °C. The temperature of the well-stirred mixture did not rise above 5 °C. When all the chlorosulfonic acid had been added, the mixture was refluxed at about 60 °C for about 1 h. Then, the solution was poured into a mixture of crushed ice and water with vigorous stirring. The precipitate was collected by filtration, washed with water, dried, and recrystallized from ethanol (Fig. 2). Yield, 3.94 g (74 %); m.p., 122 – 124°C.
Synthesis of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone.
Synthesis of 4-(substituted phenyl)-1,3-thiazol-2-amines (8). Bromine (0.025 mol) in chloroform (20 mL) was added dropwise to a solution of substituted phenylethanone (0.01 mol) in chloroform (20 mL) at room temperature and the solution was then stirred for about 12 hours until complete disappearance of bromine in the solution. Precipitates of 2,2-dibromo-1-(substituted phenyl)ethanone (6) were formed. The precipitates were washed with 10 % sodium bisulfite solution and recrystallized from methanol. To a solution of 2,2-dibromo-1-(substituted phenyl)ethanone in ethanol (0.01 mol) was added thiourea (0.76 g, 0.01 mol) in ethanol and the reaction mixture was stirred for about 1 h. The solid product was separated and recrystallized from ethanol (Fig. 3).
Synthesis of 4-(substituted phenyl)-1,3-thiazol-2-amines 6a – 6j.
2-Amino-(6-substituted)benzothiazoles (10a – 10g)
To a well stirred solution of 4-substituted aniline (0.01 mol) and potassium thiocyanate (3.88 g, 0.04 mol) in glacial acetic acid (30 mL), a solution of bromine (0.52 mL, 0.01 mol) dissolved in glacial acetic acid (25 mL) was added dropwise over a period of 5 h. The temperature of the reacting mixture was kept below 35 °C. After all bromine had been added, the reaction mixture was stirred for 12 hour at this temperature and filtered. The filtrate was neutralized with ammonium hydroxide. The precipitate was collected and filtered. The product was washed with cold water.
2-Amino-(4/5-substituted)benzothiazoles (10h – 10j).
Compounds 10h – 10j were synthesized according to a two-step procedure described below. First, 1-(2/3-substituted phenyl)thioureas (9) were synthesized from a mixture of 2/3-substituted aniline (0.01 mol), ammonium thiocyanate (0.91 g, 0.012 mol) and sodium hydrogen sulfite (0.07 g) was dissolved in 20 % hydrochloric acid (3.0 mL) and heated at 90 °C for 14 hours. The cooled mixture was filtered, washed with water till neutral and dried to give 1-(2/3-substituted phenyl)thiourea.
Then, a solution of bromine (7 mL, 0.136 mol) in chloroform (10 mL) was added dropwise to a stirred suspension of 1-(2/3-substituted phenyl)thiourea (0.068 mol) in chloroform (130 mL). The reaction mixture was refluxed for 2.5 hours and allowed to stand at room temperature for 12 hours. The residue was treated with dilute ammonium hydroxide solution. Finally, the solid product was filtered and recrystallized from chloroform to yield 2-amino-(4/5-substituted)benzothiazoles 10h – 10j (Fig. 4).
Synthesis of 2-amino-substituted benzothiazoles 10.
Synthesis of 3-(4-aminophenyl)-2-(substituted phenyl)quinazolin-4(3H)-ones (12). To a stirred solution of 2-aminobenzoic acid (1.37 g, 0.01 mol) in pyridine (15 mL), a solution of substituted acid chloride (0.015 mol) in pyridine (15 mL) was added dropwise, while the temperature was maintained at 0 – 5 °C for 2 hour. Then, the reaction mixture was stirred for another 2 hours at room temperature. The whole reaction mixture was neutralized with 10% sodiumbicarbonate solution. The solid product was separated and filtered off, washed with water, and recrystallized from benzene.
A solution of 2-(substituted phenyl)-4H-3,1-benzoxazin-4-one (0.01 mol) and 4-phenylenediamine (1.08 g, 0.01 mol) in pyridine (20 mL) was refluxed for 6 hours. After cooling, the solution was poured over ice to obtain compounds 12a – 12j, which were recrystallized from ethanol (Fig. 5).
Synthesis of 3-(4-aminophenyl)-2-(substitutedphenyl)quinazolin-4(3H)-ones 12.
