SYNTHESES CHARACTERIZATION AND ANTIMICROBIAL ACTIVITIES OF ALKYNYLATED ANGULAR PHENOXAZINES AND ALKYNYLATED NAPHTHOQUINONES

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ABSTRACT

The synthesis of ten new alkynylated  derivatives of angular phenoxazine  and  alkynylated naphthoquinone    was   thoroughly   investigated.    The   first   intermediate,    6-chloro-5H– benzo[a]phenoxazin-5-one  was obtained  by the condensation  of  2-aminophenol  with 2,3- dichloro-1,4-  naphthoquinone  in  the  presence  of  anhydrous  sodium  tricarbonate  (IV)  . Thereafter,  the  intermediate  and  2,3-dichloro-1,4-naphthoquinone  were  each suggested  to Sonogashira cross–coupling reaction under copper-, amine-, and solvent free conditions at 80

oC  with  five  different  terminal  alkynes  using  PdCL2(PPh3)2    and     tetrabutylammonium

trihydrate  (TBAF.3H2O)  as the catalyst  and ligand  respectively  to afford  the  alkynylated angular phenoxazines and alkynylated naphthoquinone derivatives in good to excellent yield . Structures of synthesized compounds were confirmed with Uv-visible, Fourier Transform – Infrared (FT-IR), 1H-NMR and 13C-NMR spectroscopy.  The  synthesized  compounds were screened   against  five  (5)  micro-organisms   viz:   Staphylococcus   aureus,  Pseudomonas aeruginosa, Klebsiella  pneumonia,  Escherichia  coli 1 and Escherichia  coli 12 using agar well  diffusion  technique.  The  results  showed  significant  improvement  in  antimicrobial activities compared with gentamycin and ampicillin (standard drugs).

CHAPTER ONE

1.0       INTRODUCTION

The chemistry of phenoxazine and its derivatives have been of considerable interest over the years because of their important and impressive number of applications1  particularly as dyes and  drugs2,3.  Phenoxazines  are  a pharmaceutically  important  class of  tricyclic  nitrogen- oxygen heterocycles4. They show tremendous pharmacological activities as anti-epileptic5, antitumour6,7, anticancer8, antituberculosis9,  antibacterial10,11, anthelminthic12,  spasmolytic, central  nervous  system  (C.N.S)  depressants,13,14   herbicides  tranquilizers,  sedatives15   and

parasiticidal  agents16.  Other  applications  of phenoxazine  derivatives  include  their  use  as

antioxidants17,    biological    stains18,19,    acid-base    indicators20,    and   bromometric    and stannometric redox indicators21-25. Phenoxazine itself has been used as a stabilizer  for the polymerization of vinylpyridines26, polyethylene and polystyrene27. Some of its derivatives were also reported as having radioprotective and antioxidative actions28.

Naphthoquinones are secondary metabolites largely found in plants, micro-organisms, and some animals29. These compounds have been widely used as colourants for comestics30, fabrics31,  foods and for pharmacological  activities  such  as  antitumor,  anti-inflammatory, antibacterial,  antiviral,  antiproliferative,  antiparasitic,  cytotoxic  activities  and  others32-34. They can be prepared synthetically and are widely produced by the chemical industry as organic  dyes35.  The  scientific  community  has  explored  the  biological  and  toxicological

activities of napthoquinones in attempts to discover and develop new drugs.

1.1      BACKGROUND OF THE STUDY

Since the discovery of the parent ring phenoxazine 1, which was synthesized first by

Bernthsen36   in 1887,  many structural  modifications  have been carried  out to enhance  its biological activities, minimize undesirable effects37  and open new areas of applications.

Such molecular modifications had yielded derivatives such as compounds 2, 3, 4, 5, 6 and 7.

Compounds 2, 3, 4, and 5 are described as “angular” phenoxazines because of the non-linear arrangement of the ring systems38. These possess fused rings at positions a39, c40, h and j bonds of the phenoxazine.

