Journal of Chemistry
Volume 2015 (2015), Article ID 524056, 8 pages
http://dx.doi.org/10.1155/2015/524056

Research Article

Amidine Sulfonamides and Benzene Sulfonamides: Synthesis and Their Biological Evaluation

Muhammad Abdul Qadir,¹ Mahmood Ahmed,¹ Hina Aslam,¹ Sadia Waseem,¹ and Muhammad Imtiaz Shafiq²

¹Institute of Chemistry, University of Punjab, Lahore 54590, Pakistan
²Institute of Biochemistry & Biotechnology, University of the Punjab, Lahore 54590, Pakistan

Received 21 May 2015; Accepted 2 July 2015

Academic Editor: Deniz Ekinci

Copyright © 2015 Muhammad Abdul Qadir et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

New amidine and benzene sulfonamide derivatives were developed and structures of the new products were confirmed by elemental and spectral analysis (FT-IR, ESI-MS, ¹HNMR, and ¹³CNMR). In vitro, developed compounds were screened for their antibacterial and antifungal activities against medically important bacterial strains, namely, S. aureus, B. subtilis, and E. coli, and fungi, namely, A. flavus, A. parasiticus, and A. sp. The antibacterial and antifungal activities have been determined by measuring MIC values (μg/mL) and zone of inhibitions (mm). Among the tested compounds, it was found that compounds 3b, 9a, and 9b have most potent activity against S. aureus, A. flavus, and A. parasiticus, respectively, and were found to be more active than sulfamethoxazole and itraconazole with MIC values 40 μg/mL. In contrast, all the compounds were totally inactive against the A. sp. except 10b and 15b to show activity to some extent.

1. Introduction

Sulfonamides are basis of several drug groups, known as sulfa drugs. Any compound that has sulfonamide moiety (SO₂NH₂) in its structure is referred to as sulfonamide. They comprise substantial class of pharmaceutical drugs, containing various kinds of pharmacological agents having antitumor [1], antibacterial [2], anticarbonic anhydrase [3, 4], diuretic [5, 6], hypoglycemic [7], and protease inhibitory activity [8–10] or antithyroid activity [11] among others. Sulfonamides are mostly used to treat the bacterial infectious cells because they do not significantly affect the antigenic properties of the infective organism or the development of specific antibodies [12]. Bacteria have liability to acquire resistance against sulfonamides by changing their cell wall permeability, enhancing essential metabolites production, or increasing production of enzyme [13]. In this way sulfonamides become ineffective to inhibit their production. But their ineffectiveness in drug therapy can be abstained, due to inductive effect of SO₂ group. Sulfonamides having first value around 10 are less soluble in water; therefore, they may readily crystalize in kidney but with advancement in medical science, and new sulfonamides have been synthesized having lower value (5-6) to avoid crystallization in kidney [14]. The compounds having pyridine and amide functional group exhibit various biological activities like antifungal and antibacterial. So these biological activities encourage us to synthesize the sulfonamides containing such important functional groups [15–18]. The motivation behind this research work was to synthesize some novel sulfonamides (Schemes 1–4) having antimicrobial properties. Different amines were chosen and reacted with sulfonyl chlorides. As a result of substitution, different functional groups were added and resulting compounds exhibited antibacterial and antifungal activities.

Scheme 1: Amidine sulfonamides.

Scheme 2: Benzene sulfonamides (series 1).

Scheme 3: Benzene sulfonamides (series 2).

Scheme 4

2. Experimental

2.1. Chemistry

Chemicals used in present work were of analytical grade obtained from E-Merck (Germany), Sigma Aldrich (USA), and BDH (UK) without further purification to synthesize desired compounds, and high purity water (0.01 μS/cm) was prepared in our own laboratory using Milli-Q purification system (USA). Alpha IR spectrometer (FTIR-ATR) and NMR spectrometer, Bruker, were used to record the IR and ¹HNMR (500 MHz) and ¹³CNMR (125 MHz) spectra, respectively. PG-T80⁺ UV-Vis spectrophotometer (UK) and Flash HT Plus elemental analyzer (Thermo Scientific, UK) were used for , and concentration of hydrogen (H), carbon (C), nitrogen (N), and sulfur (S) of synthesized compounds, respectively, while the melting point was measured by Gallenkamp apparatus. JMS-HX-110 spectrometer with electron spray ionization (ESI) interface was used for mass spectra. The ¹HNMR and ¹³CNMR spectra of all the synthesized compounds were measured using MeOD and concentration of all the compounds was 10–20 mg in 0.8–1.0 mL of solvent. Purification and progress of the synthesized compounds were confirmed on precoated TLC silica plate (Merck-Germany).

