Synthesis, Characterization, and Evaluation for Antibacterial and Antifungal Activities of <i>N</i>-Heteroaryl Substituted Benzene Sulphonamides

Igwe, Christiana Nonye; Okoro, Uchechukwu Chris

doi:https://doi.org/10.1155/2014/419518

Organic Chemistry International

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Research Article | Open Access

Volume 2014 | Article ID 419518 | https://doi.org/10.1155/2014/419518

Synthesis, Characterization, and Evaluation for Antibacterial and Antifungal Activities of N-Heteroaryl Substituted Benzene Sulphonamides

Christiana Nonye Igwe¹and Uchechukwu Chris Okoro¹

Academic Editor: Joseph E. Saavedra

Received02 May 2014

Revised06 Aug 2014

Accepted06 Aug 2014

Published27 Nov 2014

Abstract

The synthesis and biological activity of N-heteroaryl substituted benzene sulphonamides (3a–h) were successful. Simple condensation reaction of benzene sulphonyl chloride (1) with substituted heteroaromatic compounds (2a–h) under dry pyridine and acetone gave the target molecules (3a–h) in good to excellent yield. The compounds were characterized using FTIR, ¹HNMR, and ¹³CNMR. The compounds were screened for antibacterial activity against E. coli, Salmonella typhi, P. aeruginosa, B. cereus, K. pneumonia, and Sarcina lutea and antifungal activity against C. albicans and A. niger. The results of the antimicrobial activity showed improved biological activity against some tested organisms.

1. Introduction

A large number of sulphonamide derivatives have ultimately been reported to show substantial protease inhibitory properties [1]. Sulphonamides are synthetic antimicrobial agents which act as competitive inhibitors of the enzyme dihydropteroate synthetase (DHPS) [2]. The basic sulphonamide group, SO₂NH, occurs in various biological active compounds widely used as antimicrobial drugs, antithyroid agents, antitumor, antibiotics, and carbonic anhydrase inhibitors [3, 4]. Clinically, sulphonamides are used to treat several urinary tract infections and gastrointestinal infections [5]. Aromatic or heteroaromatic sulphonamides that are used as antitumor agent act by inhibiting carbonic anhydrase. Structurally, sulphonamides are similar to p-aminobenzoic acid (PABA) which is a cofactor needed by bacteria for the synthesis of folic acid and therefore could compete for incorporation. Sulphonamide antibiotics are used as veterinary medicines to treat infections in livestock herds [6, 7]. Additionally, sulphonamides are extremely useful pharmaceutical compounds because they exhibit a wide range of biological activities such as anticancer, anti-inflammatory, and antiviral activity [8–12]. The sulphonylation of amines with sulphonyl chlorides in the presence of a base is still being used as the method of choice because of high efficiency and simplicity of the reaction [13]. However, this approach is limited by the formation of undesired disulphonamides with primary amines and by the need of harsh reaction conditions for less nucleophilic amines such as anilines [14]. Additionally, side reactions take place in the presence of a base. Sulphonamides have been used as protecting groups of OH or NH functionalities for easy removal under mild conditions [15, 16].

Resistance to sulphonamides by bacteria is most likely a result of a compensatory increase in the biosynthesis of p-aminobenzoic acid by bacteria although other mechanisms may play a role [17, 18]. Resistance of E. coli strains to sulphonamide has been shown due to their containing sulphonamide-resistant dihydropteroate synthase [19]. Research has shown that all things being equal, antibacterial activities of sulphonamides decreases as the length of the carbon chain increases [20]. This work describes the synthesis, spectroscopic characterization of some N-heteroaryl substituted benzene sulphonamides (3a–h) and evaluation for their antimicrobial activities against Bacillus cereus, Sarcina lutea, Pseudomonas aeruginosa, Escherichia coli, Salmonella typhi, Klebsiella pneumonia, Aspergillus niger, and Candida albicans.

2. Experimental

2.1. General Consideration

All the starting materials and reagents were obtained from Sigma-Aldrich and were used without further purification. The melting points were determined with Fischer John’s melting point apparatus and are uncorrected. IR spectra were recorded on 8400 s Fourier Transform Infrared (FTIR) spectrophotometer using KBr disc and absorption was reported in wave number (cm⁻¹). IR analysis was done at National Research Institute for Chemical Technology (NARICT), Zaria, Kaduna State. Nuclear Magnetic Resonance (¹H-NMR and ¹³C-NMR) were determined using Jeol 400 MHz at University of Strathclyde, Scotland. The chemical shifts were reported in (δ).

