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Research Article Amidine Sulfonamides and Benzene Sulfonamides ... · PDF fileResearch Article...

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  • Research ArticleAmidine 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

    1 Institute of Chemistry, University of Punjab, Lahore 54590, Pakistan2Institute of Biochemistry & Biotechnology, University of the Punjab, Lahore 54590, Pakistan

    Correspondence should be addressed to Mahmood Ahmed; [email protected]

    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 CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

    New amidine and benzene sulfonamide derivatives were developed and structures of the new products were confirmed by elementaland spectral analysis (FT-IR, ESI-MS, 1HNMR, and 13CNMR). In vitro, developed compounds were screened for their antibacterialand 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(g/mL) and zone of inhibitions (mm). Among the tested compounds, it was found that compounds 3b, 9a, and 9b have mostpotent activity against S. aureus, A. flavus, and A. parasiticus, respectively, and were found to be more active than sulfamethoxazoleand itraconazole with MIC values 40g/mL. In contrast, all the compounds were totally inactive against the A. sp. except 10b and15b to show activity to some extent.

    1. Introduction

    Sulfonamides are basis of several drug groups, known assulfa drugs. Any compound that has sulfonamide moiety(SO2NH2) in its structure is referred to as sulfonamide. They

    comprise substantial class of pharmaceutical drugs, contain-ing various kinds of pharmacological agents having antitu-mor [1], antibacterial [2], anticarbonic anhydrase [3, 4], diu-retic [5, 6], hypoglycemic [7], and protease inhibitory activity[810] or antithyroid activity [11] among others. Sulfonamidesare mostly used to treat the bacterial infectious cells becausethey do not significantly affect the antigenic properties of theinfective organism or the development of specific antibodies[12]. Bacteria have liability to acquire resistance against sul-fonamides by changing their cell wall permeability, enhanc-ing essential metabolites production, or increasing produc-tion of enzyme [13]. In this way sulfonamides become inef-fective to inhibit their production. But their ineffectivenessin drug therapy can be abstained, due to inductive effect ofSO2group. Sulfonamides having first pa value around 10 are

    less soluble in water; therefore, they may readily crystalize inkidney but with advancement in medical science, and newsulfonamides have been synthesized having lower pa value(5-6) to avoid crystallization in kidney [14]. The compoundshaving pyridine and amide functional group exhibit variousbiological activities like antifungal and antibacterial. So thesebiological activities encourage us to synthesize the sulfon-amides containing such important functional groups [1518].The motivation behind this research work was to synthesizesomenovel sulfonamides (Schemes 14) having antimicrobialproperties. Different amines were chosen and reacted withsulfonyl chlorides. As a result of substitution, different func-tional groups were added and resulting compounds exhibitedantibacterial and antifungal activities.

    2. Experimental

    2.1. Chemistry. Chemicals used in present work were ofanalytical grade obtained from E-Merck (Germany), SigmaAldrich (USA), and BDH (UK) without further purification

    Hindawi Publishing CorporationJournal of ChemistryVolume 2015, Article ID 524056, 8 pageshttp://dx.doi.org/10.1155/2015/524056

  • 2 Journal of Chemistry

    NH2

    R1R1

    R1

    R1R1 R2

    R2

    R

    RR

    R

    N

    NSS

    S

    S SS

    S

    O O

    OOO

    O

    O

    O

    O

    OO

    OO

    OCl

    ClNH

    NH

    NH

    NH

    HN

    +

    3a, 3b

    4a, 4b

    6a

    1 2

    5

    Scheme 1: Amidine sulfonamides.

    NH2

    R1

    R1

    R1 R1

    R1R2

    R2 RR

    R

    R

    N

    N

    SS

    S

    SS

    S

    S

    O

    OO

    O

    O O

    OO

    O

    O

    O

    O O

    O

    12a9a, 9b

    10a, 10b

    Cl

    Cl

    HN

    78

    11

    +

    Scheme 2: Benzene sulfonamides (series 1).

