List of ABBREVIATIONS

S.N.

ABBREVIATIONS

1. 2. 3. 4. 5. 6.

Dimethyl formamide Melting point Concentration Thin layer chromatography Minimal inhibitory concentration Cyclo oxygenase 1 enzyme Cyclo oxygenase -2 enzyme

DMF m.p. Conc. TLC MIC COX-1 COX-2

7.

Abstract

Several new antibacterial agents are currently being developed in response to the emergence of bacterial resistance to existing drugs. The new agents include compounds that inhibit macromolecular synthesis or interfere with bacterial membrane function. Apart from the oxazolidinones and cationic peptides, the remainder of these new compounds is analogues of earlier antibiotic classes: therefore, it is probable that existing resistance mechanisms will adapt to accommodate the new derivatives. To minimize the potential for emergence of resistance to new agents, research strategies should be chosen that not only enhance the discovery of structurally novel drugs, but also direct these to new molecular targets that may themselves have decreased potential to give rise to drug-resistant variants16.

CONTENT

List of tables

S.n.
1

Table no. Properties of synthesized compounds(3a-e)

Pg.no.
16

Properties of synthesized compounds(4a-e)

17

3
4

anti-oxidant activity Antibacterial and protein denaturation activity

17 18

Index

SR.NO

CONTENTS

PAGE NO.

1. 2. 3. 4. 5. 6. 7. 8. 9.

LIST OF ABBREVIATIONS ABSTRACT CONTENT LIST OF TABLES INTRODUCTION OBJECTIVE REVIEW OF LITERATURE RESULT AND DISCUSSION REFERENCES

Introduction
Benzothiazoles are bicyclic ring system. Benzothiazole derivatives have been studied and found to have various chemical reactivity and biological activity. Benzothiazole ring made from thiazole ring fused with benzene ring. Thiazole ring is a fivemember ring consists of one nitrogen and one sulfur atom in the ring.3

(i) Compounds possessing a primary nitro group joined to a heterocyclic ring are very versatile antimicrobial compounds in vitr.They inhibit bacteria (aerobic and anaerobic, including mycobacteria), yeasts and fungi, protozoa (trypanosomes, coccidia, trichomonads and amoebae) and schistosomes. The major importance of this group is that the bacteria only rarely acquire resistance to nitrocompounds. The inherent toxicity of this group is low enough to allow the use of nitro compounds for the treatment of a variety of infections in man and in animals, and as recognized food additives. Replacement of hydrogen atoms by fluorine atoms in appropriate compounds can lead to drastic changesm in the pharmacological and biological properties while the structural dimensions of these compounds remain largely unchanged.22 Benzothiazole ring found to be possessing pharmacological activitiessuch as anti viral anti bacterial, anti microbial and fungicidal activities.They are also useful as anti allergic, antidiabetic, antitumor anti inflammatory, anthelmintic, and anti HIV agents Benzothiazoles show antitumor activity, the phenylsubstituted Benzothiazoles while condensed pyrimido benzothiazoles and benzothiazolo quinazolines show antiviral activity Substituted 6nitroand 6aminobenzothiazoles show antimicrobial activity.3
. . ,

Type II topoisomerases are the target of a number of antibacterial agents. The most prominent of these agents are the quinolones. The original quinolone antibiotics included nalidixic acid, cinoxacin and oxolinic acid. The addition of fluorine yielded a new class of drugs, the fluoroquinolones, which have a broader antimicrobial spectrum and improved pharmacokinetic properties .22 The fluoroquinolones include norfloxacin, ciprofloxacin, and fourth generation
]

quinolones gatifloxacin and moxifloxacin. The coumarins and thecyclothialidines are further classes of antibiotics that inhibit type II topoisomerases, however they are not widely used because of poor permeability in bacteria, eukaryotic toxicity, and low water solubility. However, the continuous emergence of antibiotic resistance demands that novel classes of

antibiotics continue to be developed and alternative compounds that inhibit bacterial topoisomerases are required.22 Benzoheterocycles such as benzothiazoles, benzimidazoles and benzoxazoles can serve as unique and versatile scaffolds for experimental drug design. Among the all benzohaterocycles, benzothiazole has considerable place in research area especially in synthetic as well as in pharmaceutical chemistry because of its potent and significant pharmacological activities; hence, synthesis of this compound is of considerable interest22. 2-substitued benzothiazole has emerged in its usage as a core structure in the diversified therapeutically applications31. The studies of structureactivity relationship interestingly reveal that change of the structure of substituent group at C-2 position commonly results the change of its bioactivity. Among those 2-substituted benzothiazole derivatives with fluorine substituted molecules have already received considerable attention due to their potential bioactivities.Since benzothiazoles shows multiple therapeutic values found to have diverse chemical reactivity and broad spectrum of biological activity viz antitumor, antitubercular, antimalarial, anticonvulsant anthelmintic, analgesic, anti-inflammatory, antifungal, a topical carbonic anhydrase inhibitor an antihypoxic and an anti-nematode On the other hand, individually substitution of fluorine and nitro group in basic benzothiazole skeleton shows a variety of biological activities especially antimicrobial with minimum side effect7. Fluorine functionality was introduced on the deoxynegamycin backbone structure to alter and improve the overall biological profile; hence, these findings encouraged us to explore the synthesis of benzothiazole derivatives containing fluorine and nitro moieties to examine their antibacterial property.22

