ABSTRACT
Phenylmethylidene-(1-3-thiazole-2ylmethyl) sulfonylmethylaniline Schiff bases [PTSA] was prepared by a reaction between benzaldehyde and sulphathiazole. Fe(III), Mn(II) and Ni(II) complexes of PTSA were also synthesized, melting point and conductivity of the ligand and metal complexes were determined. The PTSA and Fe(III), Mn(II) and Ni(II) complexes were characterized by Ultraviolet/Visible, IR, HNMR and 13CNMR spectroscopy. Low conductivity value ranging from 10.5-17.2 Sm2.mol-1 indicated the non-electrolytic nature of the PTSA and Fe(III), Mn(II) and Ni(II) complexes. The melting point of the PTSA and its complexes ranges from 244 - 286 The PTSA behaved as a tridentate ligand towards Mn, Fe and Ni ion, it complexed at -NH group and two C=N group. It has the general formular of [M(PTSA)n] (where M = metal ion, n = number of moles of ligand). A trigonal geometry has been proposed for the metal complexes. PTSA and metal (II) complexes have been screened for their in vitro antibacterial activity against four bacterial strains staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi. It was observed that the complexes were more potent than PTSA against the bacterial strains used. In line with the findings, PTSA metal complexes of Fe(III), Mn(II) and Ni(II) may be used as metal based drugs in the treatment of bacterial infections caused by staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi.
TABLE
OF CONTENTS
Title Page i
Declaration ii
Certification iii
Dedication iv
Acknowledgements v
Table of Contents vi
List of Tables ix
List of Figures x
Abstract xii
CHAPTER
1: INTRODUCTION 1
1.1 Background of the Study 1
1.2 Statement of the Problem 5
1.3 Objectives of the Study 6
1.4 Justification of the Study 6
1.5 Scope
of the Study 7
CHAPTER 2:
LITERATURE REVIEW 8
2.1 Schiff
Bases 8
2.2 Antimicrobial
Activity of Schiff Base Metal Complexes 10
2.3 Antimicrobial
Activity of Schiff Base of Benzaldehyde and Sulfonamide 14
2.4 Biological
Properties of Transition Metal Complexes 18
2.4.1 Biological
properties of iron 18
2.4.2 Biological
properties of manganese 19
2.4.3 Biological
properties of nickel 20
2.5 Theories
of Bonding in Transition Metal Complexes 21
2.5.1 Crystal
field theory 21
2.5.2 Molecular
orbital theory 22
2.5.3 Valence
bond theory 23
2.6 Methods
of Studying Complexes 24
2.7 Chemistry
of Transition Metals 25
2.7.1 Iron and
its complexes 25
2.7.2 Manganese
and its complexes 25
2.7.3 Nickel
and its complexes 26
CHAPTER
3: MATERIALS AND METHODS 27
3.1 Chemicals and Solvent 27
3.2. Methods 27
3.2.1 Synthesis of the
phenylmethylidene-(1-3-thiazole-2ylmethyl) sulfonyl
methylaniline schiff base. 27
3.2.2 Synthesis
of the metal complexes of PTSA 27
3.3 Physical
Measurements 28
3.3.1 Melting
point 28
3.3.2 Solubility test 28
3.3.3 Conductivity
measurement 28
3.4 Characterization of PTSA and Metal
Complexes 28
3.4.1 UV/visible
spectroscopy 28
3.4.2 Infrared
spectroscopy 29
3.4.3 Nuclear
magnetic resonance spectroscopy 29
3.5 Antibacterial
Activity Test 29
CHAPTER 4: RESULTS
AND DISCUSSION 30
4.1 Results 30
4.2 Solubility
Data 31
4.3 Spectrophotometric
Measurement 32
4.3.1 Infra-red
spectra 37
4.3.2 Ultraviolet-visible
spectra 42
4.3.3 Nuclear
magnetic resonance (NMR) spectra 48
4.3.3.1 Proton (1H) NMR 48
4.3.3.2 Carbon-13 (13C) NMR 53
4.4 Proposed
Structures for the Metal Complexes 53
CHAPTER 5: CONCLUSION AND RECOMMENDATIONS 57
5.1 Conclusion 57
5.2 Recommendations 57
References 58
LIST OF TABLES
4.1 Some physical parameters and analytical
data of PTSA and its metal
complexes 30