2.2. Antimicrobial Assay

Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC 6633, Aspergillus flavus ATCC 9643, Aspergillus parasiticus ATCC 15517, and Acremonium sp. ATCC 200667 were collected from Mycology Department, University of Punjab, Lahore, Pakistan, and were maintained in tryptic soy agar (TSA) and potato dextrose agar (PDA) medium, respectively, slants at 5°C until use. A series of four 2-fold dilutions (320, 160, 80, and 40 μg/mL) were made from stock solution of 640 μg/mL in dimethyl sulphoxide (DMSO). All the dilutions were made sterile in an autoclave at 121°C for 30 min with 15 psi pressure after filtration through 0.22 μm membrane filter. The minimal inhibitory concentration (MIC) was reported as absence of no observable growth by the lowest concentration of tested compounds after twofold serial dilution. Five individually numbered test tubes with screw caps were sterilized. Tube 1 was filled with 2 mL of tryptic soy broth culture media including the stock solution of synthesized compounds. 1.0 mL of this solution was introduced into 2 tubes and diluted with 1.0 mL culture media and we repeated the procedure up to tube 5. The tubes were incubated at 25°C for 72 hrs. Ciprofloxacin and sulfamethoxazole (sulfa drug) were used as reference (positive control to check the sensitivity of tested bacterial strains).  cfu/mL of each of Gram negative E. coli and Gram positive S. aureus and B. subtilis was obtained after adjusting the optical density of inoculum at 0.2–0.3 and 0.3–0.4 (620 nm), respectively, while fungal suspension (A. flavus, A. parasiticus, and A. sp.) with cell density of 10⁵ cfu/mL was studied in present work and the itraconazole was used as reference antifungal agent. All the compounds and reference solutions were applied (50 μL) onto a 6 mm sterile filter paper disc separately and the inoculated plates incubated at 37°C for 24 hrs. The zones of inhibition (mm) were measured and we evaluated the antibacterial activities.

2.3. General Procedure for Synthesis of Sulfonamides

A simple method in aqueous media under dynamic pH control is adopted for synthesis of sulfonamides. Filtration after acidification is involved for isolation of products [19–21]. All the amines were weighed accurately and dissolved completely by addition of distilled water by constant stirring using magnetic stirrer. The pH of the reaction contents was strictly monitored and maintained at 8–10 at regular intervals during the experimental reaction using Na₂CO₃ solution (1 M). Then benzene sulfonyl chloride or p-toluene sulphonyl chloride was accurately weighed and added carefully into the above solution. The reaction was carried in round bottom flask equipped with magnetic stirrer. During stirring sulphonyl chloride initially floats on the surface and the completion of reaction was examined by the change in pH value due to formation of HCl by the consumption of sulphonyl chlorides during the reaction. On completion of the reaction pH was adjusted at 2-3 using HCl solution (2 M). The precipitates formed were filtered through Whatman filter paper number 42, washed several times with distilled water, and recrystallized using methanol and dried using rotary evaporator.

2.4. N-Imino[(phenylsulfonyl)amino]methyl}-N-methylglycine (3a, C₁₀H₁₃N₃O₄S)

Yield: 397.9 mg (64.7%); m.p.: 172–174°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): (O-), 3084 (C-), 1768 (C=), 1707 (C=), 1438 (O-), 1033 (S=), 1165 (-N- S=), 1458 (C=C-), 706 (); UV-Vis (methanol,  mol dm⁻³): (ε) = 208 (25050) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) (br, s, 1H, NH), 7.98 (d,  Hz, 1H, CH), 7.68 (t,  Hz, 1H, CH), 7.56 (d,  Hz, 1H, CH), 4.71 (d,  Hz, 2H, CH₂), 3.15 (s, 3H, CH₃); ¹³CNMR (125 MHz, MeOD) (C-16), 155 (C-11), 141 (C-1), 135 (C-4), 129 (C-3), 51 (C-15), 35 (C-14); ESI-MS: m/z = 273.38 [M + 2]⁺, 271.31 [M]⁺.

