Bhushankumar S.Sathe et al.

/ Journal of Pharmacy Research 2011,4(4),1031-1032

Research Article Available online through
ISSN: 0974-6943 www.jpronline.info
SYNTHESIS OF NOVEL FLUOROBENZOTHIAZOLE LINKED THIADIAZOLE COMPOUNDS: AS
POSSIBLE ANTI-TUBERCULAR AGENTS.
Bhushankumar S.Sathe*,E.Jayachandran 1, Dipali Chaugule 1,and Vijay A.Jagtap2
*Research Scholar, Jawaharlal Nehru Technological University, Hyderabad.
1
Deparment of Pharmaceutical Chemistry, S.C.S College of Pharmacy, Harapanahalli. K.S.
2
Department of Pharmaceutical Chemistry, Smt.S.S.Patil College of Pharmacy
Received on: 04-01-2011; Revised on: 17-02-2011; Accepted on:16-03-2011
ABSTRACT
4-Fluoro-3-chloroanilline treated with potassium thiocyanate in presence of glacial acetic acid and bromine was converted into 2-amino-6-fluoro-7-chlorobenzothiazole, resulting into 2-amino
benzothiazole. The synthesized compound was treated with carbondisulphide ,ammonia with ethaol( 95%) followed by hydrazinehydrate to yield 6-fluoro-7-chloro (1,3) benzothiazole 2-
thiosemicarbazide which was further treated with phenyl alanine in presence of pyridine after cyclization it yields N-[5-(1-amino-2-phenylethyl)-1,3,4-thiadiazol-2-yl]-7-chloro-6-fluoro-1,3-
benzothiazol-2-amine which was treated with various aromatic amines ortho, meta and para nitroanillines, ortho, meta, para chloroanillines, morpholino, piperazine, diphenylamine in presence
of DMF to obtain various novel derivatives of N-[5-(1-amino-2-phenylethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-7-substituted 1,3-benzothiazol-2-amine. The compounds were characterized by
means of physical constants, solubility tests, TLC and by UV,IR,1HNMR, MASS spectral studies. This is followed by biological and pharmacological evaluation especially anti-tubercular
activity.

Key words:Fluorobenzothiazole,Thiadiazole,Anti-tubercular Activity.