OBJECTIVE

Several new antibacterial agents are currently being developed in response to the emergence of bacterial resistance to existing drugs. The new agents include compounds that inhibit macromolecular synthesis or interfere with bacterial membrane function., these new compounds are analogues of earlier antibiotic classes: therefore, it is probable that existing resistance mechanisms will adapt to accommodate the new derivatives. To minimise the potential for emergence of resistance to new agents, research strategies should be chosen that not only enhance the discovery of structurally novel drugs, but also direct these to new molecular targets that may themselves have decreased potential to give rise to drugresistant variants,Hence study of fluorinated benzothiazolyl heterocycles antibacterial agent may nessesory to enhanced the resistance

Review of literature

From the literature survey, it has been found that tremendous work has been reported on benzothiazole. A number of therapeutic agents have been synthesized having benzothiazole as a basic nucleus like- diamthazole dihydrochloride (ii)as antifungal, ethoxzolamide(iii) as diuretic, pramipexole(iv) as antiparkinsonian and riluzole(v) as anticonvulsant and antiparkinsonian. The present review focusing on the benzothiazoles with potential activities that are now in development.7

It is well known that the introduction of fluorine atom into an organic molecule causes dramatic changes in its biological profile, mainly due to high electro negativity of fluorine, the strong carbon-fluorine bond and increased solubility in lipids. Therefore it was thought worthwhile to synthesize better kinds of drugs by incorporating in benzothiaole moiety4. Many of the currently available classes of antibacterials were developed between the 1940s and 1960s.Sulphonamides, penicillins and streptomycins were discovered in this golden age of antibiotics, followed soon thereafter by tetracyclines, macrolides, glycopeptides and cephalosporins22 . Zyvox, has been introduced since 1962, with theremainder of the compounds introduced since that time being modifications of known antibiotics. Zyvox is a nalidixic acid derivative and progenitor of the fluoroquinolone antibiotics22 . Compounds possessing a primary nitro group joined to a heterocyclic ring are very versatile antimicrobial compounds in vitro.They inhibit bacteria (aerobic and anaerobic, including mycobacteria), yeasts and fungi, protozoa (trypanosomes, coccidia, trichomonads and amoebae) and schistosomes. The major importance of this group is that the bacteria only rarely acquire resistance to nitrocompounds. The inherent toxicity of this group is low enough to allow the use of nitro compounds for the treatment of a variety of infections in man and in animals, and as recognized food additives8. Recently it 6-nitroquinolones derivatives synthesized and found that in vitro assays of some derivatives were endowed with good inhibiting activities against tested mycobacteria while some derivatives were also found more potent than ciprofloxacin and ofloxacin (used as reference drugs) against gram-positive bacteria. Replacement of hydrogen atoms by fluorine atoms in appropriate compounds can lead to drastic changes in the pharmacological and biological properties while the structural dimensions of these compounds remain largely unchanged22.. Given below is a brief account of various biological activities of benzothiazole ring and their derivatives.3

PHARMACOLOGIACL ACTIVITIES OF BENZOTHIAZOLE AND THEIR DERIVATIVES

Antitumor activity

The benzothiazole moiety with various substitutions shows antitumor activity. Its aminomethylphenyl(vi) and carbonitrile(vii) derivatives shows selective growth inhibitory properties against human cancer cell lines15 and proliferation of cells respectively. Chlorinated and fluorinated derivatives of this moiety exhibit good in vitro as well as in vivo antitumor activity. Some Fluorinated analogues of 2(4aminophenyl) benzothiazoles were synthesized which block Coxidation. The 2cyano derivatives of benzothiazole exhibit interesting in vitro antitumor activity3. Caleta et al15 ,prepared 6-amidino-substituted-2aminobenzohiazole, N-methyl-2-(4-cynostyryl)benzothiazolium and amidino and bis amidino substituted 2-styryl benzothiazoles. These compound tested on cytostatic activities against malignant cell line. Best inhibitory effect given by N-methyl-2-(4-cynostyryl)benzothiazolium and amidino and bis amidino substituted 2-styryl benzothiazoles with slight difference between them. All of them inhibit the growth of examined tumor cell line and normal fibroblast. And remaining show moderate inhibitory effect ,depending on type of cell.

