ABSTRACT

 

In this study, a series of N-pyridin-3-yl substituted [phenylsulphonamido]
acetamide has been synthesized. The reaction of phenylsulphonyl chloride with
various amino acids in basic medium yielded phenylsulphonamido alkanoic acid
which, on chlorination with thionyl chloride, gave acid chloride derivatives of
phenylsulphonamido alkanoic acid in situ. The acid chloride derivatives on
condensation with 3-aminopyridine gave corresponding acetamide in good to
excellent yield. The compounds were characterized by FTIR, 1H-NMR and 13CNMR
and screened for antibacterial, antifugal and antioxidant activities. The result
revealed that the compounds possess antibacterial activities.One the compounds, 2-
[(phenylsulfonyl)amido]propanoic acid had better antibacterial activities than
ciprofloxacin the reference drug while others are less active. All the compounds
has less antifungal activities than ketokonazole the reference drug. 2-
[(phenylsulfonyl)amido]propanoic acid had the best antioxidant properties of all
the compounds.

 

TABLE OF CONTENTS

 

Title page – – – – – – – – – – -i
Approval page – – – – – – – – – -ii
Dedication – – – – – – – – – – -iii
Acknowledgement – – – – – – – – – -iv
Abstract – – – – – – – – – – -v
Table of contents – – – – – – – – – -vi
CHAPTER ONE
1.0. Introduction – – – – – – – – -1
1.1. Background of the study – – – – – – -1
1.1.1. Chemistry and nomenclature of sulphonamides – – – -11
1.1.2. Medicinal important or sulfonamides – – – – -12
1.2. Statement of the problem or research question – – – -16
1.3. Objective of the research – – – – – – -17
1.4. Justification of the study – – – – – – -18
CHAPTER TWO
Literature review
2.1. History of sulphonamide drug discovery – – – – -19
2.2. Synthesis of sulphonamides – – – – – – -21
2.2.1. Synthesis from amination of chalcones – – – – -26
2.2.2. Chloromethylsulphonylation of benzylisothiourea – – -26
2.2.3. Copper ii oxide catalytic sulphonylation method – – – -27
2.2.4. Synthesis from ionic liquid mediated approach – – – -28
2.2.5. Synthesis from heteroaryl thiols – – – – – -29
2.3. Sulphonamide as antimicrobial agents – – – – -29
vii
CHAPTER THREE
3.0. Experimental section – – – – – – – -31
3.1. Materials and method – – – – – – – -31
3.2 Synthesis of benzensulphonamide – – – – – -31
3.2.1. Synthesis [(phenylsulfonyl)amido]acetic acid – – – -32
3.2 .2 Synthesis of 4-methyl-2-[(phenylsulfonyl)amido]pentanoic acid -32
3.2.3 Synthesis of 2-[(phenylsulfonyl)amido]propanoic acid – – -33
3.2.4 Sythesis of 3-phenyl-2-[(phenylsulfonyl)amido]propanoic acid – -34
3.2.5 Synthesis of 4-(methylsulfanyl)-2-[(phenylsulfonyl)amido]
butanoic acid – – – – – – – – -34
3.3. General method of synthesis of N-heteroaryl substituted
Benzensulphonamide – – – – – – – -35
3.3.1 2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)acetamide – – -36
3.3.2. 4-methyl-2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)pentanamide. -36
3.3.3. 2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)propanamide – -37
3.3.4. 3-phenyl-2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)propanamide -38
3.3.5. 5-(methylsulfanyl)-3-[(phenylsulfonyl)amido]-N-(pyridin-3-
yl)pentanamide. – – – – – – – – -39
3.4 Biological activities – – – – – – – -40
3.4.1 Antimicrobial activity – – – – – – – -40
3.5. Evaluation of antioxidant activity – – – – – -40
3.5.1. Scavenging of dpph radical – – – – – – -41
3.5.2 Reducing power – – – – – – – – -41
3.5.3. Ferrous sulphate induced lipid peroxidation scavenging – – -42
viii
CHAPTER FOUR
4.0 Results and discussion – – – – – – – -44
4.1 Benzene sulphonamides – – – – – – – -44
4.1.1 [(phenylsulphonyl)amido]acetic acid – – – – – -44
4.1.2. 4-methyl-2-[(phenylsulfonyl)amido]pentanoic acid – – -45
4.1.3 2-[(phenylsulfonyl)amido]propanoic acid, – – – – -46
4.1.4. 3-phenyl-2-[(phenylsulfonyl)amido]propanoic acid – – -47
4.1.5. 4-(methylsulfanyl)-2-[(phenylsulfonyl)amido]butanoic acid – -49
4.2. Synthesis of N-pyridine-3-yl substituted benzensulphonamide- -50
4.2.1. 2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)acetamide – – -51
4.2.2. 4-methyl-2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)pentanamide -51
4.2.3. 2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)propanamide – -53
4.2.4. 3-phenyl-2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)propanamide -44
4.2.5 5-(methylsulfanyl)-3-[(phenylsulfonyl)amido]
-N-(pyridin-3-yl)pentanamide – – – – – – -56
4.3 Biological activities. – – – – – – – -57
4.3.1 Minimum Inhibitory Concentration(MIC) mg/ml – – – -57
4.3.2 Results of sensitivity test – – – – – – -59
4.4 Anti oxidant evaluation – – – – – – – -60
4.4.1 Invitro free radical scavenging effect of samples by dpph method -60
4.4.2. Ferrous sulphate induced lipid peroxidation – – – – -62
4.4.3 FRAP – – – – – – – – – -63
CHAPTER FIVE
5.1. Conclusion – – – – – – – – – -64
5.2 References – – – – – – – – – -65
ix