General Procedure for the Synthesis of Compounds 13 – 15
A solution of appropriate thiazole, benzothiazole and quinazoline derivatives (0.01 mol) in acetone was added dropwise to 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone (3.02 g, 0.011 mol) in acetone over a period of 5 hours with constant stirring. Pyridine (1 mL) was added to the well stirred solution after 1 and 2 h. Finally, the solution was poured onto ice with stirring. The precipitate was collected by filtration, washed with water, dried, and recrystallized from ethanol (Figure 6).
Synthesis of thiazole, benzothiazole and quinazoline substituted sydnone sulfonamides: (13a) R = 4-Br; ( 13b) R = 4-Cl; (13c) R = 4-OCH3; (13d) R = 4-CH3; (13e) R = 4-NO2 ;(13f) R = 4-O(CH2)3CH3; (13g) R = 2,4-F; (13h) R = 2,4-Cl; (13i) R = 2,4-Cl-6-F; (13j) R = 2,6-Cl; (14a) R = 6-CH3; (14b) R = 6-OCH3; (14c) R = 6-Cl; ( 14d) R = 6-Br; (14e) R = 6-NO2; (14f) R = 6-F; (14g) R = 6-OCH2CH3; (14h) R = 5-Cl; (14i) R = 5-CH3; (14j) R = 4-NO2; (15a) R = H; (15b) R = 4-NO2; (15c) R = 4-OCH3; ( 15d) R = 4-Cl; (15e) R = 3-NO2; (15f) R = 3-Cl; (15g) R = 3-Br; (15h) R = 2-NO2; (15i) R = 2-Cl; (15j) R = 2-Cl-6-NO2; (15k) R = 3-NO2-4-OCH3.
Physicochemical characteristics of compounds 13 – 15 are as follows:
4-{[4-(4-Bromophenyl)-1,3-thiazol-2-yl]sulfamoyl}-3-(4-methylphenyl)sydnone (13a): IR (KBr; ν, cm-1): 3285 (N-H), 2980 (CH3), 1738 (CO sydnone), 1634 (C-N thiazole), 1392 (SO2), 1177 (SO2), 713 (C-S-C thiazole), 596 (Br); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.47 (s, 3H, CH3), 7.36 – 8.00 (m, 9H, Ar-H), 9.73 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.59, 108.73, 121.74, 124.53, 127.66, 132.40, 132.66, 133.85, 136.73, 139.06, 142.66, 153.00, 175.20, 168.54
4-{[4-(4-Chlorophenyl)-1,3-thiazol-2-yl]sulfamoyl}-3-(4-methylphenyl)sydnone (13b): IR (KBr; ν, cm-1): 3266 (N-H), 2960 (CH3 stretching), 1751 (C=O sydnone), 1607 (C-N thiazole), 1346 (SO2), 1175 (SO2), 817 (Cl), 705 (C-S-C thiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.60 (s, 3H, CH3), 7.10 – 7.90 (m, 9H, Ar-H), 9.80 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.69, 108.64, 123.64, 127.86, 130.11, 132.67, 135.53, 135.84, 136.38, 139.54, 141.70, 153.10, 175.27, 168.33
4-{[4-(4-Methoxyphenyl)-1,3-thiazol-2-yl]sulfamoyl}-3-(4-methylphenyl)sydnone (13c): IR (KBr; ν, cm−1): 3244 (N-H), 2964 (CH3 stretching), 1746 (C=O sydnone), 1615 (C-N thiazole), 1347 (SO2), 1253 (COC), 1170 (SO2), 1045 (COC), 707 (C-S-C thiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.48 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 9.77 (s, 1H, SO2NH), 7.28 – 8.15 (m, 9H, Ar-H); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.63, 56.25, 108.42, 112.78, 123.83, 130.00, 132.62, 135.73, 136.78, 138.78., 140.93, 153.84, 161.11, 175.23, 168.49
4-{[4-(4-Methylphenyl)-1,3-thiazol-2-yl]sulfamoyl}-3-(4-methylphenyl)sydnone (13d): IR (KBr; ν, cm−1): 3258 (N-H), 2960 (CH3 stretching), 1755 (C=O sydnone), 1607 (C-N thiazole), 1349 (SO2), 1175 (SO2), 712 (C-S-C thiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.67 (s, 3H, CH3), 2.58 (s, 3H, CH3), 7.18 – 8.60 (m, 9H, Ar-H), 9.76 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.59, 21.86, 108.76, 121.90, 128.19, 130.73, 132.64,133.63, 134.73, 139.12, 140.52, 142.84, 151.69, 175.10, 169.06