4.2 Solubility
data of PTSA and its metal complexes in some selected
solvents 31
4.3 Summary
of the IR peaks; a comparism of the ligand and the complexes 32
4.4 Summary
of the Uv/Vis peaks; a comparism of the ligand and the
complexes 37
4.5 Summary
of the 1H NMR Bands; a comparison of the ligand and the
complexes 43
4.6 Summary
of the 13C NMR Bands; a comparison of the ligand and the
complexes 48
4.7 %
Zone of inhibition (mm) of the PTSA and the metal complexes on the
bacterial
population 55
LIST OF FIGURES
2.1: Proposed
structure of the complexes 11
2.2: The synthesis route of Schiff base ligand
derived from cephalexin
antibiotic with sulphathiazole 12
2.3: The synthesis route of Schiff base ligand
derived from cephaclor
and 1,2-diaminobenzene 13
2.4: The
synthesis route of Schiff base ligand of
2-[(4-
methylphenylimino)methyl]-6-methoxyphenol 14
2.5: Proposed
structure of compounds derived from benzoyl derivatives 15
2.6: Proposed
structure of the synthesized Schiff base compounds 15
2.7: Proposed structure of the metal complexes
derived from benzaldehyde
and sulfonamide 16
2.8: Proposed structure of the complexes
derived from 2-aminopyridine
and 2-methoxybenzaldehyde 17
2.9: Proposed structure of transition metal
(II) complexes derived from
sulfamethoxypyridazine and
2-Hydroxy-1-Napthalene aldehyde 18
4.10 IR
spectrum of PTSA (Ligand) 33
4.11 IR
spectrum of [Fe(PTSA)n] (Complex) 34
4.12 IR spectrum of [Mn(PTSA)n]
(Complex) 35
4.13 IR spectrum of [Ni(PTSA)n]
(Complex) 36
4.14 Uv/Vis
spectrum of PTSA (Ligand) 38
4.15 Uv/Vis
spectrum of [Fe(PTSA)n]
(Complex) 39
4.16 Uv/Vis
spectrum of [Mn(PTSA)n] (Complex) 40
4.17 Uv/Vis
spectrum of [Ni(PTSA)n] (Complex) 41
4.18 1H
NMR spectrum of PTSA 44
4.19 1H
NMR spectrum of [Fe(PTSA)n] (Complex) 45
4.20 1H
NMR spectrum of [Mn(PTSA)n] (Complex) 46
4.21 1H
NMR spectrum of [Ni(PTSA)n] (Complex) 47
4.22 13C
NMR spectrum of PTSA (Ligand) 49
4.23 13C
NMR spectrum of [Mn(PTSA)n] (Complex) 50
4.24 13C
NMR spectrum of [Ni(PTSA)n]
(Complex) 51
4.25 13C
NMR spectrum of [Fe(PTSA)n]
(Complex) 52
4.26 Proposed
structure of PTSA ligand 53
4.27 Proposed
structure of Fe (III) complex 54
4.28 Proposed
structure of Ni (II) complex 54
4.29 Proposed structure of Mn (II) complex 55
CHAPTER 1
INTRODUCTION
1.1 BACKGROUND OF THE STUDY
Metal
complexes have played important and diverse roles in medicine for thousands of
years. They take part in a variety of biological processes due to their
characteristic electronic features, which generally involves their binding to
electron-rich biological components, such as proteins and DNA. It is thus
reasonable to propose that metal ions may be incorporated into drugs, with the
main goal being interacting in a controlled manner with biological systems. A
Schiff base is a compound formed from the condensation of either an aldehyde or
a ketone (Holm et al., 1966; Hobday
and Smith, 1972; Pierre, 1987). The carbonyl group of the aldehyde gives
aldimines while that of ketone gives ketoimines. It has been known that
different metal ions on interaction with Schiff bases yield chelates, for
example Tsumaki, (1983) reported [Co(sal2.en) complex which received
a great attention owing to its ability to undergo reversible adduct formation
with molecular oxygen. The oxygenation ability of the complex was first
recognized by Hassan (1998). However, the mechanism for the oxygenation process
was not well understood until recently with the advent of modern physical
techniques. Xishi et al. (2003),
reported the synthesis and characterization of a novel Schiff base ligand
