ABSTRACT
The syntheses of benzothiazinophenothiazine derivatives from simple heterocyclic compounds as
precursors is described. Condensation of 2-aminothiophenol with 2,3-dichloro-1,4-naphthoquinone in
an alkaline medium furnished a good yield of the intermediate, 6-chloro-5H-benzo[a]phenothiazin-5-
one. Further condensation of the intermediate with 2,4-diamino-6-hydroxypyrimidine-5-thiol
obtained by alkaline hydrolysis of 2,4-diamino-6-hydroxy-5-thiacyanatopyrimidine gave the
benzothiazinophenothiazine ring system. On the other hand, using a facile acid-catalyzed method, the
synthesis of some benzothiazinophenothiazine ring systems were achieved with improved yield and
lesser reaction time. Structures of the compounds were characterized using UV/Visible
spectrophotometry, fourier transform infra red, 1HNMR and 13CNMR spectroscopies and elemental
analysis. The antimicrobial properties of the synthesized compounds were determined against
Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli,
Klebsiella pneumoniae, Candida albican and Aspergillus niger using agar diffusion technique.
Results showed that the complex derivatives were significantly active against the mi
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TABLE OF CONTENTS
Title page …………………………………………………………………………….i
Certification …………………………………………….………………………….ii
Dedication ……………………………………………………………………….….iii.
Acknowledgement …………………………………………………………….……iv
Abstract ……………………………………………………………………………….v
List of Figures …………………………………………………………………….…vi
List of Tables ……………………………………………………………………….vii
Abbreviations ………………………………………………………………….……vii
Table of Contents …………………………………….………………………………viii
1.0 INTRODUCTION
1.1 Background of study …………………………………………………………….1
1.2 Statement of problem ……………………………………………………….…..7
1.3 Aims and objectives of study ……………………………………………………7
1.4 Justification of study ………………………………………………………………8
2.0 LITERATURE REVIEW
2.1 Linear Phenothiazines ………………………………………………………… 9
2.2 Aza-Analogues of Linear Phenothiazines…………………………………….. 15
2.3 Angular Phenothiazines……………………………………………………….. 18
2.4 Aza-Analogues of Angular Phenothiazines …………………………………… 22
2.5 Branched Benzothiazinophenothiazine Ring systems ………………………… 27
3.0 EXPERIMENTAL
xi
3.1 2,4-Diamino-6-hydroxypyrimidine-5-thiol…………………………………….. 37
3.2 6-chloro-5H-benzo[a]phenothiazin-5-one ……………………………………………38
3.3 7-amino-9-hydroxy-6,8-diazabenzo[a][1,4]benzothiazino[3,2-c]phenothiazine…….. 38
3.4 4-amino-2-ethylthio-6-hydroxypyrimidine-5-thiol …………………………………….39
3.5 7,14-diethylthio-9,12-dihydroxy-6,8,13,15-tetraazabenzo[a][1,4]benzothiazino[3,2-
c]phenothiazine …………………………………………………………………… 40
3.6 3-amino-6-methoxypyridine-2-thiol ………………………………………………. 41
3.7 8,13-dimethoxy-9,12-diazabenzo[a][1,4]benzothiazino[3,2-c]phenothiazine ……. 47
3.8 6,13-dichloro-3,10-diethylthio-1,8-dihydroxy-2,4,9,11-tetrazatriphenodithiazine
…………………………………………………………………………………….. 42
3.9 4-amino-2-methyl-6-hydroxypyrimidine-5-thiol ………………………………….. 42
3.10 6,13-dichloro-3-methyl-9-methoxy-1-hydroxy-2,4,8-triazatriphenodithiazine
………………………………………………………………………………………………………………… 43
3.11 Evaluation of the Synthesized Phenothiazine Derivatives for Antimicrobial
Activities…………………………………………………………………………… 44
3.11.1 Sensitivity Test of the Compounds .……………………………………………. 44
3.11.2 Determination of Minimum Inhibitory Concentration (MIC) of the
Synthesized Derivatives……………………………………………………………. 45
4.0 RESULTS AND DISCUSSION
4.1 6-chloro-5H-benzo[a]phenothiazin-5-one …………………………………………….. 46
4.2 7-amino-9-hydroxy-6,8-diazabenzo[a][1,4]benzothiazino[3,2-c]phenothiazine
……………………………………………………………………………………… 48
xii
4.3 7,14-diethylthio-9,12-dihydroxy-6,8,13,15-tetraazabenzo[a][1,4]benzothiazino[3,2-
c]phenothiazine ……………………………………………………………………… 51
4.4 8,13-dimethoxy-9,12-diazabenzo[a][1,4]benzothiazino[3,2-
c]phenothiazine…………………………………………………………………… 54
4.5 6,13-dichloro-3,10-diethylthio-1,8-dihydroxy-2,4,9,11-tetrazatriphenodithiazine…
……………………………………………………………………………………. 57
4.6 6,13-dichloro-3-methyl-9-methoxy-1-hydroxy-2,4,8-triazatriphenodithiazine
…………………………………………………………………………………….. 59
4.7 Results of Antimicrobial Sensitivity Test of the Synthesized Compounds………. 62
4.8 Results of Inhibition Zones Diameter of the Compound……………………………. 63
4.9 Results of Minimum Inhibitory Concentration of the Synthesized Compounds…… 64
4.10 Conclusion…………………………………………………………………………… 65
REFERENCES ……………………………………………………………………………..66
CHAPTER ONE
1.0 INTRODUCTION
The chemistry of phenothiazine (1) and its derivatives has been of interest for over a century
due to their wide range of applications in drug, agriculture, textile, paint and other related industries.