Hutchinson et al13, have been synthesized fluorinated analogus of 2-(4-aminophenyl)benzothiazole and 2-(4amino-3-methylphenyl)5-fluorobenzothiazole which block C-oxidation and is found potent against human breast and ovarian tumor xenografts amplanted in nude mice Antimicrobial activity Microbes are the causative agents for various types of diseases like pneumonia, ameobiasis, typhoid, malaria, common cough, cold and various infections and cause some severe diseases like.

Benzothiazoles show a wide spectrum of chemotherapeutic activity and a considerable amount of work has been done on the synthesis of new potent antibacterial and antifungal benzothiazoles. Bhusari et a18, prepared some new 2-(substituted phenylsulfonamido)-6-substituted benzothiazoles(viii)10and screened them for their antibacterial activity against Bacillus subtilis , Salmonella typhi and S. dysentery . Compounds with R=Br and R'=CH 3 , NH 2 and I were found more active and others were less or moderately active. Sreenivasa et al11 synthesised 6-fluoro-7-(substituted)-(2- N -p-anilinosulfonamido) benzothiazoles (R =onitroanilino, m-nitroanilino, p-nitroanilino, o-chloroanilino, m-chloroanilino, p-chloroanilino, anilino, morpholino, piperazino, dimethylamino) and studied for their antibacterial and antifungal activities. All compounds showed moderate activity against S. aureus, S. albus and C.ablicans.11

Latrofa et al . prepared a series of N -cycloalkylidene-2,3-dihydro-1,3-benzothiazoles, N -cycloalkyl-2acylalkylidene-2,3-dihyro-1,3-benzothiazoles and N -alkyl-2-acylalkylidene-2,3-dihydro-1,3benzothiazoles(ix) and tested for in vitro antibacterial and antifungal activities against four gram positive and five gram negative bacteria. The find compound were effective against bacterial strains, whereas, only few compounds exhibited a moderate antifungal activity against the yeast strains evaluated10. Barede et al 8 synthesized on a few 5,6-disubstituted-2-(substituted phenyl carboxamido) benzothiazoles and found them active against M. tuberculosis, S. typhi, S. aureus, C. ablicans, Trichophyton rubrum and Trychophyton mentagrophyles . The compounds were also active against some helmenths like Hymenolepis nana. A few 2-[(4-amino/2, 4-diaminophenyl) sulfonyl derivatives of benzothiazoles(x) have been found to possess good activity against E. coli.

Yilidiz-Oren et al13 has synthesized a series of multisubstituted benzoxazoles, benzimidazoles and benzothiazoles as non-nucleoside fused isosteric heterocyclic compounds and tested for their antibacterial activities against Staphylococcus aureus, Streptococcus faecalis, bacillus subtilis as gram + Benzothiazole ring system enhanced the antimicrobial activity against Staphylococcus aureus. koci et al15, Synthesized 2-benzylsulfanyl derivative of benzoxazole and benzothiazole tested against mycobacterium tuberculosis and non tuberculosis mycobacteria and expressed in MIC in M1/1. The substace with two nitro group (thioamide) show appreciable activity against non tuberculosis mycobacteria.. eg. Various substituted 2-(4-acetamidophenylsulfonamido) benzothiazoles and 2-(4-amino phenyl sulfonamido) benzothiazoles containing different functional groups have been synthesized And screened for their antitubercular activity in vitro and compared with standards (Streptomycin and isoniazid).

all the compounds with R 1 =CH 3 and R 2 = Br, were found to be most potent. Overall the compounds having electron-with drawing substituents (NO 2 , COOH and halogens) showed better activity than unsubstituted one8. So, benzothiazole moiety serves as a royal warrior against almost all types of microbes3.

Ojha et al.12 give benzothiazolyl carboxamido pyrazoline derivatives and studied their antimicrobial activity. They found that when R=CH 3 and R 1 =o-OCH 3 C 6 H 4 ,compound showed no activity and when R = Cl and R 1 = p-OCH 3 C 6 H 4 , the compound was active against S. aureus . The rest of the compounds showed activity against, S. aureus, E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus mirabilis1

Anthelmintic activity: Recent reports of resistance to benzimidazoles have now forced the researchers to urgently develop new drugs with anthelmintic activity, to fight helminthiasis, which is causing untold misery to the infected individuals. This prompted synthesis of benzothiazole derivatives, which is sulfur isostere of benzimidazole, in the hope of achieving better anthelmintic activity. Nargund, et al8,14. synthesized few novel 8-fluoro-9-substituted(l,3)benzothiazolo (5, 1-b)-1,4,3-triazoles .All these compounds were studied for their anthelmintic activity against earthworm, Perituma posthuma. The compound with R= o -nitroanilino substituent was found to possess markedly higher anthelmintic activity, than other compounds compared with standard. 8-bromo-9-substituted (1, 3) benzothiazolo5, 1-b]-1, 3, 4-triazoles have been synthesized and screened for their anthelmintic activity against earthworm, Perituma posthuma . are found to be the most potent in the series. And found the properties as bellow

Table-1.Properties of synthesized compounds(3a-e)(xi)

Sr.no Compound code 1 3a 2

R=aromatic benzaldehyde

% yield

m.p.