    R1

    R1

    R1

    H3CH3C

    H3CR

    R

    R

    N

    NS

    S

    SO

    O

    OO

    O

    O

    15b

    15aCl

    1413

    NH +

    Scheme 3: Benzene sulfonamides (series 2).

    to synthesize desired compounds, and high purity water(0.01S/cm) was prepared in our own laboratory usingMilli-Q purification system (USA). Alpha IR spectrometer (FTIR-ATR) andNMRspectrometer, Bruker, were used to record theIR and 1HNMR (500MHz) and 13CNMR (125MHz) spectra,respectively. PG-T80+ UV-Vis spectrophotometer (UK) andFlash HT Plus elemental analyzer (Thermo Scientific, UK)were used for max, and concentration of hydrogen (H),carbon (C), nitrogen (N), and sulfur (S) of synthesizedcompounds, respectively, while the melting point was mea-sured by Gallenkamp apparatus. JMS-HX-110 spectrometerwith electron spray ionization (ESI) interface was used formass spectra. The 1HNMR and 13CNMR spectra of all thesynthesized compounds were measured using MeOD and

    concentration of all the compounds was 1020mg in 0.81.0mL of solvent. Purification and progress of the synthesizedcompounds were confirmed on precoated TLC silica plate(Merck-Germany).

    2.2. Antimicrobial Assay. Escherichia coli ATCC 25922,Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC6633, Aspergillus flavus ATCC 9643, Aspergillus parasiticusATCC 15517, and Acremonium sp. ATCC 200667 were col-lected 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 5C until use. A series of four 2-fold dilutions (320,160, 80, and 40 g/mL) were made from stock solution of640 g/mL in dimethyl sulphoxide (DMSO). All the dilutionswere made sterile in an autoclave at 121C for 30min with15 psi pressure after filtration through 0.22m membranefilter. The minimal inhibitory concentration (MIC) wasreported as absence of no observable growth by the lowestconcentration of tested compounds after twofold serial dilu-tion. Five individually numbered test tubes with screw capswere sterilized. Tube 1was filledwith 2mLof tryptic soy brothculture media including the stock solution of synthesizedcompounds. 1.0mL of this solution was introduced into 2tubes and diluted with 1.0mL culture media and we repeatedthe procedure up to tube 5. The tubes were incubated at25C for 72 hrs. Ciprofloxacin and sulfamethoxazole (sulfadrug) were used as reference (positive control to check

  • Journal of Chemistry 3

    R

    3a, 4a NO

    OH

    3b, 4b NO

    OH

    6a NO

    OH

    9a, 10a

    N

    9b, 10b

    N

    12a

    N

    15a

    O

    OH

    15b

    O

    OH

    H3C

    H3C

    H3C

    H3C

    H3C

    H3C

    H3C

    CH3

    CH3

    CH3

    R1 R2

    Scheme 4

    the sensitivity of tested bacterial strains). 13 108 cfu/mLof each of Gram negative E. coli and Gram positive S. aureusand B. subtiliswas obtained after adjusting the optical densityof inoculum at 0.20.3 and 0.30.4 (620 nm), respectively,while fungal suspension (A. flavus, A. parasiticus, and A. sp.)with cell density of 105 cfu/mL was studied in present workand the itraconazole was used as reference antifungal agent.All the compounds and reference solutions were applied(50L) onto a 6mm sterile filter paper disc separately andthe inoculated plates incubated at 37C for 24 hrs. The zonesof inhibition (mm) weremeasured and we evaluated the anti-bacterial activities.

    2.3. General Procedure for Synthesis of Sulfonamides. Asimplemethod in aqueous media under dynamic pH control isadopted for synthesis of sulfonamides. Filtration after acidi-fication is involved for isolation of products [1921]. All theamines were weighed accurately and dissolved completelyby addition of distilled water by constant stirring usingmagnetic stirrer. The pH of the reaction contents was strictlymonitored andmaintained at 810 at regular intervals duringthe experimental reaction usingNa

    2CO3solution (1M).Then

    benzene sulfonyl chloride or p-toluene sulphonyl chloridewas accurately weighed and added carefully into the abovesolution. The reaction was carried in round bottom flaskequipped with magnetic stirrer. During stirring sulphonylchloride initially floats on the surface and the completion

    of reaction was examined by the change in pH value due toformation of HCl by the consumption of sulphonyl chloridesduring the reaction. On completion of the reaction pH wasadjusted at 2-3 using HCl solution (2M). The precipitatesformed were filtered through Whatman filter paper number42, washed several times with distilled water, and recrystal-lized using methanol and dried using rotary evaporator.

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

    10H13N3O4S). Yield: 397.9mg (64.7%); m.p.: 172

    174C; TLC: = 0.72 (H

    2O-BuOH-Acetic acid 1 : 4 : 1);

    IR (FTIR): = 3215 (O-Hcarboxylic, stretching), 3084 (C-Haromatic, stretching), 1768 (C=Ocarboxylic, stretching), 1707(C=Nimine, stretching), 1438 (O-Hcarboxylic, bending), 1033(S=Ostretching), 1165 (-N- S=Ostretching), 1458 (C=C-Caromatic, stretching), 70

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