INTRODUCTION:

Pharmaceutical chemistry is a science that makes use of the general laws of chemistry to study drugs i.e., their preparation, chemical nature, composition, structure, influences on an organism and studies of the physical and chemical properties of drugs, the methods of quality control, and the conditions of their storage.

Pharmaceutical chemistry occupies the most important place among the related science (e.g. drug technology, toxicological chemistry, pharmacognosy, the economy and organization of the pharmacy).

At the same time, pharmaceutical chemistry, being a specialized science, depends on other chemical (inorganic, organic, analytical, physical and colloid chemistry) and also on medico biological (Pharmacology, physiology, biological chemistry) disciplines.

Knowledge of the biological disciplines is needed to understand the complex physiological processes based on chemical and its physical reactions that occur in an organism.

This makes it possible to use drugs more rationally, observe their actions on an organism, and control the molecular structure of the drugs being developed to obtain the desired pharmacological effect. The results of pharmacological tests of drugs determine the possibility of using them is medical practice.

“Chemistry must serve the protection of health instead of procuring gold”. Paracelsus proclaimed who introduced the concept of the active principle as a chemical substance.

16^th century begin pharmaceutical chemistry gave way to Medical Chemistry in the second half of the 17^th century, gave new trend in pharmaceutical chemistry. Pharmacists played a major role in the birth and development of Pharmaceutical Chemistry. Medicinal chemistry, according to Burger, “tries to be based on the ever increasing hope that biochemical rationales for drug discovery may be found.

The first use of synthetic organic molecules for interference with the life process was probably when chloroform and ether were introduced for anesthesia in the first half of 19^th century. Phenacitin probably was the first drug to be designed as a result of knowledge of biochemical transformations.

Paul Ehrlich proposed that receptors exits in mammalian cells and that both antigen and chemotherapeutic agents (a term he coined) possess hepatophoric (anchorer) and toxophoric (Poisoner) groups. Chemotherapeutic agent he considered, combine with receptor areas of the cell by ordinary chemical reactions, although modified to include more types of bond formation. Ehrlich concluded that drug resistance developed, when the drug was no longer absorbed by the parasite. His ideas where thus supported by experimental facts.

Chemical modifications of drug molecules to locate the number of series having optimal effects and will probably continued to be a factor necessary to drug discovery. To establish the structure of the drug molecule the new inventions in physiochemical directions such as X-ray analysis, UV, IR, NMR, and Mass are immensely helpful for medicinal chemist. In the biochemical view knowledge of drug receptor interactions, Pharmacokinetics, advancements in enzymology, have immensely helped medicinal chemist in hypothesizing the correct mechanism of actions of drug molecules.

The approach to practice medicinal chemistry has developed from an empirical one involving organic synthesis of new compounds, based largely on modification of structures of known activity. According to Manfred Wolf present development of medicinal chemistry has renaissance, stating that: “underlying the new age is a foundation that includes explosive development of molecular biology since 1960, the advances in physical chemistry and physical organic chemistry made possible by high speed computers, and new powerful analytical methods….”.

In view of the above considerations we have selected Tailor made approach of drug design in search of new potent bioactive drug molecules.

THIAZOLE:

A heterocyclic compounds is one that contains a ring made up of more than one kind of atom. In many of the cyclic compounds the rings are made up only of carbon atoms; such compounds are called homocyclic compounds. But there are also rings containing, in addition to carbon, other kinds of atoms, most commonly Nitrogen, Oxygen or Sulphur. Such compounds are called as heterocyclic compounds. For eg; thiazole.

Thiazole is a weakly basic liquid (B.P is 117 ⁰C) and is occurs in vitamin B₁.It is very stable compound and is not affected by the usual reducing agents; sodium and ethanol, however open the ring to form thiols (or hydrogen sulphide) and amines. Thiazoles is very resistant to substituted reactions, but if a hydroxyl group (or) an amino group is in position 2 then the molecule is readily attacked by the usual electrophillic reagents to form 5-substitution products, eg., 2-hydroxy-4-methyl thiazole is readily brominated in chloroform solution to give 5-bromo-2-hydroxy-4-methyl-thiazole.

BENZOTHIAZOLE:

Benzothiazoles may be prepared by the action of acid anhydrides (or) chlorides on o-amino thiophenols and formic acid in the presence of acetic anhydride.