4-{[4-(4-Nitrophenyl)-1,3-thiazol-2-yl]sulfamoyl}-3-(4-methylphenyl)sydnone (13e): IR (KBr; ν, cm−1): 3245 (NH), 2960 (CH3), 1751 (CO sydnone), 1629 (C-N thiazole), 1591 (NO2), 1359 (SO2), 1325 (NO2), 1174 (SO2), 693 (C-S-C thiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.20 (s, 3H, CH3), 7.25 – 7.95 (m, 9H, Ar-H), 8.90 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.43, 106.55, 123.31, 123.50, 126.88, 130.64, 136.58, 138.64, 140.00, 142.90, 148.37, 152.80, 175.70, 167.27
4-{[4-(4-Butoxyphenyl)-1,3-thiazol-2-yl]sulfamoyl}-3-(4-methylphenyl)sydnone (13f): IR (KBr; ν, cm-1): 3250 (N-H), 2964 (CH3 stretching), 2925 (CH2), 1747 (C=O sydnone), 1610 (C-N thiazole), 1255 (COC), 1345 (SO2), 1174 (SO2), 1047 (COC), 710 (C-S-C thiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 1.20 (t, 3H, CH 3 CH2CH2CH2O), 1.30-1.74 (m, 4H, CH3 CH 2 CH 2 CH2O), 2.45 (s, 3H, CH3), 4.13 (t, 2H, CH3CH2CH2 CH 2 O), 7.00-7.78 (m, 9H, Ar-H), 9.95 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 14.25, 20.55, 21.44, 30.74, 68.90, 109.07, 113.74, 123.95, 130.00, 130.73, 135.60, 136.47, 139.53, 142.75, 162.79, 153.08, 175.39, 168.96
4-{[4-(2,4-Difluorophenyl)-1,3-thiazol-2-yl]sulfamoyl}-3-(4-methylphenyl)sydnone (13g): IR (KBr; ν, cm-1): 3290 (N-H), 2963 (CH3), 1749 (CO sydnone), 1638 (C-N thiazole), 1338 (SO2), 1261 (F), 1164 (SO2), 729 (C-S-C thiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.30 (s, 3H, CH3), 7.31-8.12 (m, 8H, Ar-H), 10.00 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.52, 102.47, 108.22, 114.78, 117.73, 126.36, 123.70, 132.38, 136.37, 138.60, 140.53, 154.60, 159.83, 162.63, 175.10, 167.90
4-{[4-(2,4-Dichlorophenyl)-1,3-thiazol-2-yl]sulfamoyl}-3-(4-methylphenyl)sydnone (13h): IR (KBr; ν, cm-1): 3270 (N-H), 2964 (CH3 stretching), 1746 (C=O sydnone), 1610 (C-N thiazole), 1343 (SO2), 1170 (SO2), 812 (Cl), 712 (C-S-C thiazole) cm-1; 1H NMR (400 MHz, CDCl3; δ, ppm): 2.46 (s, 3H, CH3), 7.16-7.92 (m, 8H, Ar-H), 9.90 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.48, 108.42, 121.57, 127.38, 128.06, 128.74, 129.64, 132.50, 134.20, 136.63, 135.00, 139.66, 142.37,154.68, 173.90, 168.47
4-{[4-(2,4-Dichloro-6-fluorophenyl)-1,3-thiazol-2-yl]sulfamoyl}-3-(4-methylphenyl) sydnone (13i): IR (KBr; ν, cm-1): 3275 (N-H), 2960 (CH3 stretching), 1748 (C=O sydnone), 1614 (C-N thiazole), 1353 (SO2), 1255 (F), 1164 (SO2), 800 (Cl), 730 (C-S-C thiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.44 (s, 3H, CH3), 6.80-7.75 (m, 8H, Ar-H), 9.88 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.85, 108.70, 118.72, 121.96, 129.85, 131.30, 131.85, 132.61, 132.84, 136.38, 139.32, 141.68, 154.15, 161.68, 175.40, 168.73