formed from the condensation of 2,2-bis (Pmethoxyphenylamine) and
Salicylaldehyde and its Mn(II), Co(II) and Cu(II) complexes. Ben Saber et al. (2005), reported the synthesis
and characterization of Cr(III), Fe(III), Co(II) and Ni(II) complexes with a
Schiff base derived from 4- dimetylamino benzaldehyde and primary amines. The
chemical analysis data showed the formation of (1:1) metal - ligand ratio and a
square planar geometry was suggested for Co(II) and Ni(II) complex while an
octahedral structure was suggested for Cr(III) and Fe(III) complexes. Ben Saber
et al. (2005), reported the synthesis
of a Schiff base derived from salicylaldeyde, and histidine and its complex
compounds with divalent transition metal ions. The complexes were investigated
by elemental analysis and were found to be of 1:1 metal to ligand ratio.
In
the past many Schiff base derivatives have been prepared and employed for
applications like catalysis and enzymatic reactions, luminescent material,
magnetism and molecular architectures. However recently Schiff bases metal
complexes gain massive attention in the domain of biological chemistry and
coordination chemistry. Schiff base is named after Hugo Schiff. The field of
inorganic chemistry in medicine can be divided into two main categories; firstly,
ligand as drugs which targets metal ions in some form, whether free or protein
bound. Secondly, metal-based drugs and imaging agents where the central metal
atom is usually the key feature of the mechanism of action. Many of the organic
drug currently in use requires interaction with metal for activity,
understanding these interactions can lead the way towards rational design
metallopharmaceuticals and implantation of new co-therapies. Schiff bases and
their complexes are versatile compounds synthesized from the condensation of an
amino compounds with carbonyl compounds and widely used for industrial purposes.
They also exhibit abroad range of biological activities including antifungal
(Pandeyaa et al.,1999; Rajendran and
Karvembu, 2002), antibacterial (Chohan et
al., 2010; Karia and Parsania, 1999; Amir et al., 2002; More et al.,
2002), antimalarial (Khalaji et al.,
2010), antiproliferative (Hassan et al.,
2013), anti-inflammatory (Jayakumarswamy et
al., 2011), antiviral (Pingnatello et
al., 1994; Girgaonkar and Shirodkar, 2012) and antipyretic properties (Venkateshwarlu
et al., 2012). The activity is
usually increased by complexation. The influence of certain metals on the
biological activity of these compounds and their intrinsic chemical interest as
multidentate ligands has prompted a considerable increase in the study of their
coordination behavior.
The
development in the field of bio-inorganic chemistry has increased the interest
in Schiff base complexes, since it has been recognized that many of these
complexes may serve as models for biologically important species. Schiff bases
are a special class of ligands with a variety of donor atoms exhibiting
interesting coordination modes towards various metals. Schiff bases containing
polyfunctional groups produce stable complexes of transition, non-transition,
inner-transition and actinide metal ions. Report has it that the biological
properties of Schiff base ligands are due to the azomethine (–HC=N–) group (Ren
et al., 2002). Schiff bases of
different carbonyl compounds show antimicrobial activity against B. subtilis, E. coli, P. fluorescence, S.
aureus and A. niger (Mohamed et al.,
2005; Mohamed et al., 2010; Tumer et al., 1999).