Benzothiazoles are also formed by the action of phosphorus pentasulphide on o-Acylamidophenols, eg.

2- Mercapto benzothiazole is a vulcanization accelerator; it may be prepared as follows:

Various derivatives of benzothiazoles have been synthesized by several investigators and have been reported to exhibit a wide range of biological activities like antibacterial, anti-inflammatory, antitubercular, anthelmintic and antiulcer…etc.

Benzothiazole derivatives play a vital role in the field of medicinal chemistry. Some of the thiazolotriazoles ^1-4(1) are reported to possess the biological activities like antimicrobial⁵ and antitubercular.

Mannich bases of Isatins (2) have been reported to show a variety of biological activities like antileishmanial, anthelmintic, antimicrobial and CNS depressant activities.

The antitumour 2-(4-aminophenyl) benzothiazole (3) series possess remarkable biological properties. Their activity was first discovered in the early 1990s.

MATERIAL AND METHOD:

Preparation of 2-amino-6-substituted-1, 3-benzothiazoles (1a₁- a₅):

To glacial acetic acid (20 ml) pre cooled to 5 ⁰C were added 8.0 g (0.08 mole) of potassium thiocyanate and 1.27 g (0.01 mole) of 4-substituted aniline. The reaction mixture was placed in freezing mixture of ice and salt and mechanically stirred, while 1.6 ml of bromine in 6.0 ml of glacial acetic acid was added from a dropping funnel at such a rate that the temperature does not rise beyond 0 ⁰C. After all the bromine has been added the solution was stirred for an additional two hours at 0 ⁰C and at room temperature for 10 hours. It was then allowed to stand overnight during which period an organic precipitate is settled at the bottom. Water (6.0 ml) was added quickly and slurry was heated to 85 ⁰C on a steam bath and filtered hot. The orange residue was placed in a reaction flask and treated with 10.0 ml glacial acetic acid, heated again to 85⁰C and it was filtered hot. The combined filtrate was cooled and neutralized carefully with ammonia solution to pH 6.0, and then a dark yellow precipitate was separated and was collected. The product was recrystallized twice with benzene by treating with charcoal gave colorless product. The physical characteristics of these compounds are presented in Table-1.

Table – 1: Physical data of compounds (1a₁- a₅)

Sr. No	Product Code	R	Molecular Formula	Melting Point ^OC	Yield %
1	1a₁	H	C₇H₆N₂S	126-129	45
2	1a₂	CH₃	C₈H₉N₂S	132-134	66
3	1a₃	OCH₃	C₈H₉N₂SO	158-159	44
4	1a₄	F	C₇H₆N₂SF	180-183	50
5	1a₅	Cl	C₇H₆N₂SCl	192-195	48

Preparation of 2-chloroacetyl amino-6-substituted benzothiazole (2a₁- a₅):

To a solution of 2-amino-6-substituted benzothiazole (20gm) dissolved in 150 ml dry benzene was added a solution of 10 ml chloroacetyl chloride in 50 ml of dry benzene. The reaction mixture was then warmed at 70 ⁰C on a water bath for 90 min. The benzene was distilled off and the residue was filtered, washed with sodium bicarbonate solution followed by water and then it was dried .The product was recrystallized from alcohol. The physical characteristic data of these compounds was presented in Table-2.

Preparation of 2-hydrazino benzothiazole (4):

A mixture of 2-mercapto benzothiazole 40g (0.4 mole) and hydrazine hydrate 40g (0.4 mole, 80%) was refluxed for 2 hours. On cooling 2-hydrazino benzothiazole precipitated out .It was recrystallized from ethanol.

Melting point: 194 ⁰C, Percentage yield 60%.

Preparation of 2-(1,3-benzothiazol-2-ylthio)-N-(6-substituted-1,3-benzothiazol-2-yl) acetamide (5a₁- a₅):

A mixture of 2-chloroacetyl amino-6-substituted benzothiazole 10g (0.1 mole) and pyridine was dissolved properly then added to the RB flask containing a solution of 2-mercapto benzothiazole 10g(0.1 mole) in pyridine solution and the reaction mixture was refluxed for 5 hours. After completion of the reaction it was cooled to room temperature and the separated solid was filtered and dried. The product was recrystallized from alcohol. The physical characteristic data of these compounds was presented in Table-3.