4-{[4-(2,6-Dichlorophenyl)-1,3-thiazol-2-yl]sulfamoyl}-3-(4-methylphenyl)sydnone (13j): IR (KBr; ν, cm-1): 3263 (N-H), 2957 (CH3 stretching), 1745 (C=O sydnone), 1614 (C-N thiazole), 1350 (SO2), 1174 (SO2), 810 (Cl), 717 (C-S-C thiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.50 (s, 3H, CH3), 7.46-7.96 (m, 8H, Ar-H), 10.12 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.69, 108.47, 121.16, 130.18, 131.48, 132.10, 132.86, 133.46, 136.65, 139.55, 140.78, 154.74, 175.00, 169.36
4-[(6-Methyl-1,3-benzothiazol-2-yl)sulfamoyl]-3-(4-methylphenyl)sydnone (14a): IR (KBr; ν, cm-1): 3280 (N-H), 2956 (CH3), 1746 (CO sydnone), 1360 (SO2), 1183 (SO2), 690 (C-S-C thiazole), 1636 (C-N benzothiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.50 (s, 3H, CH3), 2.79 (s, 3H, CH3), 6.76-7.80 (m, 7H, Ar-H), 9.53 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.68, 22.18, 119.45, 122.74, 123.20, 128.53, 131.00, 132.56, 134.64, 136.63, 139.63, 142.79, 153.33, 175.83, 168.05
4-[(6-Methoxy-1,3-benzothiazol-2-yl)sulfamoyl]-3-(4-methylphenyl)sydnone (14b): IR (KBr; ν, cm-1): 3274 (N-H), 2961 (CH3), 1750 (CO sydnone), 1356 (SO2), 1235 (COC), 1180 (SO2), 694 (C-S-C thiazole), 1632 (C-N benzothiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.39 (s, 3H, CH3), 4.16 (s, 3H, OCH3), 6.82-7.49 (m, 7H, Ar-H), 9.57 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.60, 57.48, 107.55, 112.96, 119.48, 123.82, 132.50, 132.66, 136.74, 139.33, 140.17, 151.38, 156.62, 175.28, 168.75
4-[(6-Chloro-1,3-benzothiazol-2-yl)sulfamoyl]-3-(4-methylphenyl)sydnone (14c): IR (KBr; ν, cm-1): 3283 (N-H), 2960 (CH3), 1751 (CO sydnone), 1362 (SO2), 1174 (SO2), 812 (Cl), 695 (C-S-C thiazole), 1640 (C-N benzothiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.30 (s, 3H, CH3), 6.90-7.80 (m, 7H, Ar-H), 9.00 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.48, 121.52, 121.63, 123.66, 123.80, 124.97, 132.47, 133.65, 136.59, 138.86, 140.19, 153.58, 175.46, 168.42
4-[(6-Bromo-1,3-benzothiazol-2-yl)sulfamoyl]-3-(4-methylphenyl)sydnone (14d): IR (KBr; ν, cm-1): 3266 (N-H), 2995 (CH3), 1751 (C=O sydnone), 1647 (C-N benzothiazole), 1327 (SO2), 1175 (SO2), 726 (C-S-C benzothiazole), 553 (Br); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.48 (s, 3H, CH3), 7.00-7.73 (m, 7H, Ar-H), 9.63 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.50, 113.69, 121.38, 121.67, 122.74, 129.85, 132.10, 132.31, 136.33, 139.34, 142.56, 153.41, 175.52, 168.04
4-[(6-Nitro-1,3-benzothiazol-2-yl)sulfamoyl]-3-(4-methylphenyl)sydnone (14e): IR (KBr; ν, cm-1): 3271 (N-H), 2983 (CH3), 1745 (C=O sydnone), 1640 (C-N benzothiazole), 1550 (NO2), 1376 (NO2), 1336 (SO2), 1172 (SO2), 733 (C-S-C benzothiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.20 (s, 3H, CH3), 7.25-7.95 (m, 7H, Ar-H), 8.90 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.60, 118.13, 119.63, 120.78, 123.84, 132.37, 132.69, 136.70, 138.53, 140.96, 142.63, 154.00, 175.83, 168.64
4-[(6-Fluoro-1,3-benzothiazol-2-yl)sulfamoyl]-3-(4-methylphenyl)sydnone (14f):
IR (KBr; ν, cm-1): 3278 (N-H), 2983 (CH3), 1745 (C=O sydnone), 1640 (C-N benzothiazole), 1336 (SO2), 1172 (SO2), 1100 (F), 733 (C-S-C benzothiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.40 (s, 3H, CH3), 7.33-7.75 (m, 7H, Ar-H), 10.24 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.38, 108.20, 113.66, 122.89, 123.84, 130.47, 132.85, 135.11, 138.57, 142.83, 153.13, 161.40, 175.34, 168.41
