Synthesis and Biological Activity of Some Novel Heterocyclic Sulfonamides

Introduction

Sulfonamides are extensively used in therapy due to their pharmacological properties [1]. Over 30 drugs containing this functionality are in clinical use, including antihypertensive agent bosentan [2], antibacterial [3], antiprotozoal [4], antifungal [5], anti-inflammatory [6], non-peptidic vasopressin receptor antagonists [7] and translation initiation inhibitors [8]. Some important sulfonamide derivatives used as carbonic anhydrase inhibitors of commercial importance [9]. They are also effective for the treatment of urinary, intestine, and ophthalmic infections, scalds, ulcerative colitis [10], rheumatoid arthritis [11], male erectile dysfunction as the phosphodiesterase-5 inhibitor sildenafil–better known under its commercial name, Viagra [12] and obesity [13]. More recently, sulfonamides have been used as an anticancer agent [14], as the antiviral HIV protease inhibitor amprenavir [15] and in Alzheimer’s disease [16]. Prompted by the above facts and in continuation of our efforts in developing novel antimicrobial agents [17-20], we hereby report the synthesis and antimicrobial evaluation of some novel thiosemicarbazide, 1,3,4-thiadiazole, pyrazole, pyrazolo[3,4-b]pyridine, bearing sulfonamide moiety from readily available starting material.

Materials and Methods

All melting points were determined on a Gallenkamp apparatus and uncorrected. The purity of the compounds was checked by TLC. FT-IR spectra were recorded in a Pye-Unicam SP300 instrument in potassium bromide discs. 1H NMR spectra were recorded in a Varian Mercury VXR-300 spectrometer (300 MHz for 1H NMR) in DMSO-d6 and the Chemical shifts were related to that of the solvent. Elemental analyses were carried out in the microanalytical Laboratory of Cairo University, Giza, Egypt. 3-(dimethylamino)-1-(aryl) prop-2-en-1-one 10a,b [26] and arylidenemalononitriles 13a,b [21] and 1,6-diamino-4-(4-aryl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (17a,b) [22] were synthesized using methods previously published. Antimicrobial activities were carried out at the Department of Botany and Microbiology Faculty of Science Assiut, Al-Azhar University, Egypt.

Chemistry

Synthesis of 1-(2-cyanoacetyl)-N-(4-sulfamoyl phenyl) thiosemicarbazide (4)

To a solution of cyanoacetic acid hydrazide (0.1 mol), in 10 mL of dry 1,4- dioxane and the appropriate sulfonamide isothiocyanate 2 (0.1 mol) was added. The mixture was refluxed on a water bath for 15 min. The separated solid was filtered, washed with ethanol and crystallized from ethanol. Color: Creamy white crystals. Yield: 87%. mp: 195-197ºC. FT-IR (KBr, ν, cm-1): 3318, 3282, 3169 (NH/NH2), 2266 (CN), 1698 (C=O). 1H NMR (300 MHz, DMSO-d6, δ, ppm): 3.74 (s, 2H, CH2), 7.31 (s, 2H, NH2 exchangable with D2O), 7.69-7.80 (m, 4H, Ar-H), 9.80, 9.90, 10.40 (s, 3H, 3NH exchangable with D2O); m/z 313 (M+, 0.9%), 279(0.21%), 214(8.78%), 172(15%), 134(PhNCS-H; 100%), 122(19.41%), 76(23%). Anal. Calcd for C10H11N5O3S2: C, 38.33; H, 3.54; N, 22.35; S, 20.47. Found: C, 38.40; H, 3.60; N, 22.40; S, 20.50%.

