Download chapter ia brief overview of structural, spectral and

CHAPTER I
A BRIEF OVERVIEW OF STRUCTURAL, SPECTRAL
AND BIOLOGICAL ACTIVITES OF SULFONAMIDES
1.1
INTRODUCTION
Sulfonamides constitute an important class of antimicrobial agents in the
world owing to their low cost, low toxicity, and excellent activity against bacterial
diseases. Sulfonamides act as competitive inhibitors of the enzyme dihydropteroate
synthase in bacteria, and catalyze the conversion of p-aminobenzoic acid into an
essential nutrient for some bacteria [1]. After the introduction of penicillin and
other antibiotics, the popularity of sulfonamides decreased. However, they are still
considered to be useful in certain therapeutic fields, especially in the case of
ophthalmic infection in urinary and gastrointestinal tract. Besides, sulfa drugs are
till today among the drugs of first selection (together with ampicillin and
gentamycin) as chemotherapeutic agents in bacterial infections by E. coli in
human. The potentially active sulfonamide derivatives deserve more detailed
experimental and systematic theoretical studies using updated computer programs
and recently available knowledge on structure activity relations.
1.2
CHEMISTRY AND NOMENCLATURE OF SULFONAMIDES
Sulfonamide is an antibacterial consisting of any of several synthetic
organic compounds capable of inhibiting the growth of bacteria that require PABA
(para-amino benzoic acid) which is structurally similar to sulfanilamide.
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Sulphonamides are the derivatives of sulfonic acids. Sulphonamides are
chemically quite stable, these are weak acids compared to carboxylic acid amides.
The acidic nature results from the ability of the SO2 moiety to stabilize the nitrogen
anion through resonance. The sulphonamide functional group is –S(=O)2-NH-, a
sulfonyl group connected to an amine group. The general formula is RSO2NH-.
where R is some organic group. Any sulfonamide can be considered as derived
from a sulfonic acid by replacing a hydroxyl group with an amine group. In
medicine, the term "sulfonamide" is sometimes used as a synonym for sulfa drug, a
derivative or variation of sulfanilamide. Figure 1.1 shows the structural formula of
sulfanilamide and Figure 1.2 shows the structural formula of PABA.
1.3
MECHANISM OF ACTION OF SULFONAMIDES
The relationship between their chemical structures and pharmacological
activities has been under investigation since their introduction as chemotherapy but
still has not been completely elucidated. Sulfa drugs kill bacteria and fungi by
interfering with cell metabolism. The structure of sulfa drug is analogous to
PABA. The similarity between them was shown by Wood-fielder theory [2].
According to Bell and Robin [3], a structure which is analogous to the chemical
structure of PABA may interfere within its biological function. The mechanism of
sulfonamide is known at enzyme level. In bacteria, antibacterial sulfonamides act
as competitive inhibitors of the enzyme dihydropteroate synthetase (DHPS).
Sulfonamide inhibits the enzyme folic acid synthetase, which is involved in the
conversion of PABA to folic acid, resulting in the deficiency of folic acid which
causes injury to the bacterial cell. Steps involving the inhibition of synthesis of
tetrahydrofolic acid are as mentioned in Figure 1.3.
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O
O
S
NH
OH
Figure 1.1 Structural formula of sulfanilamide
O
NH2
HO
Figure 1.2 Structural formula of PABA
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Pteridine + PABA
Blocked by Sulfonamide
Dihydroptenoic acid
Glutamate
Dihydrofolic acid
NaDPH2
NaDP
Figure 1.3 Steps involving in the inhibition of synthesis of tetrahydrofolic acid
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3
1.4
REVIEW ON STRUCTURAL, SPECTRAL AND DFT STUDIES ON
SULFONAMIDES
This section deals with general survey of the literature related to the present
topic which describes pharmacological importance, crystallographic, spectral and
DFT studies of substituted sulphonamides.
The sulfonamide functionality is much more widespread in pharmaceuticals
than just in an early class of antibiotics. Sulfonamides have been the subject of
pharmaceutical interest as a result of their potent biological activities [4-8].
Chohan et al [9] reported, spectral (IR, 1H and 13C NMR), elemental
analyses and X-ray diffraction data of 4-{[(E)-(5-Bromo-2-hydroxyphenyl)
methylidene]amino}-N-(5-methyl-1,2-oxazol-3-yl)benzene
sulfonamide.
This
sulfonamide derivative crystallizes in the monoclinic space group C2/c. In the
molecule of compound, the molecule is bent at the S atom with a C–SO2–NH–C
torsion angle of -86.3(3)°.