4-[(6-Ethoxy-1,3-benzothiazol-2-yl)sulfamoyl]-3-(4-methylphenyl)sydnone (14g):
IR (KBr; ν, cm-1): 3273 (N-H), 2974 (CH3), 2932 (CH2), 1751 (C=O sydnone), 1663 (C-N benzothiazole), 1345 (SO2), 1267 (C-O-C), 1175 (SO2), 1038 (C-O-C), 726 (C-S-C benzothiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 1.40 (t, 3H, OCH2CH 3 ), 2.45 (s, 3H, CH3), 4.36 (s, 3H, OCH 2 CH3), 6.95-7.54 (m, 7H, Ar-H), 9.55 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 15.43, 21.60, 65.23, 106.55, 112.96, 118.48, 123.82, 132.50, 132.66, 136.74, 138.33, 140.17, 151.38, 154.62, 175.28, 168.51
4-[(5-Chloro-1,3-benzothiazol-2-yl)sulfamoyl]-3-(4-methylphenyl)sydnone (14h):
IR (KBr; ν, cm-1): 3268 (N-H), 2980 (CH3), 2936 (CH2), 1745 (C=O sydnone), 1643 (C-N benzothiazole), 1347 (SO2), 1260 (C-O-C), 1172 (SO2), 1047 (C-O-C), 827 (Cl), 729 (C-S-C benzothiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.40 (s, 3H, CH3), 7.13-7.79 (m, 7H, Ar-H), 10.05 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.72, 120.74, 121.37, 123.84, 125.70, 130.00, 130.70, 131.49, 136.21, 139.00, 140.00, 150.90, 175.82, 168.83
4-[(5-Methyl-1,3-benzothiazol-2-yl)sulfamoyl]-3-(4-methylphenyl)sydnone (14i):
IR (KBr; ν, cm-1): 3270 (N-H), 2977 (CH3), 2942 (CH2), 1750 (C=O sydnone), 1637 (C-N benzothiazole), 1340 (SO2), 1267 (C-O-C), 1177 (SO2), 1030 (C-O-C), 734 (C-S-C benzothiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.48 (s, 3H, CH3), 2.56 (s, 3H, CH3), 7.32-7.85 (m, 7H, Ar-H), 10.26 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.29, 21.68, 120.38, 122.35, 123.73, 124.73, 131.37, 132.68, 136.80, 136.88, 139.32, 142.73, 151.63, 175.21, 168.53
4-[(4-Nitro-1,3-benzothiazol-2-yl)sulfamoyl]-3-(4-methylphenyl)sydnone (14j):
IR (KBr; ν, cm-1): 3250 (N-H), 2962 (CH3), 1750 (CO sydnone), 1628 (C-N benzothiazole), 1554 (NO2), 1341 (SO2), 1390 (NO2), 1174 (SO2), 727 (C-S-C benzothiazole); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.20 (s, 3H, CH3), 6.70-7.65 (m, 7H, Ar-H), 8.70 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.62, 121.44, 123.63, 123.80, 126.55, 130.48, 134.72, 136.39, 139.21, 142.74, 143.00, 150.53, 175.84, 168.55
4-{[4-(2-phenyl-4-oxoquinazolin-3(4 H )-yl)phenyl]sulfamoyl}-3-(4-methylphenyl)-sydnone (15a): IR (KBr; ν, cm-1): 3275 (N-H), 2990 (CH3), 1748 (C=O sydnone), 1666 (C=O quinazoline), 1593 (C-N quinazoline), 1309 (SO2), 1174 (SO2) ;1H NMR (400 MHz, CDCl3; δ, ppm): 2.47 (s, 3H, CH3), 6.85-8.56 (m, 17H, Ar-H), 9.36 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.86, 111.79, 122.33, 123.48, 125.87, 126.62, 127.16, 127.22, 127.39, 128.94, 129.00, 132.63, 135.33, 135.70, 136.48, 136.70, 137.58, 139.64, 142.63, 149.53, 151.47, 163.17, 169.12
4-({4-[2-(4-Nitrophenyl)-4-oxoquinazolin-3(4 H )-yl]phenyl}sulfamoyl)-3-(4-methylphenyl)sydnone (15b): IR (KBr; ν, cm-1): 3270 (N-H), 2986 (CH3), 1754 (C=O sydnone), 1661 (C=O quinazoline), 1590 (C-N quinazoline), 1530 (NO2), 1323 (SO2), 1178 (SO2), 1357 (NO2); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.42 (s, 3H, CH3), 7.03-7.66 (m, 16H, Ar-H), 9.47 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.75, 142.53, 130.85, 121.49, 136.52, 133.70, 111.67, 126.47, 136.21, 163.70, 122.10, 126.38, 127.80, 135.16, 127.10, 139.34, 149.38, 153.75, 135.74, 128.63, 124.58, 150.80, 168.86