2.5. N-(Imino[(4 methylphenyl)sulfonyl]amino}methyl)-N-methylglycine (3b, C₁₁H₁₅N₃O₄S)

Yield: 779.9 mg (82.7%); m.p.: 185–187°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): = 3224 (O-), 2992 (C-), 1767 (C=), 1699 (C=), 1438 (O-), 1028 (S=), 1199 (-N- S=), 1498 (C=C-), 701 (-); UV-Vis (methanol,  mol dm⁻³): (ε) = 222 (22500) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) (br, s, 1H, NH), 7.71 (s, 1H, CH), 7.38 (d,  Hz, 1H, CH), 4.68 (s, 2H, CH₂), 3.15 (s, 3H, CH₃), 2.26 (s, 3H, CH₃); ¹³CNMR (125 MHz, MeOD) (C-17), 156 (C-12), 143 (C-1), 138 (C-4), 129 (C-2), 52 (C-16), 35 (C-15), 22 (C-7); ESI-MS: m/z = 287.39 [M + 2]⁺, 285.34 [M]⁺.

2.6. N-[[Bis(phenylsulfonyl)amino](imino)methyl]-N-methylglycine (4a, C₁₆H₁₇N₃O₆S₂)

Yield: 931.8 mg (81.3%); m.p.: 210–212°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): = 3062 (O-), 1767 (C=), 1621 (C=), 1445 (O-), 1037 (S=), 1163 (-N- S=), 1445 (C=C-), 689 (-); UV-Vis (methanol,  mol dm⁻³): (ε) = 210 (17250) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) δ = 10.86 (br, s, 1H, NH), 8.21 (t,  Hz, 1H, CH), 8.08 (d,  Hz, 1H, CH), 7.93 (s, 1H, CH), 4.75 (s, 2H, CH₂), 3.16 (s, 3H, CH₃); ¹³CNMR (125 MHz, MeOD) δ = 168 (C-25), 156 (C-13), 141 (C-1), 132 (C-4), 131 (C-5), 53 (C-24), 37 (C-23); ESI-MS: m/z = 413.59 [M + 2]⁺, 411.48 [M]⁺.

2.7. N-[Bis[(4-methylphenyl)sulfonyl]amino}(imino)methyl]-N-methylglycine (4b, C₁₈H₂₁N₃O₆S₂)

Yield: 872.1 mg (82.2%); m.p.: 195–197°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): (O-), 1707 (C=), 1600 (N-), 1660 (C=), 1399 (O-), 1043 (S=), 1182 (-N- S=), 1445 (C=C-), 685 (-); UV-Vis (methanol,  mol dm⁻³): (ε) = 222 (19000) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) δ = 10.76 (br, s, 1H, NH), 7.81 (d,  Hz, 1H, CH), 7.78 (d,  Hz, 1H, CH), 4.73 (s, 2H, CH₂), 3.15 (s, 3H, CH₃), 2.46 (s, 3H, CH₃); ¹³CNMR (500 MHz, MeOD) δ = 168 (C-27), 156 (C-14), 143 (C-1), 139 (C-4), 132 (C-6), 53 (C-26), 37 (C-24), 21 (C-25); ESI-MS: m/z = 441.53 [M + 2]⁺, 439.58 [M]⁺.

2.8. N-Imino[[(4-methylphenyl)sulfonyl](phenylsulfonyl) amino]methyl}-N-methylglycine (6a, C₁₇H₁₉N₃O₆S₂)

Yield: 626.4 mg (70.6%); m.p.: 182–184°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): = 3277 (O-), 1707 (C=), 1599 (N-), 1659 (C=), 1399 (O-), 1040 (S=), 1185 (-N- S=), 1444 (C=C-), 684 (-); UV-Vis (methanol,  mol dm⁻³): (ε) = 218 (26150) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) δ = 10.79 (br, s, 1H, NH), 8.21 (d,  Hz, 1H, CH), 8.10 (s, H, CH), 7.91 (s, H, CH), 7.87 (d,  Hz, 1H, CH), 7.73 (s, H, CH), 7.73 (d,  Hz, 1H, CH), 4.73 (s, 2H, CH₂), 3.15 (s, 3H, CH₃), 2.44 (s, 3H, CH₃); (125 MHz, MeOD) δ = 168 (C-26), 156 (C-14), 143 (C-1), 141 (C-17), 132 (C-20), 131 (C-2), 129 (C-3), 53 (C-25), 39 (C-24), 23 (C-7); ESI-MS: m/z = 427.53 [M + 2]⁺, 425.48 [M]⁺.

