Synthesis and Biological Evaluation of New Benzothiazole Derivatives
Department of Chemotherapy, Haffkine Institute for Training, Research and Testing, Parel, Mumbai- 400012.
Author E-mail: patil_vrush1@yahoo.com
ABSTRACT
A series of 2-N-acetyl-[2’-(thieno substituted aryl ketone)-5’-methyl-1’,3’,4’-oxadiazolyl] benzothiazole (5a-e) have been synthesized. These structures are determined by the elemental analysis and spectral data (IR, 1H-NMR). These new derivatives are evaluated for in vitro antimicrobial activity against Staphylococcus aureus ATCC 3750, Salmonella typhi NCTC 786, Candida albicans ATCC 10231 and Aspergillus niger ATCC 16404.
KEYWORDS: 2-amino benzothiazole, 1,3,4-oxadiazole, anti–bacterial, anti–fungal.
INTRODUCTION:
Benzothiazole derivatives are reported to posses’ wide range of activity1-4. Oxadiazolyl5 derivatives have been found to exhibit diverse biological activity such as antibacterial, fungicidal, insecticidal, anti-inflammatory and anti-HIV. Therefore it was considered worthwhile to explore the synthesis of compound built upon benzothiazole skeleton incorporating oxadiazolyl moiety with the hope of potentiating the activity of two such units in the same compound and to further evaluate antibacterial activity against S. aureus and S. typhi, and antifungal activity against C. albicans and A. niger species respectively. The synthetic routes followed for obtaining compounds (5a-e) are outlined in Scheme-I. The structures of the new compounds were established on the basis of analytical (C,H,N) and spectral (IR, 1H-NMR) data. 5a-e were evaluated for in vitro antimicrobial activity as MIC (Minimum Inhibitory Concentration) values against Staphylococcus aureus ATCC 3750, Salmonella typhi NCTC 786, Candida albicans ATCC 10231 and Aspergillus niger ATCC 16404 using the tube dilution method6.
EXPERIMENTAL:
Step I: Synthesis of 2-N- (ethyl aceto acetate) benzothiazole (1).
A mixture of 2-amino benzothiazole (0.01 mole), ethyl chloro acetate (0.01 mole) and potassium carbonate 3gm in acetone was stirred for 6-8hrs. the solvent was removed under reduced pressure and the solid mass so obtained was extracted with ether.
Yield= 51%, M.P= 110ºC.
IR (KBr) cm-1: 3240(-NH), 1620(C=O), 1730(-COOR), 3390, 2855, 750(Ar-H).
1H-NMR (DMSO): δ7.3-8.0(m, Ar-H) δ3.5 (s, 2H, -CH2), δ2.4 (t, 3H, CH3).
Step II: Synthesis of 2-N- (acetyl ethyl aceto acetate) benzothiazole (2).
Compound 1 (0.01 mole) and (0.03 mole) of acetic anhydride in 5ml of glacial acetic acid was refluxed for 15 minutes on water bath. The reaction mixture was cooled and poured into cold water. The solid obtained was filtered and recrystallised from ethanol.
Yield= 64%, M.P= 123ºC.
IR (KBr) cm-1: 1683(C=O), 1730(-COOR), 2875(-CH3), 1605(C=N).
1H-NMR (DMSO): δ7.3-8.0(m, Ar-H) δ3.5 (s, 2H, -CH2), δ2.4 (t, 3H, CH3), δ 2.1 (s, 3H, CH3).
Step III: Synthesis of 2-N- (acetyl aceto hydrazide) benzothiazole (3).
R= Substituted phenyl
An ethanolic solution of compound (2) (0.01 mole) and hydrazine hydrate (0.05 mole) was stirred and refluxed on water bath for 3-4 hrs. the excess of solvent was removed by distillation. The solid obtained was filtered, washed with water and recrystallised from ethanol.
Yield= 68%, M.P= 160ºC.
IR (KBr) cm-1: 3342(NHNH2), 3049(Ar C-H) 1680(C=O), 1605(C=N).
1H-NMR (DMSO): δ7.4-8.0(m, Ar-H) δ3.5 (s, 2H, -CH2), δ3.1 (s, 2H, NH2), δ 5.5 (s, 1H, NH).
Step IV: Synthesis of 2-N- acetyl-(2’-mercapto-5’-methyl-1’,3’,4’-oxadiazolyl) benzothiazole (4).
Compound (3) (0.01 mole), CS2 (0.01 mole), potassium hydroxide (0.01 mole) and 25ml of methanol were taken and refluxed until the evolution of H2S gas ceased. The excess of methanol and CS2 were distilled off under reduced pressure. The potassium salt of the compound was
dissolved in distilled water and then precipitated by using dilute HCl. Product was recrystallised from rectified spirit.
Yield= 76%, M.P= 220ºC.
IR (KBr) cm-1: 2358(-SH), 1630(C=N), 1600-1500 (C=C).
1H-NMR (DMSO): δ7.4-7.9(m, Ar-H), 10.94(s, 1H, SH) δ3.6 (s, 2H, -CH2).