4-({4-[2-(4-Methoxyphenyl)-4-oxoquinazolin-3(4 H )-yl]phenyl}sulfamoyl)-3-(4-methylphenyl)sydnone (15c): IR (KBr; ν, cm-1): 1267 (C-O-C), 1034 (C-O-C), 3276 (N-H), 2980 (CH3), 1746 (C=O sydnone), 1660 (C=O quinazoline), 1594 (C-N quinazoline), 1320 (SO2), 1170 (SO2); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.38 (s, 3H, CH3), 4.00 (s, 3H, OCH3), 6.87-7.53 (m, 16H, Ar-H), 9.53 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.33, 57.39, 111.59, 112.96, 120.63, 123.73, 125.00, 126.81, 127.20, 128.51, 130.38, 131.46, 133.60, 134.81, 135.10, 136.80, 139.52, 137.84, 140.48, 149.52, 151.85, 163.28, 163.78, 168.30
4-({4-[2-(4-Chlorophenyl)-4-oxoquinazolin-3(4 H )-yl]phenyl}sulfamoyl)-3-(4-methylphenyl)sydnone (15d): IR (KBr; ν, cm-1): 3248 (N-H), 2980 (CH3), 1748 (C=O sydnone), 1667 (C=O quinazoline), 1595 (C-N quinazoline), 1318 (SO2), 1174 (SO2), 819 (Cl); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.46 (s, 3H, CH3), 6.96-7.62 (m, 16H, Ar-H), 9.77 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.62, 113.63, 127.00, 122.54, 123.41, 126.73, 128.10, 128.95, 129.47, 131.59, 132.52, 134.94, 135.63, 135.84, 136.28, 137.36, 137.57, 139.11, 142.47, 149.46, 152.98, 163.67, 168.68
4-({4-[2-(3-Nitrophenyl)-4-oxoquinazolin-3(4 H )-yl]phenyl}sulfamoyl)-3-(4-methylphenyl)sydnone (15e): IR (KBr; ν, cm-1): 3250 (N-H), 2980 (CH3), 1749 (C=O sydnone), 1674 (C=O quinazoline), 1600 (C-N quinazoline), 1528 (NO2), 1328 (SO2), 1183 (SO2), 1360 (NO2); 1H NMR (400 MHz, CDCl3; δ, ppm): 7.16-7.87 (m, 16H, Ar-H), 2.37 (s, 3H, CH3), 9.55 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.37, 112.64, 122.64, 123.64, 125.37, 125.73, 126.95, 128.16, 128.58, 129.00, 129.43, 130.37, 131.78, 133.26, 135.10, 135.39, 135.93, 136.25, 138.48, 141.74, 146.48, 149.47, 153.39, 162.75, 168.10
4-({4-[2-(3-Chlorophenyl)-4-oxoquinazolin-3(4 H )-yl]phenyl}sulfamoyl)-3-(4-methylphenyl)sydnone (15f): IR (KBr; ν, cm-1): 3278 (N-H), 2985 (CH3), 1754 (C=O sydnone), 1666 (C=O quinazoline), 1599 (C-N quinazoline), 1310 (SO2), 1175 (SO2), 817 (Cl); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.30 (s, 3H, CH3), 6.80-8.30 (m, 16H, Ar-H), 9.75 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.57, 122.57, 112.64, 122.63, 126.94, 127.64, 128.47, 129.12, 129.54, 130.67, 131.43, 131.26, 132.38, 133.50, 135.00, 136.00, 135.46, 136.74, 138.17,142.48, 147.57, 152.63, 163.48, 168.08
4-({4-[2-(3-Bromophenyl)-4-oxoquinazolin-3(4 H )-yl]phenyl}sulfamoyl)-3-(4-methylphenyl)sydnone (15g): IR (KBr; ν, cm-1): 3268 (N-H), 2970 (CH3), 1750 (C=O sydnone), 1673 (C=O quinazoline), 1607 (C-N quinazoline), 1327 (SO2), 1170 (SO2), 570 (Br); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.53 (s, 3H, CH3), 9.73 (s, 1H, SO2NH), 6.74-7.50 (m, 16H, Ar-H); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.47, 112.80, 121.63, 122.58, 122.86, 126.85, 127.00, 127.24, 128.48, 128.75, 129.53, 131.69, 132.85, 133.10, 133.45, 135.36, 135.73, 136.37, 136.63, 138.75, 142.04, 149.58, 153.42, 162.69, 168.72