Synthesis of 4-(3-(cyanomethyl)-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)benzenesulfonamide (5)

A mixture of 4 (0.1 mol) was dissolved in 20 mL ethanol (95%) in the presence of potassium hydroxide (5%). The reaction mixture was left to stand for 30 minutes. Yellow precipitate that formed after poured onto acidified cold water. The solid obtained was filtered and crystallized from N,N-dimethylformamide to give compound 5. Color: Yellowish crystals. Yield: 55%. mp: 210-212ºC. FT-IR (KBr, ν, cm-1): 3470, 3315, 3140 (NH2/ NH), 2942 (CH aliph.), 2214 (C≡N), 1625 (C=N). 1H NMR (300 MHz, DMSO-d6, δ, ppm): 4.55 (s, 2H, CH2), 7.20 (s, 2H, NH2 exchangable with D2O), 7.69-7.79 (m, 4H, Ar-H), 11.21 (s, H, NH exchangable with D2O): MS: 295 (M+, 0.6%), 134 (PhNCS-H ;100%). Anal. Calcd for C10H9N5O2S2 (295.02): C, 40.67; H, 3.07; N, 23.71; S, 21.71. Found: C, 40.70; H, 3.20; N, 23.80; S, 21.90%.

Synthesis of 2-(5-((4-sulfamoylphenyl)amino)-1,3,4-thiadiazol-2-yl)acetamide (7)

Thiosemicarbazide 4 (0.01, mol) was gradually added to cold concentrated sulphuric acid (3 mL, 0ºC), and the mixture was stirred at room temperature for 30 min, then the reaction mixture was poured into ice-water, filtrated after the ice melting and a few drops of ammonia were added to the filtrate till pH=8. The precipitated product was filtered, washed with cold water, dried well, and crystallized from ethanol. Color: white crystals. Yield: 60%. mp: 240-241C. FT-IR (KBr, ν, cm-1): 3439, 3324, 3254(NH/NH2), 1667 (C=O): 1H NMR (300 MHz, DMSO-d6, δ, ppm): 3.87(s, 2H, CH2), 4.76, 7.18 (2s, 4H, 2NH2 exchangable with D2O), 7.73-7.94 (m, 4H, Ar-H), 10.60 (br, H, NH exchangable with D2O).MS: 313(M+, 1.28%), 228(42.29%), 149 (65.49%), 76 (54.0%), 64(SO2;100%). Anal. Calcd for C10H11N5O3S2 C, 38.33; H, 3.54; N, 22.35; S, 20.47. Found: C, 38.45; H, 3.60; N, 22.56; S, 20.50%.

4-cyano-N-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carbothioamide (9)

A mixture of 4 (0.01 mol), N,N-dimethylformamide-dimethylacetal (DMF-DMA) (0.015, mol) in dry 1,4-dioxane (20 mL) were refluxed for 3 h. The separated solid product obtained on standing at room temperature was collected by filtration, washed with ethanol and crystallized from 1,4-dioxane to give compound 9. Color: Pale yellow crystals. Yield: 55%. mp: 180-181ºC. FT-IR (KBr, ν, cm-1): 3306 (NH), 2200 (CN), 1625 (C=O). 1H NMR (300 MHz, DMSO-d6, δ, ppm): 3.29 (s, 6H, N(CH3)2), 6.67 (s, H, pyrazole- H), 7.21 (s, 1H, NH exchangable with D2O), 7.46, 7.67(2d, 4H, Ar-H), 8.19 (s, 1H, olefinic -H) and 9.25(s, 1H, NH exchangable with D2O). MS: 378 (M+, 0.34%), 269 (11.75%), 134 (44.73%), 90 (38.52%), 71 (100%). Anal. Calcd for C14H14N6O3S2: (378.43). C, 44.43; H, 3.73; N, 22.21; S, 16.95. Found: C, 44.s50; H, 3.82; N, 22.30; S, 16.85%.

General procedure for preparation of pyrazolo[3,4-b]pyridine compound 13a,b

To a solution of thiosemcarbazide 4 (0.01, mol) and enaminone 10 (0.01, mol) in AcOH (20 mL) containing anhydrous sodium acetate (1.5 g) were refluxed for 4 h. Then, the reaction mixture was cooled to room temperature and poured onto ice cold water. The crude product was collected by filtration, washed with water and crystallized from the appropriate solvent to give 13a,b.