 

CHAPTER ONE

INTRODUCTION
1.1 Background of the study
The growing incidence of microbial resistance to currently used antibiotics
represents a serious medical problem. Therefore, there is an urgent need to develop
new classes of therapeutic agents to treat microbial infectious. Such new
therapeutic agent has to exhibit a wide spectrum of biological activities.
Sulphonamides, an important class of pharmaceutical compounds, exhibit a wide
spectrum of biological activities1. The basic sulphonamide group [SO2, NHR]
occurs in various biologically active compounds including antimicrobial drugs,
antithyroid agents, antitumor, antibiotics and inhibitors of carbonic anhydrase2 .
Sulphonamides are widely used to treat microbial infections by inhibiting the
growth of Gram negative and Gram positive bacteria, some protozoa and fungi3 .
Clinically, sulphonamides are used to treat several urinary tract infections and
gastrointestinal infections4. Sulphonamides5 that are aromatic or heteroaromatic are
responsible for the inhibition of the growth of tumor cells. They act as antitumor
agents by inhibiting carbonic anhydrase activity. They are structurally similar to paminobenzoic
acid (PABA) which is a cofactor that is needed by the bacteria for
the synthesis of folic acid. Sulphonamide antibiotics inhibit the conversion of
x
PABA into folic acid and thus ultimately inhibit the synthesis of DNA. They are
also used in veterinary medicine to treat infections in livestock6. In primary care
medicine, sulphonamides are widely used in various conditions including
gastrointestinal7 and urinary tract infections8. Sulphonamide is the organic
framework of main focus in this research and it belongs to the family of suphurcontaining
compounds9, which are earlier referred to as sulpha drugs . Some of
these sulpha drugs that have performed “healing magic” in the world of
chemotherapy include; sulphanilamide(1), sulphadiazine(2), sulphacetamide(3),
sulphamonomethoxine(4), sulphasalazine(5), sulphadoxine(6), among others.
Sulphonamides have long been the subject of pharmaceutical interest as a result of
their potent biological activities10
H2N
S
O
O
NH2
H2N
S
O O
N+
N N
1
2 H2N
S
O
O
NH O
CH3
3
xi
S
O O
NH
N
N
O
CH3
H2N
4
S
O O
NH
N
N N
N
O
HO
OH
O
CH3
5
S
O O
NH
H2N
N
N
O
CH3
O
CH3
6
Furthermore, the sulphonamide group has been proven to have remarkable utility
in medicinal chemistry and features in a number of clinically relevant small
molecules11. For instance, some currently approved drugs with sulphonamide
structural skeletons include the antihypertensive agent bosentan(7)12, the antiviral
HIV protease inhibitor amprenavir(8)13,the phosphodiesterase-5 inhibitor
sildenafil14, antidiabetic drug glibenclamide(9)15, antidiabetic nonantibiotic
glimepiride and the diuretic drug torasemide16
xii
S
O O
NH
H C CH3 3
H3C
N
N
O
N
N
O
OH
O
CH3
7
S
O
O
N
H2N
CH3
H3C
NH
OH
O
O
O
O
8
O
NH
S
O O
NH
O
NH
OMe
Cl
9
In addition, suphonamides are also highly relevant both in the animal world and
the plant life cycle. For example, the breakdown of cyclic guanosine
monophosphate is retarded by sildenafil, a substituted guanine analog, which keeps
cut flowers fresh for another week and also strengthens plant stems to stand
straight even in the midst of storm and wind17. A preserving effect on fruits and
vegetable was also found, making sildenafil , a promising agent18. Today, it is
xiii
marketed under the trade name of Viagra19, which is a potent drug used in erectile
dysfunction in man20. It has been reported that more than 150 million men
worldwide have this dysfunction21. In another discovery, sulphonamide has been
documented as highly efficient candidate with high inhibitory activity22
Similarly, some sulphonamides have been established as potent drugs in the
treatment of insomnia and other sleep challenges in man by antagonizing orexin
