Indo American Journal of Pharmaceutical Research, 2015
ISSN NO: 2231-6876
SYNTHESIS, EVALUATION OF ANTIOXIDANT AND ANTIMICROBIAL STUDY OF 2SUBSTITUTED BENZOTHIAZOLE DERIVATIVES
Gollapalli Nagararaju*, Karumudi Bhavya Sai, Kota Chandana, Madhu Gudipati, P.V. Suresh,
Nadendla Ramarao
Chalapathi Institute of Pharmaceutical Sciences, Guntur-522 034, Andhra Pradesh, India.
ARTICLE INFO
Article history
Received 19/03/2015
Available online
31/03/2015
Keywords
Benzothiazoles,
Antioxidant,
Antimicrobial
And DPPH.
ABSTRACT
Benzothiozoles are an important class of heterocyclic compounds which possess wide
spectrum of biological properties. In the present research work, a series of new 2-substituted
benzothiozole derivatives are synthesized and evaluated as enhanced antioxidant and
antimicrobial agents. The chemical structure of newly synthesized 2-substituted benzothiazole
derivatives are characterized by the spectral studies (IR, Mass and CHN analysis). The
compounds were evaluated for their in -vitro antioxidant activity by using five standard
protocols namely diphenyl picryl hydrazyl (DPPH) scavenging activity, nitric oxide
scavenging activity, reducing power ability study, hydroxyl radical scavenging activity and
by lipid peroxidation. Ascorbic acid was used as standard for DPPH, nitric oxide, reducing
power ability and hydroxyl radical scavenging assay. Antibacterial activity was evaluated
against B. pumilis, A. niger, S. aureous, C. albican and S. dysentriae using Norfloxacin,
Ampicillin and Griseofulvin were standard. It was observed that the 2-substituted
benzothiazole derivatives confirmed the antioxidant and antimicrobial activities.
Copy right © 2015 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Please cite this article in press as Mr. Gollapalli NagaRaju et al. Synthesis, Evaluation of Antioxidant And Antimicrobial Study of
2-Substituted Benzothiazole Derivatives. Indo American Journal of Pharm Research.2015:5(03).
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Corresponding author
Mr. Gollapalli NagaRaju
Assistant professor
Department of pharmaceutical analysis
Chalapathi institute of pharmaceutical sciences
Lam, Guntur, Andhra Pradesh,
India522 034,
919966788710
[email protected]
Vol 5, Issue 03, 2015.
Mr. Gollapalli NagaRaju et al.
ISSN NO: 2231-6876
INTRODUCTION
Benzothiazoles can serve as unique and versatile scaffolds for experimental drug design. Among all benzoheterocycles,
benzothiazole has considerable place in research especially in synthetic field of pharmaceutical chemistry because of its potent and
significant pharmacological activities. Although benzothiazole nucleus still exist a real need for new procedures that support many
kinds of structural diversity and various substitutions. Benzothiazole found a simple and small molecule which shows various type of
pharmacological activity. The studies of structure activity relationship interestingly reveal that change of the structure of substituent
group at C-2 position commonly results the change of its bioactivity. Benzothiazole derivatives are useful as antimicrobial [1-5],
antheltminitic [6], antiviral [7], antileishmanial [8], fungicidal [9], antibacterial [10], antirheumatic [11], antituberculotic [12], antiinflammatory [13], CNS depressant [14], antiviral [15], antitumor [16-18] etc. 2-(4-Aminophenyl) benzothiazole derivatives were
extensively studied for their anticancer activity [19]. Benzothiazole considered as a wonder nucleus which posses almost all types of
biological activities such as hypnotic [20], anti-HIV [21], inhibition of gastric H+K+-ATPase [22], antifungal [23], antihistaminic(H1antagonist) [24], antiviral [25], anti-inflammatory [26], antimicrobial [27-28], diuretic [29], cardio protective [30], anti-ischemic [31],
Ca2+ channel blocker [32], cycloxygenase inhibitory [33], hypo-glycemic [34], anti-platelet activating factor [35], non-peptide
thrombin receptor antagonist [36].
The significance of larger use of these compounds in medicinal chemistry, also important to know the methods of synthesis
and characteristics in order to develop and reduce costs in the future. The present research work is focused to synthesize 2-substituted
benzothiazole derivatives and evaluate their antioxidant and antimicrobial properties.
MATERIALS AND METHODS
Melting points were recorded in open capillaries and are uncorrected. The IR spectra were recorded on a JASCO FTIR
Spectrophotometer as KBr pellets and the wave numbers were given in cm -1. The IR spectra were recorded on a QT OF MICROTM.