Mansour et al [10] reported theoretical and experimental structural studies
on
N-(4,6-Dimethyl-pyrimidin-2-yl)-[(2-hydroxy-benzylidene)amino]benzene
sulphonamide (SMS). SMS had been carried out by elemental analysis, FTIR,
1
H NMR, UV-Vis and MS. Optimized molecular structure and harmonic
vibrational frequencies had been investigated by DFT/B3LYP and HF methods
combined with 6-31G(d) basis set.
Mansour et al [11] reported synthesis, experimental and quantum chemical
calculations of (MnLCl(H2O)3]·H2O complex (HL = 4-amino-N-(4,6-dimethyl-2pyrimidinyl)benzenesulfonamide, sulfamethazine). Quantum chemical calculations
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were carried out at DFT/B3LYP level of theory. The compound was screened for
its biological activities.
Dabbagh et al [12] reported DFT, Ab initio and FT-IR Studies of the
Structure of sulfonamide Triazenes. sulfonamide Triazenes were theoretically
investigated using the density functional theory (DFT) and Hartree-Fock (HF)
levels of theory with the standard 6-31G* basis set. The calculated vibrational
frequencies were evaluated via comparison with experimental values.
Chandran et al [13] reported Vibrational spectroscopic and quantum
chemical
calculations of (E)-N-Carbamimidoyl-4-((naphthalen-1-yl-methylene)
amino)benzene
sulfonamide.
FT-IR
and
FT-Raman
spectra
of
(E)-N-
Carbamimidoyl-4-((naphthalen-1-yl-methylene)amino)benzene sulfonamide were
recorded and analyzed. The vibrational wavenumbers were computing at various
levels of theory. The data obtained from theoretical calculations are used to assign
vibrational bands obtained experimentally. The results indicate that B3LYP
method is able to provide satisfactory results for predicting vibrational frequencies
and structural parameters.
Chandran et al [14] reported Vibrational Spectroscopic Study of (E)-4(benzylideneamino)-N-carbamimidoylbenzenesulfonamide.
Geometry
and
harmonic vibrational wavenumbers were calculated theoretically using Gaussian
03 set of quantum chemistry codes. The calculated wavenumbers (B3LYP) agree
well with the observed wavenumbers.
Gowda et al [15] reported Synthetic, Infrared, 1H and
13
C NMR Spectral
Studies on Potassium Salts of N-Chloroarylsulphonamides. Their infrared spectra
in the solid state and NMR spectra in solution were measured and correlated.
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Comparison of the infrared spectra of the potassium salts of N-chloroarylsulphonamides with the corresponding arylsulphonamides showed that the
frequencies in the ranges 1404–1370 cm-1 and 1149–1125 cm-1 are assigned to
S=O asymmetric and symmetric vibrations respectively.
Gowda et al [16] reported the synthesis, characterization, infrared and
NMR
spectral
studies
on
N-(p-substitutedphenyl)-p-substitutedbenzene
sulphonamides. Their infrared spectra in the solid state and 1H and 13C NMR
spectra in solution were measured. The 1H and
13
C chemical shifts of N-(p-
substituted phenyl)-p-substituted benzenesulphonamides were assigned to various
protons and carbons of the two benzene rings.
Lujan et al [17] reported experimental and theoretical study of the
conformational, vibrational and magnetic properties of 4,6-di-O-acetyl-2,3dideoxy-D-threo-hex-2-enopyranosylethanesulfonamide. The IR spectrum of the
compound was recorded and theoretical calculations were performed to aid in the
assignment of both the NMR and IR spectra.
Alyar et al [18] reported tautomeric properties, conformations and structure
of 2-hydroxyacetophenone methanesulfonylhydrazone by quantum chemical
methods. The molecular geometry of the compound in the ground state has been
calculated using the restricted Hartree–Fock and density functional method. The
optimized bond lengths and bond angles obtained by using B3LYP are in better
agreement with the experimental values than those by using RHF.
Ozbek et al [19] reported synthesis, single crystal X-ray diffraction and
spectral
study
of
2-Hydroxy-1-naphthaldehyde-N-methylethanesulfonyl
hydrazone. It crystallizes in the monoclinic system, space group P21/c,
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a = 22.712(4), b = 5.793(4), c = 11.032(2) Å, α = 90.0°, β = 102.070(8)°, γ = 90.0°,
V = 1419.4(1)A3, Z = 4. Spectroscopic assignment and calculations carried out
using B3LYP/6-31G** basis set and crystallographic results indicate the
predominance of the phenol-imine in tautomeric form. Antimicrobial activity of
this compound was screened against E. coli ATCC 11230, P. aeruginosa ATCC
28753, S.enterititis ATCC 40376, S.aureus ATCC 25923 and B. cereus
RSKK 863.