2.2. General Procedures

The synthesis of N-heteroaryl substituted benzene sulphonamide (3a–h) is described below. Heteroaromatic compounds (2a–h) (10 mmol) were dissolved in anhydrous acetone (10.00 ml) with dry pyridine (3 ml) and benzene sulphonyl chloride (1) (1.76 g, 10 mmol) was added at room temperature and allowed to stir for about 5 minutes for dissolution. The reaction mixture was left for 24 hours to give N-heteroaryl substituted benzene sulphonamide (3a–h) as crystalline solid after suction filtration. The crude product was recrystallized from acetone and dimethylformamide (DMF). The products were dried in a hot air oven at 50°C for 6 hours to give the target molecule in good to excellent yields (67.8% to 85.5%).

N-(Pyridine-2-yl) Benzene Sulphonamide (3a). Yield: 1.99 g (85.0%); m.p. 169-170°C; IR (KBr) cm⁻¹ 3475 (NH), 3030 (C–H aromatic), 1617 (C=C of aromatic), 1372 (C=N), 1270 (S=O), 1119 (SO₂NH), 972 (C–H deformation), 678 (monosubstitution). ¹HNMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1 H), 7.99 (d, Hz, 1 H), 7.87 (m, 5 H), 7.54 (m, 4 H), 7.17 (d, Hz, 2 H), 6.85 (t, Hz, 2 H). ¹³CNMR (400 MHz, DMSO-d₆): δ 153.82, 143.49, 142.59, 141.15, 132.70, 129.51, 127.03, 115.93, 114.49.

N-(4 Methylpyridine-2-yl) Benzene Sulphonamide (3b). Yield: 1.95 g (85.5%); m.p 209-210°C; IR (KBr) cm⁻¹ 3468 (N–H), 3034 (C–H aromatic), 2911 (C–H aliphatic), 1613 (C=C aromatic), 1274 (S=O), 1385 (C=N), 1148 (SO₂NH), 725 (monosubstitution). ¹HNMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1 H), 7.81 (s, 1 H), 7.51 (m, 1 H), 7.03 (d, Hz, 2 H), 6.66 (d, Hz, 2 H), 2.22 (d, Hz, 3 H).

N-(3 Nitropyridine-2-yl) Benzene Sulphonamide (3c). Yield: 1.81 g (65.1%); m.p 153-154°C. IR (KBr) cm⁻¹ 3459 (N–H), 3114 (C–H aromatic), 1642 (C=C aromatic), 1450 (NO₂), 1226 (S=O), 1334 (C=N), 1069 (SO₂NH), 763 (substitution in benzene ring); ¹HNMR (400 MHz, DMSO-d₆): δ 8.38 (m, 5 H), 7.89 (s, 1 H), 6.74 (dt, Hz, 6.48 Hz, 1 H).

N-(5 Nitropyridine-2-yl) Benzene Sulphonamide (3d). Yield: 1.96 g (70.5%); m.p. 179-180°C; IR (KBr) cm⁻¹ 3484 (N–H), 3057 (C–H aromatic), 1629 (C=C aromatic), 1295 (S=O), 2647 (C–H deformation), 1110 (SO₂NH aromatic), 995 (C–H deformation) 763 (substitution in benzene), ¹HNMR (400 MHz, DMSO-d₆): δ 8.84 (t, Hz, 1 H), 8.1 1 (m, 5 H), 7.53 (s, 1 H), 6.49 (d, Hz, 1 H).

N-(3 Hydropyridine-2-yl) Benzene Sulphonamide (3e). Yield: 1.76 g (70.7%); m.p. 189-190°C; IR (KBr) cm⁻¹ 3483 (N–H), 3289 (O–H), 3143 (C–H aromatic), 1627 (C=C aromatic), 1379 (C=N), 1169 (SO₂NH), 904 (C–H deformation) 797 (substitution in benzene ring). ¹HNMR (400 MHz, DMSO-d₆): δ 7.95 (m, 5 H), 7.81 (m, 1 H), 7.64 (t, 7.86 Hz, 2 H), 7.30 (dt, Hz, 7.86 Hz, 1 H), 6.51 (ddd, Hz, 4.90 Hz, 7.86 Hz, 3 H) 6.05 (s, 1 H). ¹³CNMR (400 MHz, DMSO-d₆): δ 153.01, 146.70, 135.69, 135.01, 131.39, 130.13, 130.08, 129.08, 112.40.