All the reactions were monitored by thin layer chromatography (TLC) on pre coated silica gel 60 F254 (mesh); spots were visualized
with UV light. Sodium sulphide and o-chloro nitro benzene, benzoyl chloride, ammonium thiocyanate, potassium thiocyanate,
thiourea, Benzyltrimethylammonium tribromide, alcohol, methanol, ethanol, acetone, ethyl acetate, benzene, petroleum ether
(60‐800C), DMSO, chloroform etc. All these chemicals were bought from National Scientific Products, Guntur.
GENERAL PROCEDURE FOR THE PREPARATION OF O-AMINO THIOPHENOL:
In a Round Bottom (RB) flask, sodium sulphide was dissolved in a minimum amount of distilled water, and then alcohol (10
ml per 0.01 mole of the compound) was added to the solution. The RB flask was placed on a water bath for refluxing. Then after it
turned brown, o-chloro nitrobenzene was added and again refluxed for several hours. In this case, excess amount of sodium sulphide
was required to make complete react ion with sulphur. Synthesis of o-Nitrophenyl disulphide scheme is given in Fig 1
Na2S +
S
Na2S2
NO2
Na2S2
(Disodium disulphide)
S
S
+
Cl
1-chloro-2-nitrobenzene
NO2
O2N
Ortho nitrophenyl disulphide
Fig 1: Synthesis of o-Nitrophenyl disulphide.
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SYNTHESIS OF 2-PHENYL BENZOTHIAZOLE AND ITS PHYSICO-CHEMICAL DATA
o-Amino thiophenol (1.25 gm) was added to a stirred solution of benzoyl chloride (1.405gm) in chloroform [38]. The mixture
was stirred 2 hours at room temperature by magnetic stirrer. So finally the process has been established that stirring in room
temperature is better than reflux in water bath and time should be 2.5 hour which will give almost 45-46 % of yield. Separation of
product is done by filtration. For the above mentioned process validation through repeated experimentation, the amount of o-amino
thiophenol prepared by us was not sufficient and therefore, we required to use commercially available compound. Synthesis and
Physical data of prepared 2-phenyl benzothiazole given in Fig 2 and Table 1
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o-Nitrophenyl disulphide (0.308 gm) is dissolved in chloroform in a RB flask. Put zinc granule (1.4 gm) in the RB flask. It
should be refluxed 2 hours in a water bath for reduction of the compound and gives desire product o-amino thiophenol [37].
Separation should be done by filtration; the excess zinc granule should be removed from liquid part. Then just evaporate the
chloroform it will give the yellow crystal of o- amino thiophenol.
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Mr. Gollapalli NagaRaju et al.
ISSN NO: 2231-6876
COCl
NH2
N
Stirring in
Room temperature
+
S
2-Phenyl benzothiazole
SH
o-Aminothiophenol
Benzoyl chloride
Fig 2: Synthesis of 2-phenyl benzothiazole.
Table: 1 Physical Data of 2-Phenyl Benzothiazole.
2-Phenyl benzothiazole
Appearance
Molecular formula
Molecular weight
Melting Point
Yield (%)
White crystals
C13H9NS
211
1120C -1160C
45%-46 %
Structural Elucidation
Structural elucidation of the synthesized compound was done by means of IR, and Mass spectroscopy. The results are given
in Table 2
Table 2: Structural Elucidation Data of the Synthesized Compounds.
I.R. Spectral Data
Machine No. JASCO FT-IR
1495.53(C=C),1605.45(C=N),
1555.31 (C-C), 1303.64 (C-N),
748.245(Ar ring), 679.785(Ar ring).
Mass
Machine No. QT OF MICROTM
211.97(M+H+),123.97,155.94,163.4,
212.99,213.99,245.95,246.45,270.94
BIOLOGICAL EVALUATION:
IN-VITRO ANTIOXIDANT STUDIES
To search for anti‐oxidant activity in newer molecules five useful standard methods which have been utilized here in different
concentrations for diphenyl picryl hydrazyl, nitric oxide, hydroxyl radical, reductive ability and lipid per‐oxidation assays.
Diphenyl Picryl hydrazyl (DPPH) radical scavenging activity
0.1 m M solution of DPPH in methanol was prepared and 1 ml of this solution was added to 3 ml of various concentrations
(150, 350, 500, 1000 μg/ml) of pyridine derivatives. After 30 min, absorbance was measured at 517 nm. The percentage of inhibition
was calculated by comparing the absorbance values of the control and test samples. Ascorbic acid was used as a reference compound.
The percentage inhibition of DPPH radical was calculated by following formula [39] and results in Table 3. Graphical presentation has
been shown in Graph 1.
Percentege of inhibition =
(Absorbance of control - Absorbance of test)
× 100
Absorbance of control
Table 3: DPPH activity study.
Standard
50.13
89.80
92.13
94.48
(Ascorbic
1290
150
350
500
1000
Percentage (%) inhibition
Compound
Acid)
22.16
37.18
44.10
54.25
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Concentr
ation (μg/ml)
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Graph 1: Showing the percentage inhibition v s. concentration of drug.