Rf value

4-methoxy

52%

252

0.40 0.7

3b 3 c 4 d 5 3e 3 3

3,4,5,-trimethoxy

67% 61

240 2 40 47 23 2 54 0.56 238 0.48 0.52

2-hydroxy 4 -hydroxy 3 -methoxy4-hydroxy

Table-2.Properties of synthesized compounds(4a-e)(xii)

Sr.no

Compound code

R=aromatic benzaldehyde

% yield

m.p.

Rf value

1 4a 2 4b 3 c 4 d 5 4e -methoxy4-hydroxy 4 -hydroxy 3 % 4 2-hydroxy 4 % 56 278 % 48 6 3,4,5,-trimethoxy 60% 53 84 27 278 2 4-methoxy 49% 280 0.48 0. 62

0.5 7 0.6 2 0.4 8

Table-3.anti-oxidant activity

Conc in g/ml 50

4a 11.32

4b 13.33

4c 11.45 6.37

4d

4e 8.14

100 150 200 250 IC50

17.31 19.47 28.01 37.89 181

25.76 37.18 45.52 53.77 98

14.30 23.74 28.45 33.05 178

11.45 18.95 24.22 28.98 229

16.24 27.26 36.72 45.12 127

IC50 value not detected at the highest conc. Tested ,so it was determined by extrapolating the graph

Table-4. Antibacterial and protein denaturation activity

Sr.No

Compound code
mm)

Zone of inhibition (Diameter in

% Inhibition of denaturation of protein

S.aureus Bacillus Subtillis (+ Ve) (-Ve) 50 g 100g 100 g 50 g

01. 02. 03. 04.

3a 3b 3c 3d

1.2 1.9 2.2 2.3

1.1 2.3 1.2 2.6

1.6 2.5 2.1 1.4

1.1 2.7 1.9 1.7

73.65 41.39 54.69 68.46

05. 06. 07. 08. 09. 10. 11. 12. 13.

3e 4a 4b 4c 4d 4e

2.1 4.7 6.9 4.2 6.1 5.5

2.9 5.7 6.2 4.6 5.9 6.8 3.5 9.5

-

1.5 4.3 7.1 3.6 5.1 6.5 1.5 7.4 -

2.1 6.8 6.6 4.9 5.6 6.9 2.2 7.8

62.98 46.59 75.98 36.24 54.49 70.89 77.83

Chloroform 3 Ampicillin Diclofenac Na 8.2 -

Anticonvulsant activity: Jimonet et al15 synthesized a lot of substituted-2-benzothiazolamines (All these compounds were found to possess significant activity.

Siddiqui et al .27 synthesized by The compounds with R=4-CH 3 and 4-Cl were found to be equipotent (100%) in activity to phenobarbitone in maximal electroshock seizure test and blocked subcutaneous pentylenetetrazole and strychnine induced seizures to some extent. All other compounds also had significant anticonvulsant activity.15 Singh et al16

,synthesized 2-(4-arylthiosemicarbazidocarbonylthio) benzothiazoles. The compounds were screened for their anticonvulsant activity against pentylenetetrazole induced convulsions in mice and found that all the compounds possess measurable anticonvulsant activity. A large number of 2-(3 H )-benzothiazolone derivatives have been synthesized and evaluated for their anticonvulsant activity in mice and were found to be significantly active16

Antiinflammatory activity: Pyrazolones and pyrazolinones rank among the more venerable non-steroidal antiinflammatory agents. Phenylbutazone and its congeners incorporating a pyrazoline-3,5-dione structure are more potent antiinflammatory agents. In the recent years a number of Benzothiazole derivatives have been synthesized and found to display antiinflammatory activity.

Oketani et al 6-hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl) benzothiazoles were investigated by . against the 5-lipooxygenase activity of rat basophilic leukaemia cells, E 3040 and Zileuton (a-5-lipooxygenase inhibitor) had an IC 50 of 0.23 and 0.93 M, respectively.. Sawhney et al have prepared some novel 2-(2-benzothiazolyl)-6-aryl-4,5-dihydro-3(2 H )-pyridazinone and found that they possessed low to moderate antiinflammatory activity.17 Singh et al 19. 2-(4'-butyl-3',5'-dimethylpyrazol-1'-yl)-6-substituted benzothiazoles and 4-butyl-1-(6'-susbtituted-2'-benzothiazolyl)-3-methylpyrazol-5-ones and were found to display significant antiinflammatory activity. Paramshivappa et al18

2-[(2-alkoxy-6-pentadecylphenyl) methyl] thio]-1 H -benimidazoles/ benzothiazoles and benzoxazoles from an anacardic acid and investigated their ability to inhibit human cycloxygenase-2-enzyme (COX-2). The active compounds were screened for cyclooxygenase1 (COX-1) inhibition. Found potent .