In
the past two decades, the properties of Schiff bases stimulated much interest
for their noteworthy contributions to single molecule-based magnetism, material
science, and catalysis of many reactions like carbonization, oxidation, and
reduction (Bose et al., 2004). These
compounds had been used for industrial purposes such as pigments, catalysts,
intermediates in organic synthesis and as polymer stabilizers (Przybylski et al., 2009). Schiff base ligands
containing NO, NS, NNO and SNO donor systems are ubiquitous in coordination
chemistry being used in the synthesis of a large variety of transition metal
complexes, which remain important area of research due to their simple
synthesis, good yield, high purity and wide range of applications Popova and
Berova, (1981). The study of Schiff base have received great impetus in recent
years due to their remarkable stereochemical, electrochemical and electronic
properties. Schiff bases with N, S and O donor atoms show broad biological
activity and are of special interest because of the variety of ways in which
they are bonded to metal ions. Schiff bases have structural similarities with
neutral biological systems and due to presence of imine group are utilized in
elucidating the mechanism of transformation of racemization reaction in
biological system (Keskioˇglu et al.,
2008; Wu and Yuan, 2004).
Transition
metal Schiff base complexes are used in various fields, such as medicine,
agriculture, industries (Ugrasen and Rashmi, 2017), [Co(acac2-en)]
in dimethylformamide, pyridine and substituted pyridines proved to be involved
in oxygen metabolism (Hanna and Mona, 2001). Transition metal complexes with 1,
10 – phenanthroline and 2, 2 – bipyridine are used in petroleum refining (John et al., 1976). Schiff base formed by the
condensation of 1-formyl-2-hydry-3- naphtholic arylamide with O-hydroxyl or
O-methoxy aniline complexes of Co(II), Ni(II), Cu(II) and Zn(II) are useful as
pigments (Gupta et al., 2002).
Oxovanadium complexes have been found strongly active, against some type of
Leukemia (Dong et al., 2002).
Transition metal complexes derived from a number of amino acids have been
reported to have biological activity (Zahid et
al., 2007). reported the
antibacterial activity of Ni(II) with salicyaldehyde and 2-amino-benzoic acid
complex. Popova and Berova, (1981) reported that copper is good for liver
function, its level in blood and urine has influence in pregnancy disorders,
nephritis hepatitis, leprosy, anemia and leukemia in children. It is known that
the existence of metal ions bonded to biologically active compounds may enhance
their activities. The Schiff base metal complexes of Cu(II), Cd(II), Pt(II) and
Pd(II) have been shown to inhibit growth
of cancer cells through modulation of genes that are related to the homeostatic
control of the cell cycle and apoptosis (Zhang et al., 2012.).
Three
Schiff base compounds of N-substituted benzohydrazide and sulfonohydrazide
derivatives: N-(2-hydroxy-3-methoxybenzylidene)-4tert-butyl-benzohydrazide(1),N-(5-bromo-2-hydroxybenzylidene)-4tertbutylbenzohydrazide(2)
and N-(2-hydroxy-3-methoxybenzylidene)-4methylbenzenesulfonohydrazide(3) were
synthesized and characterized by elemental analysis, FT-IR, 1H-NMR
and 13C-NMR spectroscopy. The title compounds have been screened for
their biological activities such as antibacterial,
antifungal, antioxidant, cytotoxic, enzymatic activities as well as interaction
with SS-DNA which showed remarkable activities in each area of research
(Sirajuddin, 2013). Salama et al. (Salama,
2015) synthesized Schiff bases of chitosan by the reaction of chitosan with
3-(4-substitutedphenyl)-1-phenyl-1H-pyrazole4-carbaldehyde. The structure of
the prepared chitosan derivatives was characterized by FT-IR spectroscopy,
elemental analysis, and X-ray diffraction studies and thermogravimetric
analysis (TG). The antimicrobial activity of chitosan and Schiff bases of
chitosan were investigated against Streptococcus pneumonia, Bacillis subtilis,
Escherichia coli.