Phenothiazine and its derivatives constitute a pharmaceutically important class of heterocycles with a
broad spectrum of pharmacological activity; they are useful in medicine as anticonvulsants,1
antitumour agents,2,3 antituberculosis,4 tranquilizers and antimalaria agents5. It also has anthelmintic
activity, 6, 7, 8 to mention a few.
N
S
H
(1)
Notable among the early phenothiazine drugs are Chlorpromazine (2) and promethazine (3) which are
broad spectrum tranquilizers with diffuse antipsychotic properties9.
N
S
N
H3C CH3
Cl N
S
N
CH3
H3C CH3
(2) (3)
2
These classes of drugs were the largest and most widely investigated class of neuroleptic agents9.
Chlorpromazine, the first commercially produced phenothiazine for the management of psychosis,
was also one of the first commercially produced in the phenothiazine series shown to have antituberculosis
properties both in vitro and in vivo.10,11 Promethazine and chlorpromazine, clinically
useful in the chemotherapy of mental and emotional disturbances has further stimulated an
investigation into other phenothiazine derivatives for possible central nervous system
(CNS)depressant activity.12,13
In the petroleum industry, these compounds are useful as antioxidants in gasoline, petroleum
lubricants and stabilizers.14-18 They are used as vat dyes and pigments18-22 in textile and paint
industries and in agriculture as insecticides and nematodicides.23,24
Since the discovery of the parent ring (1), a lot of structural modifications have been carried
out to enhance their pharmacological and biological activities, minimize undesirable effects and open
new areas of applications.
3
Such molecular modifications had yielded derivatives such as (4), (5),25 (6), (7), (8) and (9).26
N
S
H
N
S
H
N
S
H
N
S
H
N
S
H
N
S
H
(4)
(5)
(6)
(7) (8)
(9)
Compounds (4), (6), (7) and (9) are described as angular phenothiazines because of the non-linear
arrangement of the ring systems27. They possess fused rings at positions a, c, h and j bonds of the
phenothiazine.
There are also systems in which two benzene rings are attached to two different positions in the
parent compound. Such structures include dibenzo[a,h]phenothiazine28 (10),
dibenzo[c,h]phenothiazine29 (11) and dibenzo[a,i]phenothiazine (12).
4
N
S
H
N
S
H
(10)
(11) (12)
N
S
H
Branched phenothiazine compounds of the types (13) and (14)30 have been reported.
(13)
(14)
N
S N
S
N
S
H
With regard to the aza analogues of angular phenothiazine compounds, there have been
reports on the monoaza, diaza and the triaza derivatives such as (15), (16)31, (17) and (18)
respectively
5
(15) (16)
N
S
H
N
S
H
N
S
H
N
S
H
N 2N
2N
N
N
N
(17)
(18)
On the search for more aza analogues of angular phenothiazine ring system, the first aza
analogues of pyrrolo[3,4-a][1,4]benzothiazino[3,2-c]phenothiazine (19) was reported by Japanese
workers32.
N
S N
S
N
H
(19)
Okafor and Okoro33 also reported the synthesis of the first three-branched diazaphenothiazine
dyes of the type (20).
6
N
S N
S
N
(20) N
The diaza (21) and triaza (22) three-branched benzoxazinophenothiazine ring systems were
reported by Okafor34 and also reported was the tetraaza analogue (23) of benzothiazinophenothiazine
ring system by Ezema.35
N
O N
S
N
O N
S
N
S N
S
N
N
N
2N
2N
2N
(21) (22)
(23)
7
Other structures synthesized are the aza and non-aza analogues of dibenzotriphenodithiazine ring
systems of the types (24)36 and (25).37
N
S
N N
S
H H
(24)
N
S
S
N
(25)
1.2 Statement of the Problem
Owing to the wide range of applications of phenothiazines 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 the
congeneric aza analogues. However, there are still limited literatures on the complex derivatives of
this phenothiazine ring system and, hence, modification of the existing ones is necessary.
The past work done was based on their dye and pigment properties. Not much is known of
antimicrobial properties of these complex phenothiazine derivatives.
1.3 Aims and Objectives of Study
The aims and objectives of this study were to:
i. Synthesize complex aza derivatives of benzothiazinophenothiazine.
ii. Characterize the synthesized compounds by spectral analysis.
iii. Undertake antimicrobial screening on the complex derivatives.
8
1.4 Justification of the Study
The wide pharmaceutical applications of phenothiazines and the need to synthesize more
derivatives with better and more desirable pharmacological properties led to the synthesis and
antimicrobial screening of the derivative undertaken in the present
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