2.9. N-(Pyridin-2-yl)benzene Sulfonamide (9a, C₁₁H₁₀N₂O₂S)

Yield: 869.6 mg (83.1%); m.p.: 145–147°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): = 3367 (N-), 1666 (N-), 1024 (S=), 1177 (-N- S=), 1445 (C=C-), 687 (-); UV-Vis (methanol,  mol dm⁻³): (ε) = 230 (43800) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) δ = 11.49 (br, s, 1H, NH), 7.91 (d,  Hz, 1H, CH), 7.81 (d,  Hz, 1H, CH), 7.65 (t,  Hz, 1H, CH), 7.61 (t,  Hz, 1H, CH), 7.55 (t,  Hz, 1H, CH), 7.25 (t,  Hz, 1H, CH), 7.15 (d,  Hz, 1H, CH); ¹³CNMR (125 MHz, MeOD) δ = 148 (C-2), 145 (C-6), 140 (C-11), 137 (C-4), 132 (C-14), 129 (C-13), 127 (C-12), 115 (C-5), 112 (C-3); ESI-MS: m/z = 236.31 [M + 2]⁺, 234.28 [M]⁺.

2.10. 4-Methyl-N-(pyridin-2-yl)benzene Sulfonamide (9b, C₁₂H₁₂N₂O₂S)

Yield: 935.6 mg (82.1%); m.p.: 178–180°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): = 3328 (N-), 1665 (N-), 1019 (S=), 1161 (-N- S=), 1455 (C=C-), 680 (); UV-Vis (methanol,  mol dm⁻³): (ε) = 224 (15380) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) δ = 11.43 (br, s, 1H, NH), 7.97 (d,  Hz, 1H, CH), 7.61 (d,  Hz, 1H, CH), 7.25 (t,  Hz, 1H, CH), 7.20 (s, 1H, CH), 7.11 (t,  Hz, 1H, CH), 7.15 (d,  Hz, 1H, CH), 2.48 (s, 3H, CH₃); ¹³CNMR (125 MHz, MeOD) δ = 148 (C-2), 145 (C-6), 143 (C-14), 137 (C-4), 129 (C-13), 115 (C-5), 111 (C-3), 21 (C-17); ESI-MS: m/z = 250.35 [M + 2]⁺, 248.30 [M]⁺.

2.11. N-(Phenylsulfonyl)-N-(pyridin-2-yl)benzene Sulfonamide (10a, C₁₇H₁₄N₂O₄S₂)

Yield: 909.8 mg (71.7%); m.p.: 166–168°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): = 3348 (N-), 1619 (N-), 1030 (S=), 1186 (-N- S=), 1445 (C=C-), 688 (); UV-Vis (methanol,  mol dm⁻³): (ε) = 215 (12830) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) δ = 8.13 (m, 1H, CH), 8.11 (m, 1H, CH), 7.95 (m, 1H, CH), 7.88 (m, 1H, CH), 7.81 (m, 1H, CH), 7.65 (qd,  Hz, 1.21 Hz, 1H, CH), 7.48 (qd,  Hz, 5.21 Hz, 1H, CH); ¹³CNMR (125 MHz, MeOD) δ = 148 (C-6), 142 (C-13), 138 (C-2), 131 (C-16), 130 (C-14), 117 (C-5), 113 (C-3); ESI-MS: m/z = 376.45 [M + 2]⁺, 374.44 [M]⁺.

2.12. 4-Methyl-N-(phenylsulfonyl)-N-(pyridin-2-yl)benzene Sulfonamide (10b, C₁₉H₁₈N₂O₄S₂)

Yield: 1140.5 mg (84.3%); m.p.: 164–166°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): = 3348 (N-), 1621 (N-), 1027 (S=), 1162 (-N- S=), 1445 (C=C-), 681 (); UV-Vis (methanol,  mol dm⁻³): (ε) = 222 (13855) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) δ = 8.19 (s, H, CH), 8.02 (d,  Hz, 1H, CH), 7.87 (t,  Hz, 1H, CH), 7.68 (d,  Hz, 1H, CH), 7.61 (d,  Hz, 1H, CH), 7.55 (d,  Hz, 1H, CH), 2.46 (s, 3H, CH₃); ¹³CNMR (125 MHz, MeOD) δ = 148 (C-6), 138 (C-2), 132 (C-15), 117 (C-5), 113 (C-3), 22 (C-27); ESI-MS: m/z = 404.55 [M + 2]⁺, 402.51 [M]⁺.