INTRODUCTION
Heterocyclic moieties can be found in a large number of compounds which display diverse preparation of N-[5-(1-amino-2-phenylethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-7-substituted
biological activities.The biological activity of the compounds is mainly dependent on their 1,3-benzothiazol-2-amine14:
molecular structures. The thiadiazole drugs were the first effective chemotherapeutic agents to To 0.0025 mol of N-[5-(1-amino-2-phenylethyl)-1,3,4-thiadiazol-2-yl]-7-chloro-6-fluoro-1,3-
be employed systematically for the prevention and cure of bacterial infection in human beings benzothiazol-2-amine was treated with equimolar quantity (0.0025 mol) of various substituted
(eg: Sulphamethizole).They are also choice for the drug as diuretic (eg: Acetazolamide). aromatic amines and refluxed for 2 hrs in the presence of DMF (dimethyl formamide) then the
Benzothiazole with thiadiazole group etc. were reported to possess various pharmacological mixture was cooled and poured in the crushed ice. The solid separated was filtered off, dried and
activity of clinical importance.Thiadiazole derivatives are well known to have number of recrystallized from benzene and absolute alcohol (1:1). 1HNMR of compound P1=-11H-Ar-
biological and antimicrobial 1,2 , anti-inflammatory3,4anthelmintic5,anti-cancer6, activities. H;7.2-7.5δ (Multiplet), 1H-NH;5.41δ (Singlet),-1H-CH2, 0.85δ (Singlet), 1H-CH1.26δ (Sin-
Benzothiazole incorporated fluorine gives a promising molecule for biological glet) 1H-NH21.72δ(Singlet). The compound P7 =11H-Ar-H7.2-7.5δ(Multiplet), -1H-NH=5.40δ
use.Fluorobenzothiazole are versatile and possess large range of biological activity,hence in (Singlet), -1H-CH2=0.85δ (Singlet), -1H-CH=0.88δ(Singlet), -1H-NH2=1.7δ(Singlet).The mass
present work we made, an attempt to link Fluorobenzothiazole with thiadiazoles in hope of spectrum of the compound code P1, Calculated Molecular weight : 507.56, Mass spectrum of
getting novel biodynamic compounds of pharmacoligal interest.The novel compounds were compound P1 exhibited [M + 2] peak = 508.5 which the molecular weight of the N2-[5-(1-
screened for anti-tubercular activity7,8. amino-2-phenylethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N7-(2-nitrophenyl)benzo[d] thiazole-2,7-
diamine.,and Compound code P7 Calculated Molecular weight : 497.01 Mass spectrum of
Experimental: compound P7 exhibited [M + 2] peak = 498.5 which the molecular weight of N2-[5-(1-amino-
Synthesis of 2-amino-6-fluoro-7-chloro (1,3) benzothiazole9, 10 2-phenyl ethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N7-(2-chlorophenyl)benzo[d]thiazole-2,7-diamine
To glacial acetic acid (20ml) cooled below room temperature were added 8gm (0.08mol) of
potassium thiocyanate and 1.45g (0.01 mol) of fluoro chloro aniline. The mixture was cooled
in a water bath and stirred in magnetic stirrer, while stirring 1.6ml of bromine in 6ml of glacial NH2
acetic acid was added from a dropping funnel at such a rate that the temperature never rise KSCN/AcOH N
beyond room temperature. After all the bromine was added (105min), the solution was stirred B r 2 / NH 3
F
in a magnetic stirrer for 2 hours below room temperature and at room temperature for 10 hours. F S NH 2
Cl
It was then allowed to stand overnight, during which period an orange precipitate settle at the Cl 2nd step
NH 2.NH 2 .H 2 O
bottom. Water (6ml) was added quickly and slurry was heated at 850C and filtered hot. The
orange residue was placed in a reaction flask and treated with 10ml of glacial acetic acid heated C 2 H 5 OH NH 3 , CS 2
again to 850c and filtered hot. The combined filtrate was cooled and neutralized with Sod. chloro acetate
concentrated ammonia solution to pH 6. A dark yellow precipitate was collected. Recrystallised
from benzene, ethanol of (1:1) after treatment with animal charcoal gave yellow crystals of 2-
amino-6-fluoro-7-chloro-(1,3)-benzothiazole. After drying in an oven at 800C, the dry material N
S
(1gm 51.02%) melted at 210-2120C. UV 307.4, 269nm, IR 1542cm -1(aromatic C=C) and
F S NH C NH.NH
3475cm -1 (NH2); 1456 cm -1(thiazole), 1215 cm -1(aromatic-F), 712 cm -1(aromatic-Cl). 2

Cl
11,12 3rd step
Preparation of 6-fluoro-7-chloro (1,3) benzothiazole 2-thiosemicarbazide Phenyl alanine
2-amino benzothiazole (0.1 mol) 20.25 gm was dissolved in ethanol (95%) 50 ml and Pyridine
4hrs. Oil bath
ammonia solution was added to it. The reaction mixture was cooled below 300C and carbon
disulphide (8 ml) was added slowly within 15 minutes with continuous shaking. After
complete addition of carbon disulphide the solution was cooled to stand for 1 hour. After that N
NH2
sodium chloroacetate (0.1 mol) 9.4 gm was added to it. The reaction was exothermic. To it S
F S NH CH CH 2
50% hydrazaine hydrate (20 ml) was added. The mixture was warmed gently, filtered and
boiled to half of its volume and kept overnight. Next day the product thiosemicarbazide was Cl
N N
filtered and recrystallised from ethanol. NH 2
4th step
Preparation of N-[5-(1-amino-2-phenylethyl)-1,3,4-thiadiazol-2-yl]-7-chloro-6-fluoro-1,3- R DMF
benzothiazol-2-amine13:
An intimate mixture of 13.9 gm (0.05 mol) of (1,3) benzothiazoles 6-fluoro-7-chloro-2-
thiosemicarbazide and phenyl alanine (0.05 mol) 8.26 gm and pyridine (100 ml) heated at N
NH2
1700-2100C for 4 hours in an oil bath under moisture free condition. The fused material after S
F S NH CH CH
cooling was treated with cold sodium bicarbonate solution (10%). The resulting solution was 2

filtered, washed and recrystallised from methanol. HN

N N

*Corresponding author. R
*Bhushankumar S.Sathe R = o, m, p – nitro (P 1 – P 3 )
Research Scholar, R = o, m, p – methoxy (P 4 – P 6 )
Jawaharlal Nehru Technological University, R = o – chloro (P 7 )
Scheme-I
Hyderabad, Andhra Pradesh, Inida.
Tel.: + 91-9420112155
E-mail:drbss1978@rediffmail.com