neural activity. Activation of orexin neurons contribute to the promotion and
maintenance of wakefulness23. Conversely, relative inactivity of orexin neurons
allows the onset of sleep24. Consequently, blocking orexin signaling with receptor
antagonists may provide a new mechanism for decreasing wakefulness. Thus , a
novel therapeutic opportunity for the treatment of insomnia was reported using a
dual receptor antagonists almorexant25. Also, a low molecular weight aryl
containing N-glycine-suphonamide (2-[(4-tert-butyl-benzenesulphonyl)-p-tolyamino]-
N,N-dimethyl-acetamide(10), was discovered as a potent and selective
antagonist with very poor oral bioavailability (F=1%) in wister rats.26
S
O O
N
N
N CH3
O
CH3
MeO
Cl
N
CH3
H3C
MeO
10
xiv
The mode of action of sulphonamide is by mimicking p-aminobenzoic acid
(PABA), which is needed in bacteria as a substrate of the enzyme dihydropteroate
synthetase for the synthesis of tetrahydrofolic acid, a basic growth factor essential
for the metabolic process of bacteria27. Sulphonamide are preferred due to the ease
of administration28, wide spectrum of antimicrobial activity29, non-interference
with host defence mechanism and relative freedom from problems of superinfection30-
31
Sulphonamides have been classified using various parameters: For instance, by
using the antibiotic properties, it can be classified into antibiotic (antimicrobial)
sulphonamides and non antibiotic (non antimicrobial) sulphonamides32. Although,
almost all therapeutically useful sulphonamides are aromatic linked as in Ar-
SO2NH2 or Ar-SO2NHR33, yet, there are important distinctions between
sulphonylarylamines (antimicrobial/suphonamides), nonarylamine (non
antimicrobial) sulphonamides, and sulphones, with regard to allergy and other drug
reactions34. Sulphone , unlike sulphonamide, has its sulphonyl unit incorporated
between two carbon systems which may be part of either aliphatic or aromatic
moieties 35.
Most reactions to sulphonylarylamines probably results from multifactorial
immunologic and toxic metabolic mechanisms, whereas less is known about the
precise mechanism of reaction of other sulphur-containing drugs. Some
xv
sulphonamides such as the anticonvulsante, sultiames are devoid of antibacterial
activity. The sulphonylurea and thiazide diuretics are newer drug groups used on
the antibacterial sulphonamides36. One of the sulphonamides of paramount
importance is benzenesulphonamide derivatives. Benzenesulphonamide moiety is
an integral part of many drugs and drug-like scaffolds37. Many derivatives of
benzenesulphonamide have been explored as important starting materials and
reactive intermediates in various organic synthesis. For example, 2-
hydroxyalkylbenzene sulphonamides have been reported as the important starting
materials 38 for the structure activity relationship (SAR) study during the search
for cycloxygenase-2 (COX-2) inhibitors as analgesic39 and anti-inflammatory
agents40.
The chemistry of sulphonamides has recently shown them to be highly efficient
synthons in the preparation of various valuable biologically active compounds41. In
exploiting the chemistry of sulphonamides as ligands, various researchers have
attempted and embarked upon designing and synthesizing various novel metal
based sulphonamides42. The chiral ligands of sulphonamides designed as first ,
second and third generation ligands for catalyzing stereoselective synthesis of
highly relevant asymmetric compounds43 has been years odyssey. In a similar
manner, a new series of sulphonamides derived Schiff bases has been synthesized
by a condensation reaction of various sulphonamides with aromatic aldehydes44.
xvi
The sulphonamides obtained were further investigated for their metal complexing
potential in terms of chelation and biological properties45 .
