Syntheses of benzothiazinophenothiazine derivatives and evaluation of their antimicrobial activities

Thesis Overview

<p> 1.0 INTRODUCTION<br>The chemistry of phenothiazine (1) and its derivatives has been of interest for over a century<br>due to their wide range of applications in drug, agriculture, textile, paint and other related industries.<br>Phenothiazine and its derivatives constitute a pharmaceutically important class of heterocycles with a<br>broad spectrum of pharmacological activity; they are useful in medicine as anticonvulsants,1<br>antitumour agents,2,3 antituberculosis,4 tranquilizers and antimalaria agents5. It also has anthelmintic<br>activity, 6, 7, 8 to mention a few.<br>N<br>S<br>H<br>(1)<br>Notable among the early phenothiazine drugs are Chlorpromazine (2) and promethazine (3) which are<br>broad spectrum tranquilizers with diffuse antipsychotic properties9.<br>N<br>S<br>N<br>H3C CH3<br>Cl N<br>S<br>N<br>CH3<br>H3C CH3<br>(2) (3)<br>2<br>These classes of drugs were the largest and most widely investigated class of neuroleptic agents9.<br>Chlorpromazine, the first commercially produced phenothiazine for the management of psychosis,<br>was also one of the first commercially produced in the phenothiazine series shown to have antituberculosis<br>properties both in vitro and in vivo.10,11 Promethazine and chlorpromazine, clinically<br>useful in the chemotherapy of mental and emotional disturbances has further stimulated an<br>investigation into other phenothiazine derivatives for possible central nervous system<br>(CNS)depressant activity.12,13<br>In the petroleum industry, these compounds are useful as antioxidants in gasoline, petroleum<br>lubricants and stabilizers.14-18 They are used as vat dyes and pigments18-22 in textile and paint<br>industries and in agriculture as insecticides and nematodicides.23,24<br>Since the discovery of the parent ring (1), a lot of structural modifications have been carried<br>out to enhance their pharmacological and biological activities, minimize undesirable effects and open<br>new areas of applications.<br>3<br>Such molecular modifications had yielded derivatives such as (4), (5),25 (6), (7), (8) and (9).26<br>N<br>S<br>H<br>N<br>S<br>H<br>N<br>S<br>H<br>N<br>S<br>H<br>N<br>S<br>H<br>N<br>S<br>H<br>(4)<br>(5)<br>(6)<br>(7) (8)<br>(9)<br>Compounds (4), (6), (7) and (9) are described as angular phenothiazines because of the non-linear<br>arrangement of the ring systems27. They possess fused rings at positions a, c, h and j bonds of the<br>phenothiazine.<br>There are also systems in which two benzene rings are attached to two different positions in the<br>parent compound. Such structures include dibenzo[a,h]phenothiazine28 (10),<br>dibenzo[c,h]phenothiazine29 (11) and dibenzo[a,i]phenothiazine (12).<br>4<br>N<br>S<br>H<br>N<br>S<br>H<br>(10)<br>(11) (12)<br>N<br>S<br>H<br>Branched phenothiazine compounds of the types (13) and (14)30 have been reported.<br>(13)<br>(14)<br>N<br>S N<br>S<br>N<br>S<br>H<br>With regard to the aza analogues of angular phenothiazine compounds, there have been<br>reports on the monoaza, diaza and the triaza derivatives such as (15), (16)31, (17) and (18)<br>respectively<br>5<br>(15) (16)<br>N<br>S<br>H<br>N<br>S<br>H<br>N<br>S<br>H<br>N<br>S<br>H<br>N 2N<br>2N<br>N<br>N<br>N<br>(17)<br>(18)<br>On the search for more aza analogues of angular phenothiazine ring system, the first aza<br>analogues of pyrrolo[3,4-a][1,4]benzothiazino[3,2-c]phenothiazine (19) was reported by Japanese<br>workers32.<br>N<br>S N<br>S<br>N<br>H<br>(19)<br>Okafor and Okoro33 also reported the synthesis of the first three-branched diazaphenothiazine<br>dyes of the type (20).<br>6<br>N<br>S N<br>S<br>N<br>(20) N<br>The diaza (21) and triaza (22) three-branched benzoxazinophenothiazine ring systems were<br>reported by Okafor34 and also reported was the tetraaza analogue (23) of benzothiazinophenothiazine<br>ring system by Ezema.35<br>N<br>O N<br>S<br>N<br>O N<br>S<br>N<br>S N<br>S<br>N<br>N<br>N<br>2N<br>2N<br>2N<br>(21) (22)<br>(23)<br>7<br>Other structures synthesized are the aza and non-aza analogues of dibenzotriphenodithiazine ring<br>systems of the types (24)36 and (25).37<br>N<br>S<br>N N<br>S<br>H H<br>(24)<br>N<br>S<br>S<br>N<br>(25)<br>1.2 Statement of the Problem<br>Owing to the wide range of applications of phenothiazines derivatives with highly improved<br>pharmacological and biological activities, several papers describing the successful synthesis of these<br>derivatives had been reported especially on the angular derivatives including the non-aza and the<br>congeneric aza analogues. However, there are still limited literatures on the complex derivatives of<br>this phenothiazine ring system and, hence, modification of the existing ones is necessary.<br>The past work done was based on their dye and pigment properties. Not much is known of<br>antimicrobial properties of these complex phenothiazine derivatives.<br>1.3 Aims and Objectives of Study<br>The aims and objectives of this study were to:<br>i. Synthesize complex aza derivatives of benzothiazinophenothiazine.<br>ii. Characterize the synthesized compounds by spectral analysis.<br>iii. Undertake antimicrobial screening on the complex derivatives.<br>8<br>1.4 Justification of the Study<br>The wide pharmaceutical applications of phenothiazines and the need to synthesize more<br>derivatives with better and more desirable pharmacological properties led to the synthesis and<br>antimicrobial screening of the derivative undertaken in the present <br></p>