4-({4-[2-(2-Nitrophenyl)-4-oxoquinazolin-3(4 H )-yl]phenyl}-3-(4-methylphenyl)sulfamoyl)sydnone (15h): IR (KBr; ν, cm-1): 3255 (N-H), 2980 (CH3), 1751 (C=O sydnone), 1665 (C=O quinazoline), 1610 (C-N quinazoline), 1511 (NO2), 1370 (NO2), 1325 (SO2), 1175 (SO2) ;1H NMR (400 MHz, CDCl3; δ, ppm): 2.58 (s, 3H, CH3), 6.70-8.80 (m, 16H, Ar-H), 9.50 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.47, 112.85, 122.42, 122.84, 125.58, 126.50, 128.00, 128.48, 128.53, 128.90, 129.47, 131.68, 132.37, 133.46, 134.25, 135.33, 135.85, 136.39, 138.84, 141.74, 149.38, 163.10, 150.76, 153.47, 168.33
4-({4-[2-(2-Chlorophenyl)-4-oxoquinazolin-3(4 H )-yl]phenyl}sulfamoyl)-3-(4-methyl phenyl)sydnone (15i): IR (KBr; ν, cm-1): 3267 (N-H), 2987 (CH3), 1752 (C=O sydnone), 1664 (C=O quinazoline), 1602 (C-N quinazoline), 1325 (SO2), 1170 (SO2), 830 (Cl); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.35 (s, 3H, CH3), 6.88-7.95 (m, 16H, Ar-H), 9.70 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.37, 112.68, 122.53, 123.10, 126.85, 127.44, 128.37, 128.48, 128.89, 129.47, 131.36, 131.90, 132.00, 132.58, 133.50, 135.35, 135.54, 135.73, 136.00, 139.36, 141.82, 149.27, 153.74, 163.35, 168.58
4-({4-[2-(2-Chloro-6-nitrophenyl)-4-oxoquinazolin-3(4 H )-yl]phenyl}sulfamoyl)-3-(4-methylphenyl)sydnone (15j): IR (KBr; ν, cm-1): 3281 (N-H), 2987 (CH3), 1745 (C=O sydnone), 1668 (C=O quinazoline), 1605 (C-N quinazoline), 1522 (NO2), 1373 (NO2), 1335 (SO2), 1178 (SO2), 823 (Cl); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.38 (s, 3H, CH3), 7.10-7.66 (m, 15H, Ar-H), 9.68 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.57, 111.74, 122.48, 122.82, 124.42, 125.48, 125.75, 126.85, 128.62, 128.80, 129.35, 131.56, 133.78, 134.10, 134.23, 135.52, 135.60, 136.32, 139.38, 141.47, 147.68, 150.37, 153.00, 163.74, 168.46
4-({4-[2-(4-Methoxy-3-nitrophenyl)-4-oxoquinazolin-3(4 H )-yl]phenyl}sulfamoyl)-3-(4-methylphenyl)sydnone (15k): IR (KBr; ν, cm-1): 3280 (N-H), 2975 (CH3), 1748 (C=O sydnone), 1664 (C=O quinazoline), 1612 (C-N quinazoline), 1520 (NO2), 1373 (NO2), 1336 (SO2), 1230 (COC), 1175 (SO2), 1053 (COC); 1H NMR (400 MHz, CDCl3; δ, ppm): 2.40 (s, 3H, CH3), 4.32 (s, 3H, OCH3), 6.88-7.79 (m, 15H, Ar-H), 9.64 (s, 1H, SO2NH); 13C NMR (100 MHz, CDCl3; δ, ppm): 21.47, 58.25, 112.74, 113.64, 120.89, 122.58, 125.83, 126.73, 127.73, 128.57, 129.14, 129.74, 131.37, 131.90, 132.48, 135.38, 135.51, 135.63, 136.72, 138.56, 141.74, 149.28, 153.53, 153.81, 162.37, 168.53
Experimental Biological Part
Antibacterial Activity
Most of the synthesized compounds exhibited moderate to good antibacterial activity against the tested organisms. S. aureus MTCC 96 and S. pyogenes MTCC 442 were taken as Gram-positive bacteria species while E. coli MTCC 443 and P. aeruginosa MTCC 424 were taken as Gram-negative bacteria species. Ampicillin, chloramphenicol, ciprofloxacin, and norfloxacin were used as standard drugs.
