TABLE OF CONTENTS
Title page – – – – – – – – – – – i
Approval Page- – – – – – – – – – – ii
Certification – – – – – – – – – – – iii
Dedication – – – – – – – – – – – iv
Acknowledgment – – – – – – – – – – v
Abstract – – – – – – – – – – – vi
Table of contents – – – – – – – – – -vii
List of Figures- – – – – – – – – – -viii
List of Abbreviations – – – – – – – – – – x
List of Tables – – – – – – – – – – -xi
CHAPTER ONE: INTRODUCTION
1.1 Background of study – – – – – – – – – 1
1.2 Statement of the Problem – – – – – – – – 4
1.3 Objectives of the Study – – – – – – – – 5
1.4 Justification of the Study – – – – – – – – 5
CHAPTER TWO: LITERATURE REVIEW
2.0 Linear Phenothiazine – – – – – – – – – 6
2.1 Synthesis of Triazaphenothiazine – – – – – – – 7
2.2 Synthesis of Tetraazaphenothiazine – – – – – – – 9
2.3 Angular Phenothiazine – – – – – – – -10
viii
2.4 Aza Analogue of Angular phenothiazine – – – – – -13
2.5 Linear Phenoxazine – – – – – – – – – 18
2.6 Angular Phenoxazine – – – – – – – – – 19
2.7 Aza- Analogue of Angular Phenoxazine – – – – – -23
2.8 Branched phenothiazine and Phenoxazine Compounds – – – – 27
CHAPTER THREE: EXPERIMENTAL
3.0 General Information – – – – – – – – – 35
3.1 6-Chloro-10-nitro-5H-benzo[a]phenoxazin-5-one – – – – – 35
3.2 14- Nitrobenzo[a][1,4]benzoxazino[3,2,-c]phenothiazine – – – -36
3.3 11-Amino-6-Chloro-9-thiol-8,10-diazabenzo[a]phenoxazin-5-one – – – 37
3.4 15-Amino-13-thiol-12,14-diazabenzo[a][1,4]benzoxazino[3,2- c]phenothiazine – 37
3.5 6,8-Dichlorobenzo[a]phenoxazin-5-one – – – – – – 38
3.6 12-Chloro-9-methoxy-8-azabenzo[a][1,4]benzoxazino[3,2-c]phenothiazine – 38
3.7 Antimicrobial Activity – – – – – – – – 39
3.8 Sensitivity testing of compounds – – – – – – – 39
3.9 Minimum inhibitory concentration testing of compounds – – – – 40
CHAPTER FOUR: RESULTS AND DISCUSSION
4.1 6-Chloro-10-nitro-5H-benzo[a]phenoxazin-5-one – – – – – 41
4.2 11-Amino-6-Chloro-9-thiol-8,10-diazabenzo[a]phenoxazin-5-one – – -44
4.3 6,8-Dichlorobenzo[a]phenoxazin-5-one – – – – – – 47
4.4 Result of Antimicrobial Sensitivity Test – – – – – – 50
ix
4.5 Minimum inhibitory Concentration Determination – – – – – 51
4.6 Result of Minimum Inhibitory Concentration – – – – – 52
CHAPTER FIVE
Conclusion – – – – – – – – – – – 53
References – – – – – – – – – – – 54
CHAPTER ONE
INTRODUCTION
1.1 BACKGROUND OF STUDY
The application of phenothiazine and phenoxazine compounds and their derivatives in
medicine, textiles, agriculture and other related industries has been of interest to chemists for
well over a century.
The chemistry of nitrogen-sulphur heteroatom-containing aromatic compounds is
becoming more popular as an area of research1
.
Phenothiazine derivatives have been shown to
possess a broad spectrum of pharmacological activity depending like antiparkinsonian2-3,
tranquilizer4, anti-inflamatory5-7, antimalarial8-9, antipsychoti10-12, antimicrobial 13-15, antitubercular
16-18, antitumor19-20, antihistaminic21-22, analgesic 23, prion disease drug24 . In textile,
paint and plastic industries, they are used as dyes and pigments25-26 and in agricultural industry as
insecticides27. In the petroleum industry, they are found useful as antioxidants in lubricants and
fuels28. It has been observed that some phenothiazines inhibit intracellular replication of viruses
including human immunodeficiency viruses (HIV) 29. On the other hand, some have been
reported to exhibit significant anticancer activity30-31
Similarly, phenoxazine derivatives are compounds of great interest because of their several
successful applications as dyes and drugs. They exhibit strong biological activities ranging from
antidepressant32, antitutour33, anticancer34, antibacterial35, antituberculosis36 and schizophrenia
agents37. Among other several industrial applications of phenoxazine derivatives is their use as
acid-base indicator38, biological stains39, laser dyes40 and chromophonic compounds41.
2
N
S
H
N
O
H
1
2
Owing to the wide range of applications of phenothiazines, intensive research has been in
progress in the search for more derivatives with highly improved pharmacological and biological
activities. Hence, several papers describing the synthesis of these derivatives had been reported
especially on the angular derivatives including the non-aza and the congeneric aza-analogues.
However, there exists limited literature on the complex derivatives of this phenothiazine ring
system. Among the non-aza angular compounds that have been reported were
benzo[a]phenothiazines of the type (3)42 and benzo[c]phenoxazine of the type (4)43 and
benzo[a]phenothiazine and benzo[c]phenoxazine of types (5)44 and (6),45 respectively.
N
S
H
N
S
H
N
O
H
3 4
5 6
N
O
H
3
Such molecular modification had yielded other derivatives such as (7)46, (8)47and (9)48.
N
S
H
N
O
H
N
S
H
7 8 9
Okafor49 also reported the synthesis of the first three branched diazaphenothiazine and
diazaphenoxazine dyes of the type (10) and (11).
N
S N
S
N
N
N
O N
O
N
N
10 11
The first three-branched benzoxazinophenothiazine ring systems of monoaza, diaza and triaza
analogues of the types (12), (13), and (14) were also reported by the same author49.
4
N
O N
S
N
O N
S
N
O N
S
N
N
N
N
2N
12 13
14
1.2 STATEMENT OF THE PROBLEM
Owing to the wide range of applications of phenothiazine derivatives with highly improved
pharmacological and biological activities, several papers describing the successful synthesis of
these derivatives had been reported especially on the angular derivatives, including the non-aza
and congeneric aza-analogues. However, there is still limited literature on the complex
derivatives of this phenothiazine ring system and hence, modification of the existing ones is
necessary. The past research done was based on their dye and pigment properties. Not much is
known of anti-microbial properties of these complex phenothiazine derivatives.
5
1.3 OBJECTIVES OF THE STUDY
The specific objectives of the study are to:
i. Synthesize derivatives of complex benzoxazinophenothiazine.
ii. Characterize the compounds synthesized using UV-Visible, FTIR, 1H-NMR and 13CNMR
spectroscopy and elemental analysis.
iii. Carry out antimicrobial screening on phenothiazine and phenoxazine compounds and
their derivatives.
1.4 JUSTIFICATION OF THE STUDY
Due to wide pharmaceutical activities of phenothiazine and phenoxazine compounds, it
became necessary to evaluate the antimicrobial activity of the synthesized derivatives which may
have better and more desirable pharmacological properties
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