Dogruer et al19 synthesized sixteen (2-benzothiazolone-3-yl and 2-benzoxazolone-3yl) acetic acid derivatives and tested them for antinociceptive and antiinflammatory activity. All have shown more potent antinonciceptive activity than others.19

Antioxidant activities Antioxidants were important because of their prophylactic an therapeutic agents in many diseases. Free radicals are formed as a result of normal organ functions or excessive oxidative stress. Free radicals of high levels can cause damage to biomolecules such as lipids, proteins, enzymes and DNA in cells and tissues, resulting in mutations can lead to malignancy. DNA mutation is a critical step in carcinogenesis. Role of free radicals was discovered in cancer diabetes, cardiovascular diseases, autoimmune diseases, neurodegenerative disorders, aging and other diseases has led to new medical insight and. Minimizing a oxidative damage is primary prevention or treatment of these diseases, since antioxidants may stop the free radical formation, or interrupt an oxidizing chain reaction. Suzen et al3, Reported the antioxidant behaviour of a series of substituted indoline2ones and indoline2thiones was investigated using an oxygen radical absorbance capacity assay.and indoline derivative had effective activities as radical scavengers. Miscellaneous: Diouf et al15 .

synthesized derivatives of 2-piperazinyl benzothiazoles (xiii)and studied as mixed ligands for serotoninergic 5-HT 1A and 5-HT 3 receptors. The studied compounds exhibited significant affinities for these two serotoninergic receptor subtypes. The pharmacological profile of these ligands was agonist for 5-HT 1A receptors and antagonist for 5-HT 3 receptor sub sites. Compounds with such a pharmacological profile are of clinical relevance in the treatment of psychotropic diseases. e.g., anxiety, depression and schizophrenia.15 Brown et al15, reported a series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents and screened against human rhinovirus (HRV). HRV cause approximately one-half of all cases of respiratory tract infection (colds). Several 2-alkoxy and 2-akylthio-benzoxazole and benzothiazoles derivatives showed excellent anti HRV activity. When tested against a panel of 16 representatives HRV types, the 2-ethxoy-benzooxazole derivatives, 13 was found to have superior HRV activity (median EC 50 3.88 ng/mL) to known capsid-binders pleconaril and pirodavir.

.Srinivasan et al. 15 have shown that the replacement of the urea moiety by benzothiazolesulfonamide provided inhibitors of HIV-1 protease with improved potency and antiviral activities. Certain members of the class showed good oral bioavailability in rats

Material and method

Chemical and Reagents

4-fluoro-3-chloro aniline, Potassium thiocyanate, Glacial acetic acid, Bromine, carbon disulphide, ammonia, alcohol, hydrazine hydrate, 2-phenyl quinolin-4- carboxylic acid, pyridine, dimethyl formamide, N-phenyl antranilic acid, aromatic primary & secondary amines

Experimental section: Step- I -General synthesis of 2-amino-6-fluoro-7-chloro-benzothiazole 20 ml GAA cooled below RT, To this added 8 g of (0.08 mol) of potassium thiocyanate 1.45 g. (0.01mol) of 3-chloro-4-fluoro aniline. Mixture was placed in freezing mixture of ice and salt andmechanically stirred while 1.6ml of bromine in 6ml of glacial acetic acid was added from a dropping funnel at such a rate that the temperature never rosebeyond room temperature. After all the bromine was added (105min), the solution was stirred for 2 hours below room temperature and at room temperature for 10 hours then allowed to stand overnight, during which period an orange precipitate settle at the bottom water (6ml) was added quickly and slurry was heated at 850c on a steam bath and filtered hot The orange residue was placed in a reaction flask and treated with 10ml of glacial acetic acid heated again to 850c and filtered hot. The combined filtrate was cooled and neutralized with concentrated ammonia solution to p H 6 A dark yellow precipitate was collected. Recrystalised from benzene, ethanol of (1:1) after treatment with animal charcoal gave yellow plates of 2-amino-6-fluoro-7chlorobenzothiazole after drying