N-(5 Chloropyridine-2-yl) Benzene Sulphonamide (3f). Yield: 1.88 g (74.02%); m.p. 150-151°C. IR (KBr) cm⁻¹ 3684 (N–H), 3060 (C–H aromatic), 1695 (C=C aromatic), 1483 (S=O), 1354 (C=N), 1159 (SO₂NH), 937 (C–H deformation), 747 (substitution in benzene ring). ¹HNMR (400 MHz, DMSO-d₆): δ 8.21 (d, Hz, 2 H), 7.91 (m, 5 H), 7.79 (ddd, Hz, 3.45 Hz, 9.12 Hz, 3 H), 7.09 (d, Hz, 2 H).

N-(2,6-Dichloropyridine-4-yl) Benzene Sulphonamide (3g). Yield: 2.17 g (71.6%); m.p. 199-200°C; IR (KBr) cm⁻¹ 3314 (N–H), 3124 (C–H aromatic), 1657, 1533 (C=C aromatic), 1141 (SO₂NH), 1042 (C–N), 995 (C–H deformation), 797 (substitution in benzene ring). ¹HNMR (400 MHz, DMSO-d₆): δ 7.60 (, 1 H), 6.86 (, 5 H).

N-(3,5-Dichloropyridine-2-yl) Benzene Sulphonamide (3h). Yield: 2.20 g (72.6%); m.p. 71-72°C. IR (KBr) cm⁻¹ 3465 (N–H), 3152 (C–H aromatic), 1621 (C=C aromatic), 1461 (S=O), 1235 (C–S), 1041 (SO₂NH), 732 (substitution in benzene ring). ¹HNMR (400 MHz, DMSO-d₆): δ 7.92 (d, Hz, 2 H), 7.76 (dt, Hz, 7.13 Hz, 2 H), 6.52 (s, 1 H).

2.3. Sensitivity Tests

Agar cup diffusion technique method as described by Vincent (2005) [21] was used to determine the antimicrobial activities of the synthesized compounds. Sensitivity test agar plates were seeded with 0.1 ml of 24 hours culture of each microorganism into its corresponding petri dish previously labeled using the molten agar already prepared. The plates were allowed to set after which cups were made in each sector previously drawn on the backside of the bottom-plate using marker. Using the pipette (sterile), each cup was filled with six drops of their corresponding antimicrobial agent (in appropriate solvent at a concentration of 2 mg/mL). The plates were finally incubated at 37°C for 24 hours for bacteria and 48 hours for fungi. The solubilizing solvent used was dimethylformamide (DMF). Mueller Hinton agar was prepared in 20 mL portions kept molten at 45°C. The zone of inhibition (clearance) produced after 24 hours on incubation at 37°C was measured. The procedure was repeated for ciprofloxacin and ketoconazole drugs (bacteria and fungi standard, resp.).

2.4. Minimum Inhibitory Concentration (MIC) Tests

The MIC was determined by further dilution of the test sample found to be sensitive against a particular organism. Serial dilutions of the sulphonamides were prepared from 2 mg/mL solution of the sulphonamides to give 2.0–0.125 mg/mL. After dilution, the test solutions were added to their corresponding cups previously made in the molten agar starting from the lowest concentration (0.125–1.0 mg/mL). This was followed by incubation at the appropriate incubation temperature and time. The resultant inhibition zones of diameter (IZD) were measured and the value was subtracted from the diameter of the cork borer (8 mm) to give the inhibition zone diameter (IZD). The MIC was also determined using graph of logarithm of IZD² against concentration for each plate containing a specific compound and a microorganism. The antilogarithm of the intercept on -axis gives the MIC.

IZD = inhibition zone diameter.