Shainyan et al [20] reported spectral, DFT and intramolecular hydrogen
bonds in the sulfonamide derivatives of oxamide, dithiooxamide, and biuret.
Variation of the strength of the intra- and intermolecular H-bonds in the complexes
is consistent with the calculated frequencies of the NH and OH stretching
vibrations, and the analysis of the corresponding bands in the IR spectra allows to
suggest the preferable structure of the formed H-complexes.
Cami et al [21] reported experimental data and quantum chemistry
calculations of 5-amino-1,3,4-thiadiazole-2-sulfonamide. The optimized geometry
was obtained by means of the DFT methods of quantum chemistry, resulting in a
structure which agrees quite well with that obtained by X-ray diffraction.
Singh et al [22] reported DFT Based QSAR Studies of derivatives of
Benzene Sulphonamide using quantum chemical descriptors. Heat of formation
(ΔHf), molecular weight (MW), total energy (TE), HOMO energy (EHOMO),
LUMO Energy (ELUMO), absolute hardness (η) and electronegativity (χ) have been
used as descriptors for QSAR studies of derivatives of benzene sulphonamides.
Yu et al [23] reported crystal structure of N-(4-pyridyl)benzene
sulfonamide, (C11H10N2O2S). It crystallizes as a zwitterionic tautomer,
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N-(4-pyridinio)benzene sulfonamidate, with the pyridine N atom protonated and
the amide N atom deprotonated. There is evidence for conjugation between the
anionic N atom and the pyridinium ring. In the crystal structure, intermolecular NH N hydrogen bonds link the molecules into chains along the c axis. Weak CH O and C-H π interactions further stabilize the structure.
You et al [24] reported N-(3,4-Difluorophenyl)-3,4-dimethoxybenzenesulfonamide derivative (C14H13F2NO4S). The dihedral angle between the benzene
rings is 66.05 (9)°. The crystal structure is stabilized by weak intermolecular
N-H O hydrogen bonds involving the amine and methoxy groups, which link the
molecules into a one-dimensional chain.
El-Ghamry et al [25] reported, crystal structural of [(3-Formyl-4hydroxyphenyl) diazenyl]-N-(pyrimidin-2-yl)benzenesulfonamide (C17H13N5O4S).
It has a trans configuration with respect to the diazenyl (azo) group. The
pyrimidine ring and the terminal benzene ring are inclined at angles of 89.38 (4)
and 1.6 (6)°, respectively, with respect to the central benzene ring. The
conformation of the molecule is in part stabilized by an intramolecular O-H O
hydrogen bond.
Karabacak et al [26] reported quantum chemical investigation of the
molecular conformation, NMR chemical shifts and vibrational transitions of N-(2methylphenyl)methanesulfonamide and N-(3-methylphenyl)methanesulfonamide
(C8H11NO2S) using DFT B3LYP exchange correlation. The vibrational
wavenumbers were calculated and the complete assignments were performed on
the basis of the total energy distribution (TED) of the vibrational modes, calculated
with scaled quantum mechanics (SQM) method. The 1H and
13
C NMR chemical
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shifts of the compounds were calculated in CDCl3 and DMSO using the GIAO
method.
Karabacak et al [27] reported structural and vibrational spectroscopic
properties of 2-,3-4-nitrobenzenesulfonamide using FT-IR and FT-Raman
experimental techniques and
quantum chemical calculations. The complete
assignments of fundamental vibrations were performed on the basis of the
experimental results and total energy distribution (TED) of the vibrational modes,
calculated with scaled quantum mechanics (SQM) method. The effects of the nitro
group substituent on the characteristic benzene sulfonamides bands in the spectra
were discussed. Optimized structure of compounds were interpreted and compared
with the earlier reported experimental values for studied molecules. The observed
and the calculated geometric parameters and vibrational wavenumbers were
compared and found to be in good agreement.
Suneel et al reported [28] the crystal structure of N-(5-Bromo-2chlorobenzyl)-N-cyclopropylnaphthalene-2-sulfonamide (C20H17BrClNO2S). The
dihedral angle between the benzene ring and the naphthalene plane is 8.95 (8)°.
The crystal packing is stabilized by weak intermolecular C-H O, C-H Cl and
π -π [centroid-centroid distance = 3.8782 (16) [Å] interactions.