Step-II-General synthesis of N-(7-chloro-6-fluoro-1, 3-benzothiazole2-yl)-2(3 or 4)-nitrobenzamides Solution of 2-(3 or 4)-nitrobenzoylchloride (5.36g, 0.026mol) in dry acetone (50 ml) was add into a solution of 2-amino-6-fluoro-7-chloro-benzothiazole (5.22g,0.026 mol) in dry pyridine (50ml), drop wise with continuous stirring at room temperature. After addition was complete, stirring was continued for another 30 minutes. The reaction mixture was poured in ice cold water (200ml) recrystallized with ethanol Step-III (S-1 to S-15) The 2.7 gm (0.0075 mol) of N-(7-chloro-6-fluoro-1, 3-benzothiazole-2-yl)- 2 (3 or 4)nitrobenzamides was treated with 0.008 mol of various substituted aniline and refluxed for 2 hrs in presence of DMF (dimethyl formamide) then the mixture was cooled and poured into crushed ice. The solid separated was filter off, dried and recrystallize with super dry alcohol.

General reaction 3-chloro-4-fluoroaniline

Acetic acid, Br2, NH3

Potassium thiocyanate, 0-50C

2-amino-6-fluoro-7-chloro- benzothiazole

Dry pyridine

,Reflux at 70 0C, 2hr

N-(7-chloro-6-fluoro-1,3-benzothiazole-2-yl)-2 (3 or 4)-nitrobenzamide

DMF Reflux at 700 C; 2hrs

N-(6-fluoro-7-[(substituted)-amino]-1,3-benzothiazole-2-yl)-2 (3 or 4)-nitrobenzamide (S-1 to S-45)

s.n.

Name of the compound/Compound Code

Mean zone of inhibition (in mm) S.aureus 50g 100 g 11 E. coli 50g 13 100 g 21

s1

N-{6-fluoro-7-[(2-chlorophenyl)-amino] 1, 3-benzothiazole-2-yl}-2-nitrobenzamides

s2

N-{6-fluoro-7-[(3-chlorophenyl)amino]1,3benzothiazole-2-yl}-2-nitrobenzamides

11

14

20

s3

N-{6-fluoro-7-[(4-chlorophenyl)amino]1,3benzothiazole-2-yl}-2-nitrobenzamides

12

12

19

s4

N-{6-fluoro-7-[(2-methylphenyl)amino]1,3benzothiazole-2-yl}-2-nitrobenzamides

13

12

21

s5

N-{6-fluoro-7-[(3-methylphenyl)amino]1,3benzothiazole-2-yl}-2-nitrobenzamides

19

14

23

s6

N-{6-fluoro-7-[(4-methylphenyl)amino]1,3benzothiazole-2-yl}-2-nitrobenzamides

13

17

22

s7

N-{6-fluoro-7-[(2-nitrophenyl)-amino]1,3-

14

21

15

19

benzothiazole-2-yl}-2-nitrobenzamides s8 N-{6-fluoro-7-[(2-nitrophenyl)-amino]1,3benzothiazole-2-yl}-2-nitrobenzamides s9 synthesis of N-{6-fluoro-7-[(4-nitrophenyl)- 5 amino]1,3benzothiazole-2-yl}-2-nitrobenzamides s10 synthesis of N-{6-fluoro-7-[(2hydroxyphenyl)-amino]1,3benzothiazole-2-yl}-2-nitrobenzamides s11 N-{6-fluoro-7-[(3-hydroxyphenyl)amino]1,3benzothiazole-2-yl}-2-nitrobenzamides s12 N-{6-fluoro-7-[(4-hydroxyphenyl)amino]1,3benzothiazole-2-yl}-2-nitrobenzamides s13 N-{6-fluoro-7-[(2-methoxyphenyl)amino]1,3benzothiazole-2-yl}-2-nitrobenzamides s14 N-{6-fluoro-7-[(3-methoxyphenyl)amino]1,3benzothiazole-2-yl}-2-nitrobenzamides s15 N-{6-fluoro-7-[(4-methoxyphenyl)-amino] 7 13 11 24 5 12 14 19 13 20 16 18 8 13 17 22 9 15 15 23 7 13 13 21 12 14 20 6 14 13 23

1, 3benzothiazole-2-yl}-2-nitrobenzamides s16 N-{6-fluoro-7-[(2-chlorophenyl)amino]1,3benzothiazole-2-yl}-3-nitrobenzamides s17 N-{6-fluoro-7-[(3-chlorophenyl)amino]1,3benzothiazole-2-yl}-3-nitrobenzamides s18 N-{6-fluoro-7-[(4-chlorophenyl)amino]1,3benzothiazole-2-yl}-3-nitrobenzamides s19 N-{6-fluoro-7-[(2-methylphenyl)amino]1,3benzothiazole-2-yl}-3-nitrobenzamides s20 N-{6-fluoro-7-[(3-methylphenyl)amino]1,3benzothiazole-2- yl}-3-nitrobenzamides s21 N-{6-fluoro-7-[(4-methylphenyl)amino]1,3benzothiazole-2-yl}-3-nitrobenzamides s22 N-{6-fluoro-7-[(2-nitrophenyl)-amino]1,3benzothiazole-2-yl}-3-nitrobenzamides 7 14 16 21 8 18 11 21 9 20 14 18 7 13 15 21 8 12 14 21 11 15 16 20 7 15 18 23