On the issue of side effect, it is important to make a distinction between sulpha
drugs and other sulphur containing drugs and additives, such as sulphates and
sulphites, which are chemically unrelated to the sulphonamide group, and do not
cause the same hypersensitivity reaction seen in the sulphonamides. Although there
are reported cases of allergy to sulphonamide drug but the term sulpha allergy is
imprecise and misleading and therefore should be discouraged46. Sulpha allergies
are commonly reported as side effect of sulphonamide drugs, hence medications
containing sulphonamides are prescribed carefully. In fact, issues in understanding
the clinical evidence and drug dynamics as they relate to individuals and
populations have been explored47. Statistics have shown that approximately 3% of
the general populations show sulpha drug allergies, when treated with
sulphonamides and other similar antibiotics48.
The potential utilization of sulpha drug compounds as corrosion inhibitors has also
been established49. The inhibitory effect of four sulpha drug compounds namely,
sulphamethazine , sulphaguanidine , sulphamethoxazole and sulphadiazine , on
mild steel corrosion in 1.0 M HCl solution was evaluated using galvanostatic
polarization weight loss technique50. All the sulpha drug compounds examined
were reported to reduce the corrosion of mild steel indicating their high potency as
xvii
anti-corrosion agents. Among the compounds studied, sulphadiazine was shown to
have the best inhibition efficiency51. Some quantum mechanical studies have
successfully linked the inhibition efficiency with molecular properties for different
kinds of organic compounds52. Sulphonmide derivatives of azo dyes achieve
improved light stability, water solubility and fixation to fibre. The sulphonamide
dyes, especially secondary sulphonamide dyes, exhibited superior dye exhaustion
and colour fastness to washing, sublimation and rubbing on fine denier PP
fabrics53. They have been used as protecting groups of hydroxyl or amino
functionalities for easy removal under mild conditions54.
Even though many synthetic methods have been reported for the preparation of
sulphonamides55, the sulphonylation of ammonia56 or primary and secondary
amines with sulphonyl chlorides in the presence of a base is still the method of
choice because of high efficiency and simplicity of the reaction . Nevertheless,
various acceptable techniques involve the need to reduce the amount of toxic waste
and by-products arising from chemical processes required thereby increasing
emphasis on the use of less toxic and environmentally compatible materials in the
design of new synthetic methods57. One of the most promising approaches is using
water as the reaction media58 while others include microwave irradiation
technique, heterogeneous catalytic approach, solvent free media usage, nontoxic
solid support resin59 etc. Sulphonamides an ionizable, polar antimicrobial
xviii
compounds, may reach the environment in substantial amount by the spreading of
manure60 or other means.
In a similar manner, amide formation is a fundamental reaction of great interest in
organic chemistry61. The development of efficient methods for the synthesis of
amides remains a great challenge because of their importance in chemistry and
biology, with a wide range of industrial and pharmaceutical applications and as
valuable intermediates in organic synthesis62. Hence, it is convincing to design the
synthetic route in such a way to have a second amide functionality, being
incorporated within the frame work of the synthesized sulphonamides, this will
help in the comparative study of the antimicrobial activity of the ordinary
sulphonamide with amide bearing sulphonamide derivatives.
Despite the various hazardous effects posed by deadly microbes63, it is highly
