ABSTRACT
The syntheses of benzoxazinophenothiazine was thoroughly explored. Condensation of 2,3- dichloro-1,4-naphthoquinone with 2-amino-4-nitrophenol, 4,5-diamino-6-hydroxypyrimidin-2- thiol and 2-amino-6-chlorophenol, respectively in alkaline medium yielded the intermediates: 6- chloro-10-nitrobenzo[a]phenoxazin-5-one(136), 11-amino-6-chloro-9-thiol-8,9- diazabenzo[a]phenoxazin-5-one (148) and 6,8-dichlorobenzo[a]phenoxazin-5-one (160). Further treatment of the intermediates with 2-aminothiophenol and 3-amino-6-methoxypyridin-2-thiol gave the complex derivatives: 14-nitrobenzo[a][1,4]benzoxazino[3,2-c]phenothiazine (137), 15- amino-13-thiol-12,14-diazabenzo[a][1,4]benzoxazino[3,2-c]phenothiazine (149) and 12-chloro-
9-methoxy-8-azabenzo[a][1,4]benzoxazino[3,2-c]phenothiazine (161). The compounds were characterized by UV/Visible, FT-IR, (1H and 13C-NMR) spectroscopy and elemental analysis. The  synthesized compounds were screened  against eight  (8)  micro-organisms viz: Bacillus subtilis, Bacillus cereus, Staphylococcus aureus,Pseudomonas aeruginosa, Escherichia coli, Kebsiella pneumonia, Asperigellus niger and Candida albicans using agar-cup diffusion method. The results showed that the complex derivatives were significantly active against the micro- organisms when compared to anti-bacterial and anti-fungal drugs.
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, anti- tubercular 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.
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.
Such molecular modification had yielded other derivatives such as (7)46, (8)47and (9)48.
Okafor49 also reported the synthesis of the first three branched diazaphenothiazine and diazaphenoxazine dyes of the type (10) and (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.
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.
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 13C- NMR 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.
This material content is developed to serve as a GUIDE for students to conduct academic research
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF BRANCHED BENZOXAZINOPHENOTHIAZINES AND THEIR DERIVATIVES
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