s23

N-{6-fluoro-7-[(2-nitrophenyl)-amino]1,3benzothiazole-2-yl}-3-nitrobenzamides

12

23

16

11

s24

synthesis of N-{6-fluoro-7-[(4-nitrophenyl)- 12 amino]1,3benzothiazole-2-yl}-3-nitrobenzamides

13

09

16

s25

N-{6-fluoro-7-[(2-hydroxyphenyl)amino]1,3benzothiazole-2-yl}-3-nitrobenzamides

11

24

14

17

s26

N-{6-fluoro-7-[(3-hydroxyphenyl)amino]1,3benzothiazole-2-yl}-3-nitrobenzamides

10

17

13

17

s27

N-{6-fluoro-7-[(4-hydroxyphenyl)amino]1,3benzothiazole-2-yl}-3-nitrobenzamides

17

14

16

s28

N-{6-fluoro-7-[(2-methoxyphenyl)amino]1,3benzothiazole-2-yl}-3-nitrobenzamides

16

15

20

s29

N-{6-fluoro-7-[(3-methoxyphenyl)amino]1,3benzothiazole-2-yl}-3-nitrobenzamides

11

24

14

21

s30

N-{6-fluoro-7-[(4-methoxyphenyl)-amino] 1, 3benzothiazole-2-yl}-3-nitrobenzamides

13

18

12

s31

N-{6-fluoro-7-[(2-chlorophenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

10

18

23

s31

N-{6-fluoro-7-[(3-chlorophenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

15

17

13

s33

N-{6-fluoro-7-[(4-chlorophenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

11

16

10

12

s34

N-{6-fluoro-7-[(2-methylphenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

17

22

s35

N-{6-fluoro-7-[(3-methylphenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

12

22

15

22

s36

N-{6-fluoro-7-[(4-methylphenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

12

14

16

18

s37

N-{6-fluoro-7-[(2-nitrophenyl)-amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

17

12

16

s38

N-{6-fluoro-7-[(2-nitrophenyl)-amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

10

14

12

16

s39

N-{6-fluoro-7-[(4-nitrophenyl)-amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

10

12

12

20

s40

N-{6-fluoro-7-[(2-hydroxyphenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

12

19

13

22

s41

N-{6-fluoro-7-[(3-hydroxyphenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

11

26

15

21

s42

N-{6-fluoro-7-[(4-hydroxyphenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

10

11

14

21

s43

N-{6-fluoro-7-[(2-methoxyphenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

12

24

16

20

s44

N-{6-fluoro-7-[(3-methoxyphenyl)amino]1,3benzothiazole-2-yl}-4-nitrobenzamides

11

20

16

21

s45

N-{6-fluoro-7-[(4-methoxyphenyl)-amino] 1, 3benzothiazole-2-yl}-4-nitrobenzamides Procaine penicillin Streptomycin

11

26

17

20

20 -

27 -

21

25

Fig. No. 01 Antibacterial activity of synthesized compounds against Staphylococcus aureus

Fig. No. 02 Antibacterial activity of synthesized compounds against Escherichia coli The antibacterial activities are performed by cup plate method (diffusion technique). And found Fluoro benzothiazoles with nitrophenyl having chlorine, methyl, nitro, and hydroxyl and methoxy group exhibited no significant inhibitory properties against S.aureus (gram +ve) but among all the synthesized compounds m-nitro with o-nitro (compound S-23), o-hydroxyl (compound S-25) and m-methoxy (compound S-29) group exhibited moderate while p-nitro with m-hydroxyl (compound S-41) and p-meyhoxy (compound S-45) sustituents exhibited significantinhibitory property against S.aureus (gram +ve). on the other hand, activity towards E. coli (gam ve) It was found that most of the synthesized compound exhibited promising inhibitory property viz o-nitro with o,m and p-nitro (compound S-7, S-8, S-9), p-hydroxyl (compound S-12) and m-nitro with o-methyl (compound S-19) and p-nitro with p-methyl (compound S-34), o-meyhoxy (compound S-43), p-meyhoxy (compound S-45).

Result and discussion

The reviewed new class of 2-substituted fluorinated benzothiazoles has shown a wide spectrum of biological activities. The substituted fluorinated benzothiazolyl heterocycles, benzothiazolylimino dithiazolidines and the 2-(2'-aryl-1, 3, 4-oxadiazol-5-yl)mercaptomethyl benzothiazoles are may having significant antibacterial activity. The biological profiles of these new generation of benzothiazoles represents much progress with regard to the older compoundsand may result to minimize the resistance of older compound.