2.13. 4-Methyl-N-(phenylsulfonyl)-N-(pyridin-2-yl)benzene Sulfonamide (12a, C₁₈H₁₆N₂O₄S₂)

Yield: 529.5 mg (65.1%); m.p.: 188–190°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): = 3280 (N-), 1620 (N-), 1021 (S=), 1158 (-N- S=), 1445 (C=C-), 682 (); UV-Vis (methanol,  mol dm⁻³): (ε) = 220 (42550) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) δ = 8.15 (d,  Hz, 1H, CH), 8.07 (d,  Hz, 1H, CH), 7.98 (d,  Hz, 1H, CH), 7.91 (t,  Hz, 1H, CH), 7.65 (d,  Hz, 1H, CH), 7.51 (d,  Hz, 1H, CH), 7.45 (d,  Hz, 1H, CH), 2.44 (s, 3H, CH₃); ¹³CNMR (125 MHz, MeOD) δ = 147 (C-6), 138 (C-2), 132 (C-15), 117 (C-5), 112 (C-3), 21 (C-27); ESI-MS: m/z = 390.53 [M + 2]⁺, 388.49 [M]⁺.

2.14. N-Methyl-N-(phenylsulfonyl)alanine (15a, C₁₀H₁₃NO₄S)

Yield: 786.1 mg (51.7%); m.p.: 132–134°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): = 3215 (O-), 1743 (C=), 1444 (O-), 1041 (S=), 1183 (-N- S=), 1444 (C=C-), 688 (); UV-Vis (methanol,  mol dm⁻³): (ε) = 215 (13070) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) δ = 7.73 (d,  Hz, 1H, CH), 7.53 (d,  Hz, 1H, CH), 7.36 (t,  Hz, 1H, CH), 4.51 (q,  Hz, 1H, CH), 3.75 (br, s, 1H, OH), 2.71 (s, 3H, CH₃), 1.11 (d,  Hz, 3H, CH₃); ¹³CNMR (125 MHz, MeOD) δ = 178 (C-14), 138 (C-1), 131 (C-4), 62 (C-12), 29 (C-11), 15 (C-13); ESI-MS: m/z = 245.38 [M + 2]⁺, 243.35 [M]⁺.

2.15. N-Methyl-N-[(4-methylphenyl)sulfonyl]alanine (15b, C₁₁H₁₅NO₄S)

Yield: 910.9 mg (63.6%); m.p.: 140–142°C; TLC: (H₂O-BuOH-Acetic acid 1 : 4 : 1); IR (FTIR): = 3268 (O-), 1710 (C=), 1449 (O-), 1054 (S=), 1146 (-N- S=), 1422 (C=C-), 677 (); UV-Vis (methanol,  mol dm⁻³): (ε) = 220 (17250) nm (mol⁻¹ dm3 cm⁻¹); ¹HNMR (500 MHz, MeOD) δ = 7.69 (d,  Hz, 1H, CH), 7.32 (d,  Hz, 1H, CH), 4.48 (t,  Hz, 1H, CH), 3.75 (br, s, 1H, OH), 2.69 (s, 3H, CH₃), 2.39 (s, 3H, CH₃), 1.08 (d,  Hz, 3H, CH₃); ¹³CNMR (125 MHz, MeOD) δ = 178 (C-14), 138 (C-1), 133 (C-4), 129 (C-5), 61 (C-12), 29 (C-11), 15 (C-13); ESI-MS: m/z = 259.38 [M + 2]⁺, 257.35 [M]⁺.