The
growing interest in transition metal complexes containing Schiff base
antibiotics is derived from their functions and well-established chemical in
biological systems as well as their pharmaceutical and catalytic applications
(Rehder et al., 2003; Rehder, 2003).
This work therefore seeks to study the synthesis, characterization and antibacterial studies of
PTSA schiff base and its metal complexes.
1.2 STATEMENT OF THE PROBLEM
Schiff’s
bases represent an important class of pharmacologically active molecules which
have triggered the interest of medicinal chemist as they possess a variety of
pharmacological properties. A number of Schiff’s base derivatives have been
reported to exert notably antibacterial (Chohan et al., 2010; Karia and Parsania, 1999; Amir et al., 2002; More et al.,
2002), antifungal (Pandeyaa et al.,1999;(
Rajendran and Karvembu, 2002), antitubercular, antitumor, antileishmanial,
DNA-binding activities, etc. It is for this purpose that this study seeks to
extend the landscape of drug design and enable novel mechanisms of action of PTSA
schiff’s bases and some of their metal derivatives.
1.3 OBJECTIVES OF THE
STUDY
The aim of this study is the synthesis,
characterization and antibacterial studies of PTSA schiff bases and Fe(III), Mn(II) and Ni(II) complexes.
The aim was achieved through the following
objectives:
1. Synthesis of l the PTSA schiff base ligand.
2. Synthesis of the PTSA Schiff base metal
complexes derived from selected metal salts (Ni(II), Fe(III) and Mn(II)).
3. Characterization of the Schiff base and Schiff
base metal complexes prepared using variable techniques such as Infrared
spectroscopy, Ultraviolet/Visible spectroscopy, Proton and Carbon-13 NMR,
molecular conductivity, melting point and elemental analysis as well as
measurement of their solubility.
4. Comparism of the antibacterial effects of the
Schiff bases ligand and its synthesized metal complexes using gram-positive and
gram-negative strain.
1.4 JUSTIFICATION OF THE
STUDY
The growing interest in transition metal
complexes containing Schiff base antibiotics as well as their pharmaceutical
applications is what brought about the researchers investigation into the
synthesis, characterization and biological studies of Schiff base with some
metal complexes. The development in the field of
bio-inorganic chemistry has increased the interest in Schiff base complexes,
since it has been recognized that many of these complexes may serve as models
for biologically important species. Schiff base ligands are easily synthesized
and they form complexes with almost all metal ions. Over the past few years,
there have been many reports on their applications in pharmacological activites
such as antibacterial (Venugopal and Jayashree, 2008), antifungal (Pandey et al., 2003), anticancer (Villar et al., 2004), antitubercular (Bhat et al., 2005) antimicrobial (Wadher et al., 2009), antimalarial (Li et al., 2003) and antiviral activities
(Karthikeyan et al., 2006) and also serve
as a back bone for the synthesis of various heterocyclic compounds (Wang et al., 2008).
Schiff
base ligands in recent years have received much recognition and yet there is
much scope for thorough probe on metal complexes with such ligands which are
also of biochemical interest. Schiff base ligands with transition metals have
gained much attention in the recent years towards synthesis and
characterization. Hence, due to the growing interest in pharmacological
properties of nitrogen, oxygen or sulphur containing Schiff bases and their
complexes, we decided to synthesize new Schiff base PTSA and its transition
metal complexes. The tremendous interest in studies related to the screening of
antimicrobial activity of transition metal complexes due to their relevance in
the development of new reagents for medicine led us to the study of their
antibacterial properties.
1.5 SCOPE OF STUDY
The
study focused on the synthesis of PTSA Schiff base ligand and the synthesis of Fe(III), Mn(II) and Ni(II) complexes from
PTSA. It also focused on the characterization of the prepared Schiff base and
its metal complexes using the variable techniques such as Infrared
spectroscopy, Ultraviolet/Visible spectroscopy, Proton and Carbon-13 NMR,
measurement of the melting point and solubility. Finally, it studied
antibacterial activities of PTSA and Fe(III), Mn(II) and Ni(II) metal
complexes.
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