Minimum inhibitory concentration (MIC) was determined by the broth dilution method [12]. DMSO was used as solvent to get desired concentration of the compounds. In primary screening, different concentrations (e.g. 1000, 500, 250, 125, and 62.5 μg/mL) of synthesized compounds were prepared. The active compounds found in the primary screening were chosen for secondary screening and further diluted to obtain 200, 100, 50, 25, 12.5, and 6.250 μg/mL concentrations. Mueller Hinton broth was used as nutrient medium to grow and dilute the drug suspension for the test bacteria. The lowest concentration inhibiting growth of the organism was recorded as the MIC.
Zone of inhibition was determined by the Kirby – Bauer technique [13]. Aliquot of 0.01 mL of 250 μg/mL concentration for each test compound was used for to determine the zone of inhibition. The incubation was carried out at 37 oC for 24 h. The antibacterial activity of compounds is shown in Table 1. From these data, it seems that compound 13h containing a 2,4-dichlorophenyl thiazole linkage showed highest activity besides compounds; 13c possessing a 4-methoxyphenyl thiazole linkage, 13f containing a 4-butoxyphenylthiazole linkage, 14a having a 6-methylbenzothiazole linkage, and compound 15g having a 3-bromophenyl quinazolinone linkage exhibited higher activity against S. aureus MTCC 96. Compounds 13b having a 4-chlorophenyl thiazole, 14a having a 6-methylbenzothiazole substituent, 13j containing a 2,6-dichlorophenyl thiazole, 15c having a 4-methoxyphenyl quinazolinone linkage were found to possess higher activity against S. pyogenes MTCC 442. Compound 14i containing a 5-methylbenzothiazole, compound 13i containing a 2,4-dichloro-6-florophenyl thiazole, 14c having a 6-chlorobenzothiazole, and 15i having a 2-chloro quinazolinone group were found to show good activity against E. coli MTCC 443. Compounds 14i containing 5-methylbenzothiazole was found to possess highest activity, whereas Compounds 13c having 4-methoxyphenyl thiazole, 14g having a 6-ethoxybenzothiazole linkage and 14h possessing 5-chlorobenzothiazole, 15h having a 2-nitroquinazolinone were found to possess good activity against P. aeruginosa MTCC 424.
Antifungal Activity
The antifungal activity was evaluated against C. albicans MTCC 227, A. niger MTCC 282 and A. clavatus MTCC 323. Griseofulvin and nystatin were used as standard drugs. Seborane dextrose broth was used for fungal nutrition. The incubation was carried out at 22 oC for 74 hours.
The antifungal activity of the compounds is depicted in Table 2. Compound 14e having a 6-nitro benzothiazole linkage was the most active. Compound 13b having a 4-chloro phenylthiazole, 14e having a 6-nitro benzothiazole were found to possess good antifungal activity against C. albicans MTCC 227. Compound 13f having a 4-butoxyphenyl thiazole, 13g containing a 2,4-diflorophenyl thiazole, 14c having 6-chloro benzothiazole, 14e 6-nitro benzothiazole were found to possess highest activity against A. niger MTCC 282. Compound 13g having a 2,4-difluro phenyl thiazole, 14d having a 6-bromobenzothiazole linkage, 15d having a 4-chloroquinazolinone, 15f having a 3-chloroquinazolinone were found to possess potent activity, while the other compounds were found to possess moderate to poor activity against A. clavatus MTCC 1323.
Anti-HIV Activity
Antiviral activity and cytotoxicity of synthesized compounds was tested according to the MTT method [14]. The compounds were tested for antiviral activity and cytotoxicity against cytomegalovirus (CMV) and varicella-zoster virus (VZV) in human embryonic lung (HEL) cells and evaluated for their anti-HIV activity against HIV-1 and HIV-2 in MT-4 cells. None of the compounds exhibited a specific antiviral activity against either CMV, VZV or HIV.
Antiproliferative Activity
Compounds 3b, 3h and 4a were tested against 60 human tumor cell lines derived from nine different cancer types (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer) by the National Cancer Institute (NCI). The compounds did not display anticancer activity having GI50 values (the concentration required to achieve 50 % growth inhibition) at a high concentration. Therefore, these compounds were not selected for further testing.
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Acknowledgements
One of the authors (STA) thanks the University Grants Commission (New Delhi) for providing a Research Fellowship. He is also thankful to Atul Limited, Valsad and Ami Organics, Sachin for providing some useful chemicals.
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Asundaria, S.T., Pannecouque, C., De Clercq, E. et al. Sydnone Sulfonamide Derivatives as Antibacterial, Antifungal, Antiproliferative and Anti-HIV Agents. Pharm Chem J 48, 260–268 (2014). https://doi.org/10.1007/s11094-014-1090-y
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DOI: https://doi.org/10.1007/s11094-014-1090-y