Step V: Synthesis of 2-N-acetyl-[2’-(thieno substituted aryl ketone)-5’-methyl -1’,3’,4’-oxadiazolyl] benzothiazole (5a-e).
Compound (4) (0.01 mole) was dissolved in 10% NaOH solution (15ml) and fluoro benzoyl chloride (0.01 mole) was added dropwise. The mixture was stirred for 1 hour and filtered. The filtered product was dried and recrystallised from rectified spirit.
Yield= 53%, M.P= 147ºC.
IR (KBr) cm-1: 1237(ether grp.), 2849(-CH2), 1681(C=O), 1605(C=N).
1H-NMR (DMSO): δ7.1-8.4(m, Ar-H), δ3.5 (s, 2H, -CH2).
Table-1: Physical properties and antimicrobial activity of compounds 5a-e.
|
Comp |
Substituent (R) |
Yield (%) |
M.P. (°C) |
Antimicrobial activity (mg/ml) MIC |
|||
|
S.aureusATCC 3750 |
S.typhiNCTC 786 |
C. albicans ATCC 10231 |
A. niger ATCC 16404 |
||||
|
5a |
4-fluoro phenyl |
58 |
147 |
50 |
100 |
100 |
50 |
|
5b |
4-chloro phenyl |
60 |
162 |
200 |
100 |
200 |
100 |
|
5c |
3-chloro phenyl |
52 |
138 |
200 |
200 |
100 |
200 |
|
5d |
2,5-dimethyl phenyl |
61 |
171 |
100 |
50 |
100 |
100 |
|
5e |
2-fluoro phenyl |
59 |
151 |
50 |
50 |
100 |
100 |
· Elemental analysis (C, H, N) of the compounds was in the range of ±0.4%.
· Ampicillin (MIC-0.04 µg/ml) used as standard against S. aureus.
· Trimethoprim (MIC 0.01 µg/ml) used as standard against S. typhi.
· Miconazole (MIC 0.01 µg/ml) as standard against C. albicans and A. niger.
RESULTS:
The newly synthesized compounds (5a-e) showed varying degree of inhibition. Synthesized compound showed moderate to good antibacterial and antifungal activity. The physical properties and the antimicrobial activity of the synthesized compounds are mentioned in Table-I.
DISCUSSIONS:
A total of 5 compounds (Table-1) were subjected to antimicrobial screening against Staphylococcus aureus ATCC 3750, Salmonella typhi NCTC 786 using tube dilution technique6. Ampicillin and Trimethoprim and were used as the standard drugs against Staphylococcus aureus and Salmonella typhi, respectively.
All the compounds (5a-e) were found to possess moderate activity upto 100µg/ml against Staphylococcus aureus and Salmonella typhi. While some of the compounds such as 5a, 5d and 5e showed good activity upto 50µg/ml.
The SAR (Structure activity relationship) of antifungal agents has revealed that the basic nitrogen-carbon linkage is an essential feature for the activity8. All the five synthesized compounds were screened for antifungal activity against standard strain of Candida albicans in Sabouraud-Dextrose broth by tube dilution method using Miconazole as the standard drug. The compounds exhibited varying degree of antifungal activity. 5a showed good activity against A. niger.
Suitable electronegative substitutions at the different positions of the phenyl ring may lead into compounds with enhanced anti-bacterial activity. Presence of fluorine as a substituent contributes more activity imparted to the compound as compared to the other substitution analogues. Hence, fluorine substitution seems to be more favorable for antimicrobial activity. The results are recorded in Table-1.
The authors are thankful to SAIF, IIT, Powai, Mumbai for carrying out the elemental analysis (CHN) and also thankful to Institute of Science, Fort, Mumbai for recording the NMR spectra.
1. Rathod A S, Patil S D, Berad B N and Doshi A G, Oriental Journal of Chemistry, 14(1), 1998, 107.
2. Ryu C, Kang H, Shin K and Lee B, Bio. Med. Chem. Lett., 10, 2000, 1598.
3. Gurupadaiah B M, Jayachandran E, Kumar B S, Nagappa A N, Nargund L V G, Indian Journal of Heterocyclic Chemistry, 7, 1998, 213.
4. Bhusari K P, Khedekar P B, Umathe S N, Bahekar R H, Rao A R R, Indian Journal of Heterocyclic Chemistry, 10, 2001, 231.
5. Patel K D, Mistry B D, Desai K R, Indian Journal of Heterocyclic Chemistry, 11, 2001, 63.
6. E. Joan Stokes, Clinical Bacteriology, 4th Edition 1995, 226.
7. Pelczar, Reid and Cohn, Antibiotics and other Chemotherapeutic agents Microbiology, 1989.
8. Wilson Giswold’s “Textbook of Organic Medicinal Chemistry and Pharmaceutical Chemistry”, 11th Edition.
Received on 10.08.2009 Modified on 30.09.2009
Accepted on 28.10.2009 © AJRC All right reserved
Asian J. Research Chem. 2(4):Oct.-Dec. 2009 page 513-515