Nitric oxide scavenging activity [40]
100 mM sodium nitroprusside (SNP) was prepared by dissolving the powder in phosphate buffer saline (PBS) pH 7.4. The
reaction mixture (2ml) containing 100mM sodium nitroprusside (0.2ml, final conc.10mM) and different concentrations of drug
solution in PBS (1.8ml) was incubated at 25°C for 150 min. From the incubated mixture, 1 ml was taken out and 1 ml of Griess’
reagent (1% sulphanilic acid in 20% glacial acetic acid and 0.1% naphthylethylene diamine dihydrochloride in 20% glacial acetic
acid) was added to it. Absorbance of the chromophore formed by the diazotization of nitrite with sulphanilic acid and subsequent
coupling with naphthylethylene diamine was read at 540 nm and percentage inhibition was calculated by using the formula. Data is
listed in Table 4 and Graphical presentation has been shown in Graph 2.
Table 4: Nitric oxide scavenging activity study.
Concentration
(μg/ml)
150
350
500
1000
Percentage (%) inhibition
Compound
Acid)
23.25
32.56
44.18
54.12
Standard
(Ascorbic
39.14
54.48
59.96
65.19
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Reductive ability:
1 ml of different concentrations of the drug was mixed with potassium ferricyanide (2.5 ml, 1%) and 2.5 ml of phosphate
buffer (pH 6.6). The mixture was incubated at 50°C for 20 min. 2.5 ml TCA (10%) was added to it and centrifuged at 3000 rpm for 10
min. 2.5 ml of supernatant was taken out and to this 2.5 ml water and 0.5 ml FeCl 3 (0.1%) were added and absorbance was measured
at 700 nm. Higher absorbance of the reaction mixture indicated higher reducing power. Data and Graphical presentation has been
shown in Table 5, Graph 3.
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Graph 2: Showing the percentage inhibition v s concentration of drug.
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Mr. Gollapalli NagaRaju et al.
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Table 5: Reductive ability study.
Concentration
(μg/ml)
150
350
500
1000
Percentage (%) inhibition
Compound
Standard (Ascorbic Acid)
0.1214
0.3362
0.2584
0.3598
0.3254
0.3865
0.5124
0.6281
Graph 3: Showing the percentage inhibition vs concentration of drug.
Hydroxyl radical (OH) scavenging activity [42]
The reaction mixture contained in a final volume of 1.0 ml, 100 μL of 28 mM 2‐deoxy‐2‐ribose in 20 mM KH2PO4‐KOH
buffer of pH 7.4, 500 μl of the selected concentrations of drug 44 solution (10, 25, 50, 75, 100 μg/ml) in KH 2PO4‐KOH buffer (20
mM, pH 7.4), 100 μL of 1.04 mM EDTA, 100 μl 200 mM FeCl 3, 100 μl of 1.0 mM H2O2 and 100 μl of 1.0 mM ascorbic acid was
incubated at 370C for 1 h. Then 1.0 ml of thiobarbituric acid (1%) and 1.0 ml of trichloroacetic acid (2.8 %) were added to the test
tubes and were incubated at 1000C for 20 min. After cooling, absorbance was measured at 532nm against control containing
deoxyribose and buffer (not treated with drug). Ascorbic acid was used as a positive control. Reactions were carried out in triplicate.
The percentage inhibition was determined by comparing the results of the test and control compounds. The hydroxyl radical
scavenging activity of the extract is reported as % inhibition of deoxyribose degradation and is calculated by using the formula. Where
a Control is the absorbance of the control reaction and a test is the absorbance in the presence of the sample of the synthesized
compounds considered as drug. Data and graphical presentation has been shown in Table 6, Graph 4.
Table 6: Hydroxyl radical scavenging activity study.
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150
350
500
1000
Percentage (%) inhibition
Compound
Standard (Ascorbic Acid)
35.15
45.41
44.10
55.52
52.25
62.12
61.18
75.45
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Concentration
(μg/ml)
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Graph 4: Showing the percentage inhibition v s concentration of drug.
ANTIMICROBIAL ACTIVITY:
The screening of anti‐microbial activity of the compounds under study was done by the determination of minimum inhibitory
concentration (MIC) by agar dilution method.
Preparation and sterilization of nutrient broth media
Nutrient broth media was prepared from the prescribed solid and other ingredients namely 0.5% sodium chloride, 0.5% beef
extract and 1.0% peptone extract. Solid ingredients were dissolved appropriately in double distilled water to form a clear solution. For
this, a little heating in boiling water bath was necessary. Then the volume was made up to 100% with double distilled water and if
necessary, the pH of the final media solution was adjusted to 7.2‐7.4 with the addition of a required amount of sodium hydroxide
solution. The prepared nutrient broth media in different BG bottles were taken and sterilized by autoclaving for 15mins at 121°C
temperatures and at 15 psi pressure.
