SYNTHESES OF BENZOTHIAZINOPHENOTHIAZINE DERIVATIVES AND EVALUATION OF THEIR ANTIMICROBIAL ACTIVITIES

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 microorganisms.

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.

Notable among the early phenothiazine drugs are Chlorpromazine (2) and promethazine (3) which are broad spectrum tranquilizers with diffuse antipsychotic properties9.

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 anti- tuberculosis 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.

Such molecular modifications had yielded derivatives such as (4), (5),25 (6), (7), (8) and (9).26                                              

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).

Branched phenothiazine compounds of the types (13) and (14)30 have been reported.

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

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.

Okafor and Okoro33 also reported the synthesis of the first three-branched diazaphenothiazine dyes of the type (20).

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

Other structures synthesized are the aza and non-aza analogues of dibenzotriphenodithiazine ring

systems of the types (24)36 and (25).37

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.

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 work.

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