Journal of Pharmacy Research Vol.4.Issue 4. April 2011 1031-1032

 Bhushankumar S.Sathe et al. / Journal of Pharmacy Research 2011,4(4),1031-1032
Table 1. Thin Layer Chromatography Table.3. Characteristics IR absorption bands 15,16
Sl. No Compound Solvent system Proportion Rf Sl. No. Compd Ar-NH2 ArC=C Cyclic C-F C-Cl ArNO2 C-S-C
Code for developing of Components Value code cm-1 cm-1 C=N cm-1 cm-1 cm-1 cm-1 cm-1
1 P1 n-Butanol: Ethyl acetate: Benzene 1:4:1 0.79 1 P1 3450 1475 1650 1200 - 1540 1070
2 P2 n-Butanol: Ethyl acetate: Benzene 1:4:1 0.85 2 P2 3450 1475 1650 1200 - 1540 1070
3 P3 n-Butanol: Ethyl acetate: Benzene 1:4:1 0.86 3 P3 3450 1475 1650 1200 - 1540 1070
4 P4 n-Butanol: Ethyl acetate: Benzene 1:4:1 0.78 4 P4 3450 1475 1650 1200 - - 1070
5 P5 n-Butanol: Ethyl acetate: Benzene 1:4:1 0.77 5 P5 3450 1475 1650 1200 - - 1070
6 P6 n-Butanol: Ethyl acetate: Benzene 1:4:1 0.90 6 P6 3450 1475 1650 1200 - - 1070
7 P7 n-Butanol: Ethyl acetate: Benzene 1:4:1 0.84 7 P7 3450 1475 1650 1200 690 - 1070

Table .2.. Analytical Data

Table. 4..Anti-tubercular activity
Sl. No Compd M.P/ B.P °C % Yield Mol. Formula M.Wt. C% H% N%
Compd. No. Activity H37RV strain of
Code
Data Codes M. tuberculosis 21 days
1 P1 235-236 80% CH
23 18
FN7 O2 S2 507.56 54.43 3.57 19.32
01 P1 13
2 P2 231-233 82% C23 H18 FN7 O2 S2 507.56 54.43 3.57 19.32
3 P3 223-225 65% C23 H18 FN7 O2 S2 507.56 54.43 3.57 19.32 02 P2 16
03 P3 17
4 P4 239-241 72% C24 H21 FN6 OS2 492.59 58.52 4.30 17.06
04 P4 15
5 P5 225-227 74% C24 H21 FN6 OS2 492.59 58.52 4.30 17.06
6 P6 222-224 73% C24 H21 FN6 OS2 492.59 58.52 4.30 17.06 05 P5 18
06 P6 17
7 P7 224-226 76% C23 H18 ClFN6 S2 497.01 55.58 3.65 16.91
07 P7 23

Standard 1 – Rifampicin 0.25, Standard 2 – Isoniazide 0.007

Anti-Tubercular Screening
Procedure
Sterile Kirchner’s medium was dispensed in each borosilicate test tube (150 x20mm) and to
this sterile horse serum (0.5 mL) was added. The stock solution was sterile by passing through
a 0.2 mm polycarbonate sterile membrane (Nuclepore) filters. Further the serial dilution of test
compounds were carried out. Test compounds at various concentrations (250, 125, 62, 32, 16,
8, 4 and 1 µg/mL) were added to culture medium in a sterilized borosilicate test tube and strain
of M.tuberculosis was inoculated at concentration (106 bacilli/mL). The tubes were incubated
at 370 for 21 days and then examined for the presence or absence of growth of the test organisms.
All experiments were performed in triplicate. The lowest concentration, which showed no
visible growth, was taken as the end point i.e. minimum inhibitory concentration (MIC).
Rifampin and Isoniazid (INH) were used as standard for anti-tubercular activity.
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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.4.Issue 4. April 2011 1031-1032