There are also systems in which naphthalene is attached to two different positions in the     parent     compound.     Such     structures     include     dibenzo[a,h]phenoxazine     841,

dibenzo[a,i]phenoxazine 9 and dibenzo[a, j]phenoxazine 10.

There are variations of “angular” phenoxazine  in which one of the ring carbon atoms  has been replaced with oxygen, known as benzopyrano[3,4-b]benzoxazine  11, and structures in which the attached benzene ring possesses a substituent. Example of the later is compound

Many derivatives  of non-linear  phenoxazine  formed by fusion of benzene ring in the  [a] position have been reported. These compounds such as 2 have been used as dye  stuff and suitable indicators42.

A number of intermediates including naphthoquinones 13 derivatives have been used for the synthesis of non- linear phenoxazines. Naphthoquinone  13 and its derivatives  have been the subject  of much research  due to  their  pharmacological  activities.  Quinone  and naphthoquinone  fragments are often encountered in natural biologically active compounds. Natural naphthoquinone derivatives

found in plants, such as 2-hydroxy-1,4-naphthoquinone,  have antibacterial effect on several species of aerobic and anaerobic organism43-44. Some 1,4-naphthoquinone derivatives possess biological activities45-46. 2-Hydroxy-1,4-naphthoquinone  83 (Lawsone) is a naphthoquinone dye isolated from leaves of Lawsonia inermis, the Henna plant used for preparing decorative hair and skin dyes. It also demonstrates antimicrobial and antioxidant effects43. Baker and co- workers in 1990 isolated naphthoquinone from culture extracts of Fusarium oxysporum and Fusarium solani47. Brandelli and  co-workers in 2004 also reported that the presence of an imino group instead of a keto group in the position 1 or 4 in 1,4-naphthoquinone results in the loss of antimicrobial activity48. This may indicate that both free groups are required for full activity49. The incidence of bacterial infections is an important and challenging problem due to the  emerging new infectious diseases and increasing multi-drug resistance of microbial pathogens50. For critically ill people with a compromised  immune system including AIDS patients,  burn  victims,  individuals  undergoing  chemotherapy  as well as organ  transplant recipients taking immunosuppressive drugs, fungal infections are a serious concern51.

Modern organic synthesis has been greatly improved by the use of reactions catalyzed by transition metal complexes especially palladium, and this has led to the development of new methods of constructing  carbon-carbon  bonds and  carbon-heteroatom  bonds52-55. The transition metal-catalyzed  C-C bond forming  reactions  have gained increasing  importance over the last decade. The development and finetuning of reaction parameters for known and newly  discovered   metal–catalyzed   transformations   have  had  an  important  impact  on

successes in the synthesis of natural and non-natural biologically active compounds and  as theoretically interesting molecules of high complexity56a-c. In addition, process development for  valuable  intermediates  in  the  pharmaceutical  and  agrochemical  industry  as  well  as

research towards new materials have benefited a great deal.

The increasing popularity of processes harnessing coupled catalysis is highlighted by the  number  of recent  reviews  in this area,  especially  the  well-documented  work  on Pd- catalyzed  C-C bond formation57-60.  One of the most general and widely used  palladium– catalyzed  cross–coupling  reactions  is the  alkynylation  of the  aryl  halides  using terminal

alkynes, generally known as the Sonogashira cross–coupling reaction61a-c. Other  palladium

catalyzed coupling reactions that have changed the face of organic synthesis include Heck- Mizoroki coupling reaction, Buchwald-Hartwig coupling reaction, Suzuki- Miyaura reaction and Negishi reaction.

There are two different approaches to the application of transition metal-  catalyzed reactions to the chemistry of heterocyclic compounds62a-c. One of them, involves the building of the heterocyclic backbone whereas in the other aspect, the heterocyclic fragment is used as

one of the reaction components. These examples are given in (i) and (ii) below, respectively.



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SYNTHESES CHARACTERIZATION AND ANTIMICROBIAL ACTIVITIES OF ALKYNYLATED ANGULAR PHENOXAZINES AND ALKYNYLATED NAPHTHOQUINONES

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