3. Results and Discussion

A total of twelve novel sulfonamides were synthesized in aqueous basic media by simple reaction of creatine (amidine derivatives), amino pyridine (benzene sulfonamide series 1), and methyl alanine (benzene sulfonamide series 2) with benzene sulfonyl chloride and para toluene sulphonyl chloride, respectively, with continuous stirring and details of reaction conditions are explained in Experimental section and synthetic pathways of sulfonamides are explained in Schemes 1, 2, 3, and 4. Compounds 3a, 3b, 9a, 9b, 15a, and 15b were synthesized in equimolar concentration of creatine, amino pyridine, and methyl alanine with benzene sulphonyl chloride and para toluene sulphonyl chloride, respectively, while 4a, 4b, 9a, and 9b were obtained by bimolar concentration of respective sulphonyl chlorides, respectively. Compounds 6a and 12a were synthesized by the reaction of 3b and 9b with benzene sulphonyl chloride and para toluene sulphonyl chloride in equimolar concentration, respectively. All the compounds except compound 15a (57.5%) were obtained in good yield. Elemental analysis was performed for the conformation of all the compounds and measurement of absorption maximum () provided the justification. The analytical data of synthesized sulfonamides are presented in Table 1. The synthesized compounds were characterized by FT-IR, and the characteristics band at 1621–1707 cm⁻¹ for imine stretching of amidine sulfonamides, 3280–3367 cm⁻¹ of N-H amide stretching for benzene sulfonamides (series 1), 3250–3268 cm⁻¹ for O-H stretching (benzene sulfonamide series 2), and 1082–1199 cm⁻¹ for (-N-S=O) and 1019–1054 cm⁻¹ (S=O) for all compounds reveals the formation of sulfonamides. [M + 2]⁺ peaks obtained by ESI-MS represented the isolation of sulfonyl group in all synthesized compounds. The structures of all the compounds were also confirmed by ¹HNMR and ¹³CNMR by dissolving in MeOD. ¹HNMR spectra of compounds 3a and 3b showed a broad signal at δ 9.91, 9.96 while signal at δ 10.76–10.86 for 4a, 4b, and 9a and 11.43, 11.49 ppm for 9a and 9b corresponds to NH group of sulfonamide. A broad singlet at δ 3.75 ppm due to -OH group was also obtained for compounds 15a and 15b. The characteristics C-SO-NH signals at δ 155-156 ppm and δ 138–140 ppm for amidine and benzene sulfonamides, respectively, were showed by ¹³CNMR which identified the structures correctly.

Table 1: Physiochemical and analytical data of sulfonamides.

Compounds
Molecular weight
Elemental analysis (found/cal.) %

C
H
N
S
p

3a
271.29
44.33/44.27
4.85/4.83
15.42/15.49
11.83/11.82
10.8

3b
285.32
46.35/46.30
5.39/5.31
14.68/14.73
11.29/11.24
10.8

4a
411.45
46.77/46.71
4.15/4.16
10.26/10.21
15.65/15.59
4.7

4b
439.51
49.17/49.19
4.89/4.82
9.58/9.56
14.57/14.59
4.7

6a
425.48
47.96/47.99
4.54/4.50
7.88/7.98
15.12/15.07
4.7

9a
234.28
56.33/56.39
4.28/4.30
11.88/11.96
13.61/13.69
8.5

9b
248.30
58.03/58.05
4.81/4.87
11.22/11.28
12.85/12.91
8.5

10a
374.44
54.50/54.53
3.68/3.77
7.51/7.48
17.15/17.13
5.3

10b
402.49
56.73/56.70
4.52/4.51
6.88/6.96
15.86/15.93
5.3

12a
388.46
55.63/55.65
4.11/4.15
7.16/7.21
16.46/16.51
5.3

15a
243.28
49.43/49.37
5.41/5.39
5.73/5.76
13.16/13.18
5.0

15b
257.31
51.33/51.35
5.81/5.88
5.36/5.44
12.49/12.46
4.8

p values from ACD, Inc.

Synthesized compounds were also screened for their antibacterial against Gram negative bacteria E. coli and Gram positive S. aureus and B. subtilis by following the guidelines of CLSI [22, 23] using ciprofloxacin and sulfamethoxazole as reference antibacterial agents. Antifungal activity was also evaluated for synthesized compounds against three strains, namely, A. flavus, A. parasiticus, and A. sp, using itraconazole as reference antifungal agent. Among the bacterial strains, compound 3b has excellent antibacterial activities having MIC 40 μg/mL against S. aureus with zone of inhibition comparable with control drug (ciprofloxacin). The of compound 3b is 10.8 which has electron withdrawing inductive effect (mild acidic) for which supports its cell permeability against the particular bacterial strain to bind the proteins. As far as SAR is concerned, amide functional group further supports its activity. Compounds 4b and 15b showed better activity against E. coli and compounds 3a, 4a, 4b, and 6a have no activity against the Gram positive S. aureus and B. subtilis while 10b, 12a, 15a, and 15b have good activity against these bacterial strains which is higher (MIC 80 μg/mL) than already existing sulfa drug (sulfamethoxazole; MIC 160 μg/mL). The MIC values and zone of inhibitions are presented in Table 2. The activities of above-mentioned compounds are their high permeability into cell due to their acidic behavior by virtue of their lower values (4.7–5.3), while the value of sulfamethoxazole is 5.7. The electrostatic interaction of methyl group with protein and pyridine further supports their antibacterial activities [24].