3-oxo-6-phenyl-N-(4-sulfamoylphenyl)-2,3-dihydro-1H-pyrazolo [3,4-b]pyridine-1-carbothioamide (13a)

Color: Brawn crystals. Yield: 60%. mp: 260-261ºC. FT-IR (KBr, ν, cm-1): 3430, 3350, 3268 (NH/NH2), 1705 (C=O); 1H NMR (300 MHz, DMSO-d6, δ, ppm): 5.94, 6.97 (2s, 2H, pyridine-H), 7.17 (s, 2H, NH2 exchangable with D2O), 7.59-7.98 (m, 9H, Ar-H+NH), 10.40 (br, 1H, NH exchangable with D2O). MS:425 (M+, 0.23%), 211 (10.76%), 156 (52.81%), 134 (21.75%), 108 (62.69%), 65 (100%). Anal. Calcd for C19H15N5O3S2 (425.48): C, 53.63; H, 3.55; N, 16.46; S, 15.07. Found: C, 53.70; H, 3.65; N, 16.50; S, 15.20%.

3-oxo-N-(4-sulfamoylphenyl)-6-(p-tolyl)-2,3-dihydro-1H-pyrazolo [3,4-b]pyridine-1-carbothioamide (13b)

Color: Pale yellow crystals. Yield 65%. m.p.: 245-246ºC. FT-IR (KBr, ν, cm-1):3421, 3307, 3152 (NH/NH2), 1660 (C=O); 1H NMR (300 MHz, DMSO-d6, δ, ppm): 2.41 (s, 3H, CH3), 5.22, 6.96 (2s, 2H, pyridine- H), 7.29 (s, 2H, NH2 exchangable with D2O), 7.32-7.95 (m, 8H, Ar-H), 10.90 (hump, H, NH exchangable with D2O), 12.10 (br, H, NH exchangable with D2O). Anal. Calcd for C20H17N5O3S2 (439.51): C, 54.65; H, 3.90; N, 15.93; S, 14.59. Found: C, 54.80; H, 3.79; N, 15.85; S, 14.70%.

General procedure for the synthesis of compounds (16a,b)

Method A: A mixtures of thiosemcarbazide 4 (0.01, mol) and the appropriate arylidenmalononitrile 14 (0.01, mol) in ethanol (30 mL) containing few drops of piperidine (5 drops) was refluxed for 4 h. Then, the reaction mixture was cooled to room temperature. The solid which formed was collected by filtration, washed with hot ethanol and crystallized from ethanol to afford 16a,b.

Method B: Equimolar amounts of 2 (0.01, mol) and the appropriate N-Amino-2-pyridone derivatives 17a,b (0.01, mol) in 1,4-dioxane (30 mL) was treated with triethylamine (0.5 mL) and the reaction mixture was heated under reflux for 3 h. After cooling, the precipitate was filtered off, washed with ethanol and then recrystallized from the proper solvent to give 16a,b.

4-(3-(6-amino-3,5-dicyano-2-oxo-4-phenylpyridin-1(2H)-yl)thioureido)- benzenesulfonamide (16a)

Color: Yellow crystals. Yield 72%. mp: 165-166ºC. FT-IR (KBr, ν, cm-1): 3441, 3334, 3220 (NH/NH2), 2214 (CN), 1624 (C=O); 1H NMR (300 MHz,DMSO-d6, δ, ppm): 3.86, 7.12 (2s, 4H, 2NH2 exchangable with D2O), 7.22-7.98 (m, 9H, Ar-H), 10.11, 11.32 (2s, 2H, 2NH exchangable with D2O). Anal. Calcd for C20H15N7O3S2 (465.51): C, 51.60; H, 3.25; N, 21.06; S, 13.78. Found: C, 51.52; H, 3.30; N, 21.30; S, 13.84%.

4-(3-(6-amino-4-(4-chlorophenyl)-3,5-dicyano-2-oxopyridin-1(2H)-yl)thioureido)benzenesulfonamide (16b)

Color: Pale yellow crystals. Yield 68%. M.p.: 170-171ºC. FT-IR (KBr,ν, cm-1): 3328, 3243, 3126 (NH/NH2), 2215 (CN), 1625 (C=O); 1H NMR (300 MHz, DMSO-d6, δ, ppm): 3.86, 7.12 (2s, 4H, 2NH2 exchangable with D2O), 7.22-7.81 (m, 8H, Ar-H), 9.40 (s, 1H, NH exchangable with D2O), 10.20 (s, H, NH exchangable with D2O). MS: 501(0.12%), 500 (0.17%), 499(0.11%), 294 (1.88%), 253 (11.85%), 214 (19.94%), 156 (60.47%), 92 (87.10%), 65 (100%). Anal. Calcd for C20H14ClN7O3S2 (499.95): C, 48.05; H, 2.82; Cl, 7.09; N, 19.61; S, 12.83. Found: C, 48.20; H, 2.92; Cl, 7.25; N, 19.72; S, 12.90%.