surprising to know that no new antimicrobial drug has been discovered in the last
few years. Therefore, there is a continuous need for the design and synthetic
formulation of new class of antimicrobial drugs in order to control rapid spread of
harmful microbes.
There has been a frequent failure in treatment of infections using antibiotics.
Biofilm effect is the mechanism responsible for the frequent failure of antibiotic
treatment to cure infections of medical devices and other prosthetic materials64. In
xix
the biofilm stage, a phenotypic change occur in which the bacteria require
generally much higher concentrations of antibiotics to inhibit their growth. In fact,
it has been recently discovered that the comparative study of the minimum
inhibitory concentration (MIC) and minimum biofilm eliminating concentration
(MBEC) is a potential factor determining the changes in the pattern of antibiotic
sensitivity of gram negative bacilli from the planktonic to the biofilm stage of
growth65. In addition, the rapid emergence of drug resistance has become the most
urgent concern because it renders current treatments ineffective and therefore
compels the scientific community to continue efforts in the design of inhibitory
agents that can efficiently combat drug resistance
1.1.1 Chemical classification and Nomenclature of sulphonamides
Sulphonamides are derivatives of sulfuric acids. Sulphonamides are
chemically quite stable, these are weak acids compared to carboxylic acid amides.
The sulphonamide functional group is – (SO2-NH2, a sulfonyl group connected to
an amine group). The general formula is RSO2NH2. where R is some organic group
such as alkyl, benzyl etc..
Any sulfonamide can be considered as derived from a sulfonic acid by
replacing a hydroxyl group with an amine group. In medicals, the term
xx
“sulfonamide” is sometimes used as a synonym for sulfa drug, a derivative or
sulfamilamide.
1.1.2 Medicinal properties of sulfonamide
The sulphonamide scaffold is well known for the design of many sulphonamide
compounds with diverse medicinal properties. The presence of benzene ring
allows sulfonamides to partition through bacterial cell walls. Once inside of the
bacteria cells, sulfonamides must be ionizable and contain both a positive and
negative charge on opposite sides of its structure, which further resembles the
structure of PABA and result in binding of sulfonamide.
Antibacterial activity
Kumar and coworkers66 have reported the synthesis of some Schiff bases or
sulfonamides by condensing 4–aminobenzene sulphonamide with different
aromatic aldehydes in the presence or glacial acitic acid and ethanol at 50-600C.
The antimicrobial activity of these compounds was evaluated by agar diffusion
xxi
method. Several Schiff bases derived from sulphonamide have shown good
antibacterial activity.
Anti-inflammatory Activity
Benzene sulfonamide derivatives carrying a pyrozole moity were prepared
by Abddaal et al67 which where structurally related COX-2 inhibitor celecoxib
(celebrex®) and were found to be potent anti-inflammatory agents with little or no
tendency to evoke gastric ullercities. In these derivatives, N-Ethyl -2- (3-merthyl –
5- oxo-4, 5- dihydro-pyazile -1- carboxyl)-benzensulfonamide (11) was found to
be more active than the celebrex.
S
O O
NHC2H5
O
N
N
CH3
O
11
Growth Hormone scretagogue Receptor
High specific activity sulfur -35- labeled sulphonamide radioligand has been
developed by Dean and co-workers68 for the identification of a GH secretagogue
receptor [355] – MK – 0677 was found to posses the necessary concentration of
high selectivity, affinity and specific activity required for utilization as a
radioligand in the study of this nearly discovered receptor.
xxii
Cancer-Associated carbone anhytrases (CAs)