Bibliography

1. Delgado JN and Remers WA. Wilson and Giswolds. Textbook of Organic Chemistry Medicinal and Pharmaceutical Chemistry. 10th ed. Philadelphia: Lippincott Raven; 1998 2. Miller D, Remington. The Science and Practice of Pharmacy. 19th ed. Pennsylvania: MACK Publishing Company; 1995. p. 425 3. International Journal of current pharmaceutical research ISSN- 0975-1491 Vol 2, Issue 4, 2010
4. Journal of Pharmaceutical Sciences and Research Author: Vedavathi, M Date

published: January 1, 2010

5. . International Journal of Current Pharmaceutical Research Vol 2, Issue 2, 2010

6. Livermore DM. Bacterial resistance: origins, epidemiology, and impact. Clin Infect Dis2003;36(Suppl 1):S11-23 7. International Journal of Current Pharmaceutical Research Vol 2, Issue 2, 2010
8. Bhusari, S.R., Pawar, R.P., and Vibute Y.B., Indian J. Heterocycl. Chem., 2001, 11, 79

9. Acta Pharmaceutica Sciencia 52:213-218 (2010) 10. Brien, S.E.O., Browne, H.L., Bradshaw, T.D., Westwell, A.D., Stevens, M.F.G. and Laughton, C.A., Org. Biomol. Chem., 2003, 1, 493 11. . Sreenivasa, M.V., Nagappa, A.N. and Nargund, L.V.G., Indian J. Heterocycl. Chem., 1998, 8, 23 12. Monks, A., Harris, E., Hose, C., Connelly, J. and Sausville, E. A., Mol. Pharmacol., 2003, 63, 766. 13. Hutchinson, I., Chua, M.S., Browne, H.L., Trapani, V., Bradshaw, T.D., Westwell, A.D. and Stevens, M.F.G., J. Med. Chem., 2001, 44, 1446 14. Nargund, L.V.G., Indian Drugs, 1999, 36, 137.

15. Rana A, Siddiqui N, Khan SA. Benzothiazoles: A new profile of biological activities. Indian J Pharm Sci 2007;69:10-7 16. Singh, S.P., Misra, R.S., Parmar, S.S. and Brumleve, S.J., J. Pharm. Sci., 1978, 64, 1245 17. Wells, G., Lowe, P. R., Malcolm, F. and Stevens, F.G., ARKIVOC, 2000, 1, 5,779 18. . Paramashivappa, R., Kumar, P.P., Rao, S.P.V. and Rao, S., Bioorg. Med. Chem. Lett., 2003, 13, 657. 19. Dogruer, D. S., Unlu, S., Sahin, M. F. and Yesilada, E., Il Farmaco, 1998, 53, 80.
20. H.Y. AboulEnein, A. Kladna, I. Kruk, K. Lichszteld, T. Michalska and S. Olgen,

Biopolymers 78 (2005), pp. 171178

21. .ISSN: 0973-4945; CODEN ECJHAO E-Journal of Chemistry http://www.e-

journals.net 2009, 6(3), 775-779

22. Research Article ISSN: 0974-6943Journal of Pharmacy Research 2010, 3(11),2615-

2619 23. Lacova M, Chovancova et al., J. Chem. Pap., 1991; 45:411 24. Bryson M., Fulton, B. and Benfield, P., Riluzole: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis, Drugs , 1996; 52: 549-563
25. 25 ISSN :0975-1459 M. Vedavathi et al, /J. Pharm. Sci. & Res. Vol.2(1), 2010, 53-63

26. January March 2010 RJPBCS Volume 1 Issue 1 Page No. 124Research Journal of Pharmaceutical, Biological and Chemical Sciences 27. E. Vicente et al. / European Journal of Medicinal Chemistry 43 (2008) 1903e1910 28. United states patent application publication storey et al. Pub.no. US 2010/0234611A1
29. Heterocyclic chemistry,volume2 By Royal Society of Chemistry (Great Britain) Page

119

30. international Journal of Pharma and Bio Sciences ISSN 0975-6299 Vol.1/Issue-3/Jul-

Sep.2010 www.ijpbs.net Medicinal Chemistry 31. Research Journal of Pharmaceutical, Biological and Chemical sciences january-march 2010 RJPBCS vol-I, issue 1 Pg124-129
32. Phosphorus, Sulfur, and Silicon, 183:17221734, 2008 ISSN: 1042-6507 print / 1563-

5325 online DOI: 10.1080/10426500701729653 33. Digest journal of nanomaterials and biostructures vol.5, No.1, march 2010, p 67-76