2-(2-Oxo-2H-chromene-3-carbonyl)-N-(4-sulfamoylphenyl)hydrazine- carboxamide (18)

A mixture of thiosemcarbazide 4 (0.01, mol) and salicylaldehyde (0.01, mol) was refluxed in ethanol (25 mL) in the presence of piperidine (5 drops) for 3 h. Then, the reaction mixture was allowed to cool to room temperature, the formed crude product was collected by filtration washed with ethanol and recrystallized from dimethylformamide to give compound 18. Color: Pale yellow crystals, yield 68% and mp:180-182ºC. FT-IR (KBr,ν, cm-1): 3320, 3240, 3140 (NH/NH2), 1706, 1652 (2C=O); 1H NMR (300 MHz, DMSO-d6, δ, ppm): 3.88 (s, 1H,NH exchangable with D2O), 7.22 (s, 2H,NH2 exchangable with D2O), 7.42-7.71 (m, 8H, Ar-H), 8.65 (s, 1H, chromene H-4) 9.42, 10.45 (2s, 2H, 2NH exchangable with D2O). MS:403 (M+-NH;3.45%), 214 (31.56%), 150 (16.59%), 135 (8.50%), 77 (12.03%), 57 (100%). Anal.Calcd for C17H14N4O5S2 (418.04): C, 48.80; H, 3.37; N, 13.39; S, 15.33. Found: C, 48.90; H, 3.40; N, 13.50; S, 15.20%.

General procedure for the synthesis of compounds (19a,b)

A cold solution of aryl diazonium chloride (0.01, mol) was prepared by adding a solution of sodium nitrite (1.4 g dissolved in 10 mL water) to cold solution of aryl amine hydrochloride (0.01 mol of amine in 10 mL, 6M HCl) with stirring.

The resulting solution of aryl diazonium chloride

was then added to a cold solution of cyanoacety 4 (0.01, mol) in ethanol (50 mL) in the presence of sodium acetate trihydrate (0.015, mol). The reaction mixture was stirred at room temperature for 1 h. The solid product was collected directly from the reaction mixture by filtration and

washed with water then ethanol. Finally the obtained products were recrystallized from ethanol to afford 19a,b respectively.

N'-(4-chlorophenyl)-2-oxo-2-(2-((4-sulfamoylphenyl) carbamothioyl)hydrazinyl)acetohydrazonoylcyanide (19a)

Color: Orange crystals. Yield 75%. mp: 235-236ºC. FT-IR (KBr,ν, cm-1): 3330, 3240, 3254, 3180 (NH/NH2), 2227 (CN), 1693 (C=O); 1H NMR (300 MHz, DMSO-d6, δ, ppm): 5.83 (s, 2H, NH2 exchangable with D2O), 7.40-7.83 (m, 9H, Ar-H+NH), 10.52 (s, 1H, NH exchangable with D2O) 12.60 (hump, 1H, NH exchangable with D2O), 12.80 (br, H, NH exchangable with D2O). MS: 454 (0.27%), 453 (0.42%), 452 (0.29%), 214 (55.79%), 156 (8.39%), 134 (100%). Anal. Calcd for C16H14ClN7O3S2 (451.91): C, 42.52; H, 3.12; Cl, 7.85; N, 21.70; S, 14.19. Found: C, 42.65; H, 3.30; Cl, 7.95; N, 21.80; S, 14.25%.