3. Result and Discussion

We described here the synthesis of various N-heteroaryl substituted benzene sulphonamides (3a–h) using simple condensation of benzene sulphonyl chloride (1) and substituted pyridine (2a–h) as starting materials shown in Schemes 1 and 2. The N-heteroaryl substituted benzene sulphonamides (3a–h) were synthesized as white crystalline solid in exception of 2-amino-5-nitropyridine 3d and 2-amino-3-nitropyridine 3c derivatives that were yellowish solid. The FTIR spectra revealed the presence of a sulphonamide group (1373–1140 cm⁻¹), –NH group (3640–3461 cm⁻¹). The ¹HNMR and ¹³CNMR signals agree with the structures of the compounds. Worthy to mention is the appearance of peaks at 6.86 which is assigned to heteroaromatic protons. The N-heteroaryl substituted benzene sulphonamide derivatives (3a–h) synthesized were screened for their antibacterial activities against some of the pathogenic bacteria, namely, Bacillus cereus, Sarcina lutea, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi, and Escherichia coli, and antifungal activities against some pathogenic fungi, namely, Candida albicans and Aspergillus niger. The antimicrobial activity of the analogues was compared with standard drug ciprofloxacin and ketoconazole for antibacterial and antifungal activities, respectively. The result of inhibition zone diameter IZD as presented in Table 1 indicates that compound 3f was inactive. The result of the minimum inhibitory concentration MIC as presented in Table 2 shows that compounds 3e, as against S. typhi, 3c, as against K. pneumoniae, and 3g, as against A. niger, have more actives than the standard drugs. A further observation of table indicates that most of the synthesized compounds had comparable antimicrobial property. We used ciprofloxacin and ketoconazole as standards because ciprofloxacin and ketoconazole are antibacterial and antifungal standard drugs that show zone of inhibition like other antimicrobial synthesized compounds. We discuss piperidine/acetone as other base/solvent combination that has been examined other than pyridine/acetone because piperidine/acetone and its derivatives are ubiquitous building blocks in the synthesis of pharmaceuticals compounds like antidepressant drug [22–24] and vasodilators [25]. Piperidine/acetone is also commonly used in sequencing of DNA16 and in solid phase peptide synthesis [26]. This is together with the steric factor which potentiates formation of p-nucleophiles (saturated heterocyclic amines) that are added in excess moles to serve as base picking the released HCl and yielding water soluble salt and enhancing the yield of products that were now ready for the next step, that is, acid hydrolysis of amide linkage rather than sulphonamide.

4. Conclusions

The present study describes a convenient and efficient protocol for the synthesis of N-heteroaryl substituted benzene sulphonamide derivatives using benzene sulphonyl chloride and heteroaromatic compounds under dry pyridine and acetone conditions. We believe that this procedure is convenient, economic, and user-friendly process for the synthesis of these various sulphonamide compounds. All the synthesized compounds were supported by IR, ¹HNMR, and ¹³CNMR spectral data. The sulphonamide derivatives were screened for their antimicrobial activity against few bacterial and fungal strains and it was observed that some of the compounds showed more biological activity than the standard drug.