Chandran et al [29] reported FT-IR and computational Study of
Sulphaguanidine. The vibrational wavenumbers of sulphaguanidine were
calculated using Gaussian 03 software at different levels and compared with
experimentally observed data. The predicted infrared intensities, Raman activities
and first hyperpolarizability are reported. The calculated geometrical parameters
(DFT) are in agreement with that of similar derivatives. The potential energy scan
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studies for different torsion angles are also reported. The splitting of NH stretching
wavenumber in the infrared spectrum indicates the weakening of the NH bond.
Chandran et al [30] reported FT-IR, FT-Raman spectroscopy and
computational
study
of
(E)-4-((anthracen-9-ylmethylene)amino)-N-
carbamimidoylbenzene sulphonamide. The infrared and Raman spectra of (E)-4((anthracen-9-ylmethylene)amino)-N-carbamimidoylbenzene
sulfonamide
have
been recorded and analysed. Geometry and harmonic vibrational wavenumbers
were calculated theoretically using Gaussian 03 set of quantum chemistry codes.
The data obtained from vibrational wavenumber calculations are used to assign
vibrational bands found in infrared and Raman spectra of the studied molecule.
The calculated first hyperpolarizability is comparable with the reported value of
similar structures and may be an attractive object for further studies on non-linear
optics. The important thermodynamical parameters are also reported.
Recently, Rajamani et al [31], studied Electronic absorption, vibrational
spectra, nonlinear optical properties, NBO analysis and thermodynamic properties
of N-(4-nitro-2-phenoxyphenyl)methane sulfonamide molecule by ab initio HF and
density functional methods.
Girisha et al [32] reported Molecular docking studies of cis-2,6-dimethyl
piperidine sulfonamides as inhibitors of acetylcholinesterase. These piperidine
sulfonamides were subjected to in vitro AChE enzyme inhibition studies and in
vivo antiamnesic study to reverse scopolamine induced memory loss in rats. Two
derivatives in this class of piperidines showed considerable inhibition.
Kamel et al [33] reported Synthesis, antitumor activity and molecular
docking study of Sulfonamide-Schiff’s bases, thiazolidinones, benzothiazinones
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and their C-nucleoside derivatives. AutoDock molecular docking into PTK has
been done for lead optimization of the compounds in study as potential PTK
inhibitors.
1.5 Scope of the work
Due to the wide variety of the biological importance of the sulfonamides,
the synthesis of several substituted sulfonamides and the study of their crystal and
molecular structure and other physico-chemical and biochemical studies, continue
to be an interesting field of research. Investigations have been done on these
compounds in the field of crystallographic studies whereas, much of complete
vibrational analysis and molecular properties using DFT and biological activities
on these are yet to be known.
With this idea in mind, six number of p-toluene sulfonamides are
synthesized and crystallised by slow evaporation method. The harvested crystals
are characterized by FTIR, NMR and structural analysis. The structure,
conformation and packing of the molecules in the crystal lattice may have an
important role to play on many of the properties of the sulfonamides. The crystal
structure and conformation of these p-toluene sulfonamides have been determined
by single crystal x-ray studies. The bond length, bond angle and interplanar angles
are determined. Thermal stability of compounds is an important factor to be
considered for the standardization of drugs and pharmaceuticals. In order to study
the behaviour of p-toluene sulphonamides with respect to change in temperature,
thermo analytical studies have been carried out. From the analysis, the melting
point, the relative stability and decomposition have been studied and the results are
discussed in relation to the structures.
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Quantum chemical calculations of para toluene sulfonamide derivatives at
density functional theory (DFT) have been carried out aiming to obtain complete
reliable and precise vibrational assignments of the investigated compound. Atomic
charges, distribution of electron density (ED) in various bonding and anti-bonding
orbitals and stabilization energies, E(2) have been calculated by NBO analysis.
Investigations have been done to identify HOMO-LUMO energy gap, non-linear
optical (NLO) effects, harmonic vibrational modes, electronic structure, and
chemical shift. Correlation between biological activity and some appropriate
quantum descriptors such as EHOMO, ELUMO, energy gap, dipole moment (μ), global
hardness (η), softness (S), electrophilicity index (ω), molecular polarizability (α),
Mulliken electronegativity (χ), molecular electrostatic potential (MEP) and
Mulliken charge (Qi) have also been carried out.
As the para toluene sulfonamides are reported to be either biologically
active or of biological importance, all of them are screened for their biological
activity. The results of the above studies are presented in the thesis.
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