Neogluco conjugate a new class of sulfonamide link was designed by Moore and
co-workers69 to selectively target and inhibit the extracellular domains of the
cancer-relevant CA isozymes. The carbohydrate fragment in these compounds is
linked to the classical aromatic sulfonamide CA pharmacore to target inhibition
of cancer associated CAs. The CA inhibitors design were very good CA IX
inhibitors and potent CA XII inhibitors.
Antimicrobial activity
Iqbal and coworkers70 synthesized benzene sulphonamides bearing 2,5
disubstituted 1,3, 4- oxadiazole moiety and tested these compounds for
antimicrobial and antifugal activity. Compound (12) exhibited significant
antibacterial and significant antifugal activities due to the presence of a chloro
group on position 4 of the phenyl substitutent, the free SH group at position 5 of
the oxadiazole ring, and the free – NH2 group of the sulphonamido moiety.
Cl
S
O
H2N O
N N
O SH
12
xxiii
B – Lactamase inhibitors
Eidam71 synthesized new sulfonamide boronic acids, derived from the
conversion of the canonical R1 caboxamide. This has substantial inhibition activity
against B- Lactamases, they also rescued antibiotic resistance when used in
combination with third generation antibiotics in bacterial cell cultures. This
superficially modest substitution changes the geometry of the inhibitors enough to
scramble the SAR observed in the analogue carboxamides.
R S
O O
NH
B
HO OH 13
Protein kinase inhibitors
The isoquinoline sulphonamide (14) derivatives synthesized by Hidaka et
al72 had ability to inhibit protein kinases, some of the derivatives (15-20) exhibited
selective inhibition towards certain protein kinase. The inhibtors where freely
reversible and of the noncompetitive type with respect to the phosphate acceptor.
The isoquinoline sulphonamides which are structurally unrelated to ATP, compete
with ATP for free emzyme but do not interact with same enzyme form as does the
phosphate acceptor.
xxiv
N
S
O
O
R
14
R= N
H3C
H3C
CH3
NH
N
CH3
CH3
H3C
NH
H3C NH
H3C
H2N
HN
CH3
NH
N
H3C
CH3
15
16 17
19 20
1.2 STATEMENT OF THE PROBLEM
Sulphonamides are a class of broad antibacterial compounds that have a wide
range of application. The group belongs to distinctive class of compounds that
constitute at least five different classes of pharmacologically active agents73. The
basic sulfonamide group, SO2NH-, occurs in various biologically active
compounds, including antimicrobial drugs, antithyroid agents, antitumor,
antibiotics and inhibitors of carbonic anhydrase74.
xxv
There is a vast increase in resistance of infectious disease to antibiotics, which
negates treatment by almost all the known classes of antimicrobial compounds.
Under these circumstances, the development of novel classes of antimicrobial
compound becomes imperative75.
Literature survey reveales that minor modifications in the structure of
sulphonamide can lead to quantitative as well as qualitative changes in the
biological activity.76
Inspite of the wide biological application of benzene sulphonamide derivatives,
nothing is known of the N-heteroaryl substituted derivatives. The biological
activities of these class of compound are yet unexploited.
1.3 OBJECTIVE OF THE RESEARCH
The objectives of these research are as follows;
Ø To synthesize benzene sulphonamide from benzene sulphonyl chloride and
amino acids.
Ø To synthesize the N-pyridine-3-yl derivatives of the
Ø benzenesulphonamides.
Ø To characterize the synthesizes compounds using FTIR,1HNMR and
13CNMR.
Ø To screen the new compounds for antibacterial, antifungal and antioxidant
activities.
1.4 Justification Of The Study
xxvi
The wide application of sulphonamides and the need to synthesize new
functionalized derivatives with probable improved biological activities justifies
this research.

 

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