Conflict of Interests

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

References

A. Casini, A. Scozzafava, and C. T. Supuran, “Sulfonamide derivatives with protease inhibitory action as anticancer, anti-inflammatory and antiviral agents,” Expert Opinion on Therapeutic Patents, vol. 12, no. 9, pp. 1307–1327, 2002.
View at: Google Scholar
Sulphanomide—Medicine, “The Free Encyclopedia,” 2009, http://en.wikipedia.org/wiki/su/fonamide.
View at: Google Scholar
C. T. Supuran, A. Scozzafava, L. Menabuoni, F. Mincione, F. Briganti, and G. Mincione, “Carbonic anhydrase inhibitors. Part 71: synthesis and ocular pharmacology of a new class of water-soluble, topically effective intraocular pressure lowering sulfonamides incorporating picolinoyl moieties,” European Journal of Pharmaceutical Sciences, vol. 8, no. 4, pp. 317–328, 1999.
View at: Publisher Site | Google Scholar
M. Remko and C.-W. von der Lieth, “Theoretical study of gas-phase acidity, pK_a, lipophilicity, and solubility of some biologically active sulfonamides,” Bioorganic & Medicinal Chemistry, vol. 12, no. 20, pp. 5395–5403, 2004.
View at: Publisher Site | Google Scholar
A. K. Gaded, C. S. Mahajanshetti, A. Nimbalkar, and A. Raichurkar, “Synthesis and antibacterial activity of some 5-guanylhydrazone/thiocyanato-6-arylimidazo[2,1-b]-1,3,4-thiadiazole-2-sulfon amide derivatives,” European Journal of Medicinal Chemistry, vol. 35, no. 9, pp. 853–857, 2003.
View at: Google Scholar
N. S. El-Sayed, E. R. El-Bendary, S. M. El-Ashry, and M. M. El-Kerdawy, “Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a]pyrimidines,” European Journal of Medicinal Chemistry, vol. 46, no. 9, pp. 3714–3720, 2011.
View at: Publisher Site | Google Scholar
M. J. Garcia-Galan, M. S. Diaz-Cruz, and D. Bercelo, “Identification and determination of metabolites and degradation products of sulfonamide antibiotics,” Trends in Analytical Chemistry, vol. 27, no. 11, pp. 1008–1022, 2008.
View at: Google Scholar
C. T. Supuran, A. Casini, and A. Scozzafava, “Protease inhibitors of the sulfonamide type: anticancer, antiinflammatory, and antiviral agents,” Medicinal Research Reviews, vol. 23, no. 5, pp. 535–558, 2003.
View at: Google Scholar
A. Scozzafava, T. Owa, A. Mastrolorenzo, and C. T. Supuran, “Anticancer and antiviral sulfonamides,” Current Medicinal Chemistry, vol. 10, no. 11, pp. 925–953, 2003.
View at: Publisher Site | Google Scholar
W. G. Harter, H. Albrect, K. Brady et al., “The design and synthesis of sulfonamides as caspase-1 inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 3, pp. 809–812, 2004.
View at: Publisher Site | Google Scholar
N. S. Reddy, M. R. Mallireddigari, S. Cosenza et al., “Synthesis of new coumarin 3-(N-aryl) sulfonamides and their anticancer activity,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 15, pp. 4093–4097, 2004.
View at: Publisher Site | Google Scholar
B. R. Stranix, J. F. Lavallee, G. Sevigny et al., “Lysine sulfonamides as novel HIV-protease inhibitors: Nε-Acyl aromatic α-amino acids,” Bioorganic & Medicinal Chemistry Letters, vol. 16, no. 13, pp. 3459–3462, 2006.
View at: Google Scholar
K. K. Anderson and D. N. Jones, vol. 3, Pergamon Press, Oxford, UK, 1979.
A. Yasuhara, M. Kameda, and T. Sakamoto, “Selective monodesulfonylation of N, N-disulfonylarylamines with tetrabutylammonium fluoride,” Chemical and Pharmaceutical Bulletin, vol. 47, no. 6, pp. 809–812, 1999.
View at: Publisher Site | Google Scholar
J. F. O'Connell and H. Rapoport, “1-(Benzenesulfonyl)- and 1-(p-toluenesulfonyl)-3-methylimidazolium triflates: efficient reagents for the preparation of arylsulfonamides and arylsulfonates,” Journal of Organic Chemistry, vol. 57, no. 17, pp. 4775–4777, 1992.
View at: Publisher Site | Google Scholar
S. Chandrasekhar and S. Mohapatra, “Neighbouring group assisted sulfonamide cleavage of sharpless aminols under acetonation conditions,” Tetrahedron Letters, vol. 39, no. 7, pp. 695–698, 1998.
View at: Publisher Site | Google Scholar
R. Gleckman, S. Alvarez, and D. W. Joubert, “Drug therapy reviews: trimethoprim-sulfamethoxazole,” The American Journal of Hospital Pharmacy, vol. 36, no. 7, pp. 893–906, 1979.
View at: Google Scholar
S. R. Bushby and G. H. Hitchings, “Trimethoprim, a sulphonamide potentiator,” British Journal of Pharmacology, vol. 33, no. 1, pp. 72–90, 1968.
View at: Google Scholar
G. Thomas, Medicinal Chemistry, John Wiley and Sons, 2nd edition, 2007.
N. Ozbek, H. Katircioglu, N. Karacan, and T. Baykal, “Synthesis, characterization and antimicrobial activity of new aliphatic sulfonamide,” Bioorganic and Medicinal Chemistry, vol. 1, no. 15, pp. 5105–5109, 2007.
View at: Google Scholar
C. O. Vincent, Pharmaceutical Microbiology: Principles of the Pharmaceutical Applications of Antimicrobial Agents, El 'Demak Publishers, Enugu, Nigeria, 2005.
R. Soleymani, N. Niakan, S. Tayeb, and S. Hakimi, “Synthesis of novel aryl quinoxaline derivatives by new catalytic methods,” Oriental Journal of Chemistry, vol. 28, no. 2, pp. 687–701, 2012.
View at: Publisher Site | Google Scholar
S. K. Anandan, “1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent, selective, and orally available soluble epoxide hydrolase inhibitor with efficacy in rodent models of hypertension and dysglycemia,” Bioorganic & Medicinal Chemistry Letters, vol. 21, no. 3, pp. 983–988, 2011.
View at: Publisher Site | Google Scholar
L. Tietze and F. FMajor, “Synthesis of new water-soluble DNA-binding subunits for analogues of the cytotoxic antibiotic CC-1065 and their prodrugs,” European Journal of Organic Chemistry, vol. 10, pp. 2314–2321, 2006.
View at: Google Scholar
G. P. Claxton, L. Allen, and J. M. Grisar, “For peptide synthesis, synthesis of 2,3,4,5-tetrahydropyridine,” Organic Syntheses. Collective Volume, vol. 6, p. 968, 1988.
View at: Google Scholar
K. Shin-Ya, J.-S. Kim, K. Furihata, Y. Hayakawa, and H. Seto, “Structure of kaitocephalin, A novel glutamate receptor antagonist produced by eupenicillium shearii,” Tetrahedron Letters, vol. 38, no. 40, pp. 7079–7082, 1997.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2014 Christiana Nonye Igwe and Uchechukwu Chris Okoro. 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.

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