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, 1
HNMR and 13CNMR spectroscopies and elemental analysis. The antimicrobial properties of the synthesized compounds were determined against Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa,
scherichia coli, Klebsiella pneumoniae, Candida albican and Aspergillus niger using agar diffusion technique. Results showed that the complex derivatives were significantly active against the microorganisms.
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
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
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[3,2c]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 …
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
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.
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.
REFERENCES
Kumar, A, , K. Parashar., Bhati S.K. and Yadav B.P. (2011); Synthesis of 10-[7, 11- (2,4-Disubstitutedphenyl)-3-oxo-9-aminoimino-2,4-diazaspiro[5,5]-phenothiazine Derivatives as Anticonvulsant Activity. Int. J. Pharm. And Biol. Archives, 2(1), 577-582.
Odin, E.M., Onja, P.K and Akabueze, B.O. (2013); Synthesis, characterization and neuropharmacological activity of novel Angular Pentacyclic phenothiazine. Continental J.pharmacology & Toxicology Research 6(2), 1-12.
Hirata, T., Peng G., Driscoll, J.S. (1978); Potential CNS Antitumour Agents – phenothiazines II: Fluphenazine Analogs; Pharm. Sci; 67(2), 157-162.
Amaral, L., Kristiansen, J.E., Viveiros and Mand Atouguai J. (2001); Activity of phenothiazines against Anti-biotic Resistant Mycobacterium Tuberculosis., Antimicrobial Chemotherapy, 47, 505-511; The British Soc. For Antimicrobial chemotherapy.
Kalkanidis, M., Klonis, N., Tiley, L and Deady, L.W; (2002); Novel phenothiazine antimalarial: synthesis, antimalarial activities and inhibition of the formation of beta-haematin. Pharmacol: 65 (5), 833.
Craig-Cymerman, J., Tate, M.E., Warmick, G.P and Roger W.P (1960); Chemical Constitution and Anthelmintic activity, IV. Substituted phenothiazine., Med. Pharm. Chem; 2, 659, Chem. Abstr, (1961), 55 19032e.
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