N'-(4-methoxyphenyl)-2-oxo-2-(2-((4-sulfamoyl phenyl) carbamothioyl) hydrazinyl) acetohydrazonoyl cyanide(19b)

Color: Orange crystals. Yield 80%. M.p.: 250-252ºC. FT-IR (KBr,ν, cm-1): 3418, 3365, 3240, 3150 (NH/NH2), 2227 (CN), 1693 (C=O); 1H NMR (300 MHz, DMSO-d6, δ, ppm): 3.57 (s, 3H, OCH3), 5.74 (s, 2H, NH2 exchangable with D2O), 7.18-7.79 (m, 9H, Ar-H+NH), 10.48 (s, 1H, NH exchangable with D2O) 12.53 (hump, 1H, NH,exchangable with D2O), 13.10 (br, 1H, NH exchangable with D2O). Anal. Calcd for C17H17N7O4S2 (447.49): C, 45.63; H, 3.83; N, 21.91; S, 14.33. Found: C, 45.75; H, 3.90; N, 21.85; S, 14.40%.

4-((5-(3,5-diamino-4-cyanothiophen-2-yl)-1,3,4-oxadiazol-2-yl) amino)benzenesulfonamide (21)

Equimolar amounts of 4 (0.01, mol), malononitrile (0.01 mol) and elemental sulfur (0.01 mol) in dimethylformamide (20 mL) were treated with little amount of triethylamine (0.5 mL) and refluxed for 4 h. The solid that formed after cooling was collected and recrystallized from 1,4- dioxane/ethanol to give 21. Color: Brawn crystals.Yield 62%. mp: >300ºC. FT-IR (KBr, ν, cm-1): 3301, 3220, 3191 (NH/NH2), 2212 (CN), 1H NMR (300 MHz, DMSO-d6, δ, ppm): 3.30 (br, 2H, NH2 exchangable with D2O), 7.18 (s, 2H, NH2 exchangable with D2O), 7.70-7.71 (m, 6H, Ar-H+NH2), 10.42 (s, 1H, NH exchangable with D2O). Anal. Calcd for C13H11N7O3S2 (377.04): C, 41.37; H, 2.94; N, 25.98; S, 16.99. Found: C, 41.45; H, 2.80; N, 25.75; S, 16.80%.

Biological activity

The in vitro antimicrobial activities of all the synthesized compounds were evaluated for five Gram-positive bacteria viz. Bacillus Cereus, Micrococcus luteus, Enterococcus faecium, Staphylococcus aureus, Streptococcus pneumoniae and five Gram-negative organisms’ viz. Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella enteritidis, Serattia marcescens. Bacterial cultures were maintained in nutrient agar slants and kept at 4ºC. Each bacterial strain was reactivated prior to susceptibility testing by transferring them into a separate test tube containing nutrient broth media and incubated overnight at 37ºC. For Standardization of bacterial suspensions, Approximately 1 mL of tested bacterial culture was transferred to 9 mL of broth media of beef extract 3 g, peptone 5 g, and NaCl 5 g. The ingredients were mixed and boiled in 1000 ml distillate water, then autoclaved at 121ºC for 15 min. and incubated at 37ºC for 24 h. Antibacterial activity of tested substance was determined by saturated disks method using nutrient agar media of beef extract 3 g, peptone 5 g, NaCl 5 g and agar 20 g. The ingredients were mixed and boiled in 1000 mL distillate water, then autoclaved at 121ºC for 15 min. For each of the tested strain 200 μL of standardized bacterial stock suspensions colony were injected in 20 mL of semisolid modified nutrient agar media by sterilized tips, then this media were poured in agar plate and let to solidify. Saturated disks with the subjected chemical compound were placed on the surface of each plate then the plates incubated at 37ºC for 24 h. After incubation, the diameters of the inhibition zones for each well were measured in millimeters (mm) in three replicates.

Conclusion

The reactivity of 1-(2-cyanoacetyl)-N-(4-sulfamoyl phenyl) thiosemicarbazide (4) was investigated as a versatile and readily accessible building block for the synthesis of new heterocyclic compounds such as 1,2,4-triazole,1,3,4-thiadiazole, pyrazole,and pyrazolo[3,4-b]pyridine derivatives incorporating a sulfamoyl moiety of antibacterial importance.

Acknowledgement

The authors would like to thank the Chemistry Department, Faculty of Science, Al-Azhar University at Assist for their financial support to facilitate the publication of this study. Also, the author is grateful to Botany and Microbiology Department for doing the microbiological screening.

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