Preparation of nutrient broth culture
With the help of a sterile swab, the organisms were inoculated from the different solid bacterial slant cultures to the different
nutrient broth media in BG bottles. The inoculation process was done under aseptic conditions. After the inoculation was completed,
all BG bottles were incubated at 37°C for 24 hrs. Turbid growth of bacteria was observed in each of the BG bottles after 24 hrs of
incubation.
Preparation and sterilization of nutrient agar media
The prescribed solid ingredients namely 0.5% sodium chloride, 0.5% beef extract, 1.0% peptone extract and 1.5% agar were
dissolved properly in double distilled water to make a clear solution. For this, a little heating in a boiling water bath was necessary.
Then the volume was made up to 100% with double distilled water and if necessary, the pH of the prepared nutrient agar media was
adjusted, if necessary, to 7.2‐7.4 with the addition of a required amount of sodium hydroxide solution. Required numbers of suitable
bottles (already sterilized by keeping 1 hr at 160° C in a hot air oven, i.e. by dry heat sterilization) were taken and in each of the
bottles 20 ml of prepared nutrient agar media was poured, closed properly with the cap and finally sterilized by autoclaving.
Inoculation of bacterial organism into Petri dishes
After keeping overnight, the pre‐incubated dry Petri dishes were checked for any microbial contamination and if no growth
was there, it was ready for inoculation of organism. With the help of a sterile swab, a loop full of organism from already prepared 24
hrs nutrient broth culture was inoculated in specific location on the surface of a specific box like place of agar media inside the Petri
dish. Similarly all other organisms were inoculated on the surface of a particular box like marked area of agar media inside all the
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Preparation of drug solutions
Stock solution of the synthesized compounds (10 mg/ml) was prepared by dissolving in DMSO.
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Preparation of Petri dishes with nutrient agar media
Different test compounds in different concentrations (200, 400, 500, and 1000μg/ml in DMSO were prepared and separately
mixed well with a prepared sterile 20 ml nutrient agar media in bottle prior to its 50 solidification. These different drug solution (test
compounds in 20ml of the media) containing nutrient agar media (20 ml each) were poured separately into different sterile Petri dishes
in an aseptic atmosphere. All Petri dishes were kept aside for the proper solidification of the agar media. Finally the Petri dishes were
kept overnight in an incubator at 37 °C in inverted position to avoid the accumulation of water drops inside the Petri dishes.
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Mr. Gollapalli NagaRaju et al.
ISSN NO: 2231-6876
Petri dishes. After 1 hr when all inoculated loop full of broth culture penetrated properly into the agar media, the Petri dishes were
placed inside an incubator and were incubated at 37 °C for 24 hrs. The result was observed after 24 hrs of incubation.
RESULTS AND DISCUSSION
The structures of the synthesized compounds have been established unambiguously on the basis of F.T. I.R. and Mass
Spectroscopy. Melting points were determined with a standard electrically operated melting point apparatus and are uncorrected. The
synthesized compound was evaluated under two parameters, namely in-vitro antioxidant and antimicrobial activities. In-vitro
antioxidant activity has been performed for all synthesized pyridine derivatives using five standard protocols namely Diphenyl picryl
hydrazyl radical scavenging activity, Nitric oxide scavenging activity, reducing power ability study, Hydroxyl radical scavenging
activity and by lipid peroxidation. Ascorbic acid was used as standard for DPPH, nitric oxide, reducing power ability and OH radical
scavenging assay. In this antioxidant study of 2-substituted benzothiazole derivatives, the compound has been shown significant
antioxidant activity.
The antimicrobial activity study on synthesized benzothaizole derivatives was done by a standard antibacterial screening
procedure. From the result of the MIC determination study, it can be clearly seen that in 1000 µg there is no growth of bacteria.
Results are given in Table 7.
Table 7: Antimicrobial Activity.
Name of the Organisms
Tricoloma gigipus
Bacillus subtilis
Vibrio cholerae
E.coli
Salmonella typhimuria
Streptococcus faecalis
Bacillus pumilis
Asperg. niger
Streptococcus aureous
Candida albican
L.lati
Shigella dysentriae
+ Presence of growth, ‐ Inhibition of growth
Minimum Inhibitory Concentration (μg/ml)
2
4
500
1000
00 μg/ml
00 μg/ml
μg/ml
μg/ml
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
-
CONCLUSION
2-substituted benzothiazole derivatives of the class benzothiazole have been synthesized by a simple method. They have been
characterized by their melting points, solubility and spectral data. The compound was tested for in vitro antioxidant activity and
antimicrobial activity. Results of such study indicated that the compound has potential antioxidant properties and its microbiological
study shows it potent nature as anti microbial drugs.
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