Table 2: Zone of inhibition and MIC of sulfonamides against pathogenic bacterial strains.

Compounds
Name of bacteria

Gram (+) bacterial strains
Gram (−) bacterial strains

S. aureus
B. subtilis
E. coli

(ATCC 25923)
(ATCC 6633)
(ATCC 25922)

Zone of inhibition
MIC
Zone of inhibition
MIC
Zone of inhibition
MIC

3a
—, —, —
—
—, —, —
—
9, —, —
>160

3b
32, 29, 26
40
8, —, —
>160
—, —, —
—

4a
—, —, —
—
—, —, —
—
—, —, —
—

4b
—, —, —
—
—, —, —
—
28, 25, 22
80

6a
—, —, —
—
—, —, —
—
9, —, —
>160

9a
—, —, —
—
9, —, —
160
9, —, —
>160

9b
—, —, —
—
8, —, —
>160
—, —, —
—

10a
9, —, —
>160
—, —, —
—
14, 10, —
160

10b
27, 24, 22
80
—, —, —
—
—, —, —
—

12a
9, —, —
>160
28, 24, 21
80
—, —, —
—

15a
29, 26, 21
80
—, —, —
—
—, —, —
—

15b
—, —, —
—
27, 24, 22
80
28, 25, 20
80

Ciprofloxacin
36, 34, 31
0.5
36, 33, 31
0.5
35, 34, 31
0.5

Sulfamethoxazole
—, —, —
—
16, 13, —
160
33, 28, 25
40

Zone of inhibition was measured in mm at concentration of 160, 80, and 40 μg mL⁻¹.

MIC (minimum inhibitory concentrations) were measured in μg mL⁻¹.

Control drug; sulfa drug.

Among the fungal strains, compounds 9a and 9b have excellent activity against A. parasiticus and A. flavus, respectively, while 10a and 15a showed better activity against A. parasiticus and A. sp. was insensitive to all strains except compound 15b (MIC 160 μg/mL). The amide bond formations in the above-mentioned synthesized compounds have excellent activities against the fungal strains as far as the SAR is concerned [25–27]. It is concluded that newly synthesized sulfonamides exhibited greater activity than reference itraconazole. The MIC values and zone of inhibitions are reported in Table 3.

Table 3: Zone of inhibition and MIC of sulfonamides against pathogenic fungal strains.

Compounds
Name of fungi

A. parasiticus
A. flavus
A. sp.

(ATCC 15517)
(ATCC 9643)
(ATCC 200667)

Zone of inhibition
MIC
Zone of inhibition
MIC
Zone of inhibition
MIC

3a
—, —, —
—
—, —, —
—
—, —, —
—

3b
—, —, —
—
12, —, —
160
—, —, —
—

4a
9, —, —
>160
—, —, —
—
—, —, —
—

4b
—, —, —
—
—, —, —
—
—, —, —
—

6a
—, —, —
—
—, —, —
—
—, —, —
—

9a
24, 21, 18
40
—, —, —
—
—, —, —
—

9b
22, 19, 13
80
22, 19, 15
40
9, —, —
>160

10a
21, 18, 12
80
—, —, —
—
—, —, —
—

10b
—, —, —
—
24, 20, 18
80
13, —, —
160

12a
—, —, —
—
12, —, —
160
—, —, —
—

15a
24, 21, 18
80
—, —, —
—
—, —, —
—

15b
11, —, —
>160
—, —, —
—
15, 12, —
160

Itraconazole
18, 11, —
160
21, 19, 15
80
12, —, —
>160

Zone of inhibition was measured in mm at concentration of 160, 80, and 40 μg mL⁻¹.

MIC (minimum inhibitory concentrations) were measured in μg mL⁻¹.

Control drug.

4. Conclusion

Amidine and benzene sulfonamides derivatives were synthesized and evaluated biologically. Among the synthesized compounds 3b was proved potent antibacterial agent with MIC 40 μg/mL and zone of inhibition comparable with ciprofloxacin and more effective than sulfamethoxazole. Synthetic compounds 9a and 9b showed better inhibition than itraconazole against A. parasiticus and A. flavus, respectively, with MIC 40 μg/mL.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

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