Preparation of 2-[2-(1,3-benzothiazol-2-yl)hydrazino]-N-(6-substituted-1,3-benzothiazol 2-yl) acetamide (6a₁- a₅):

A mixture of 2-chloroacetyl amino-6-substituted benzothiazole 10g (0.1 mole) and pyridine was dissolved properly then added to the RB flask containing a solution of 2-hydrazino benzothiazole 10g (0.1 mole) in pyridine and refluxed for 5 hours. After completion of the reaction, it was cooled to room temperature, filtered and dried. The product was recrystallized from alcohol. The physical characteristic data of these compounds was presented in Table-3.

Table – 2: Physical data of compounds (2a₁- a₅)

Sr. No	Product Code	R	Molecular Formula	Melting Point ^OC	Molecular Weight	Yield %
1	2a₁	H	C₉H₇N₂SOCl	163-165	226	56
2	2a₂	CH₃	C₁₀H₁₀N₂SOCl	190-195	241	47
3	2a₃	OCH₃	C₁₀H₁₀N₂SO₂Cl	180-184	257	53
4	2a₄	F	C₉H₇N₂SOClF	175-180	245	48
5	2a₅	Cl	C₉H₇N₂SOCl₂	210-215	261	45

Table – 3: Physical data of compounds (5a₁- a₅) and (6a₁- a₅)

Sr. No	Product Code	R	R¹	Molecular Formula	Melting Point ^OC	Molecular Weight	Yield %
1	5a₁	H		C₁₆H₁₁N₃S₃O	245-250	357	44
2	5a₂	CH₃		C₁₇H₁₃N₃S₃O	265-270	370	56
3	5a₃	OCH₃		C₁₇H₁₃N₃S₂O₂	250-252	386	43
4	5a₄	F		C₁₆H₁₁N₃S₃OF	270-275	368	46
5	5a₅	Cl		C₁₆H₁₁N₃S₃OCl	272-275	391	43
6	6a₁	H		C₁₆H₁₃N₅S₂O	240-245	384	50
7	6a₂	CH₃		C₁₇H₁₅N₅S₂O	260-265	370	46
8	6a₃	OCH₃		C₁₇H₁₅N₅S₂O₂	255-260	384	50
9	6a₄	F		C₁₆H₁₃N₅S₂OF	265-268	373	42
10	6a₅	Cl		C₁₆H₁₃N₅S₂OCl	270-272	389	46

Table-4. Antibacterial activity of benzothiazole derivatives

Sample Code	*Inhibition zone diameter in mm
	*B.subtilis*		*B.pumillis*		*E.coli*		*P.aeruginosa*
	50mg	100mg	50mg	100mg	50mg	100mg	50mg	100mg
5a₁	13	13	14	19	13	13	14	21
5a₂	15	15	14	13	13	15	15	14
5a₃	13	13	15	13	14	18	19	18
5a₄	12	12	16	16	15	13	20	14
5a₅	15	15	15	20	12	15	15	21
6a₁	12	12	16	19	14	22	12	19
6a₂	13	13	15	16	14	15	15	16
6a₃	12	12	14	20	13	13	17	13
6a₄	13	13	15	13	12	15	20	21
6a₅	13	13	13	19	13	15	15	16
Ampicillin	22	22	21	24	22	24	21	25
DMSO	-	-	-	-	-	-	-	-

*Each value is an average of three independent determination ± Standard deviation Note: ‘-‘denotes no activity, 8-12 mm poor activity, 13-17 mm moderate activity, 18-20 and above good activity.

Table-5. Data showing anti-inflammatory activity of benzothiazole derivatives in Carageenan induced acute rat paw oedema model

Group	Treatment	Dose mg/kg	Paw oedema volume
			After 1^st hr		After 2^nd hr		After 3^rd hr		After 4^th hr
			Mean	% ROV	Mean	% ROV	Mean	% ROV	Mean	% ROV
1	Control	0.5 ml	0.393	-	0.516	-	0.583	-	0.55	-
2	Standard	50	0.168	57.25	0.166	67.75	0.166	71.43	0.050	90.90
3	5a₁	200	0.212	46.05	0.26	49.67	0.187	67.94	0.087	84.18
4	5a₂	200	0.325	17.30	0.362	29.92	0.275	52.85	0.162	70.54
5	5a₃	200	0.337	14.24	0.387	25.08	0.237	59.36	0.10	81.81
6	5a₄	200	0.225	42.74	0.287	44.44	0.175	69.99	0.075	86.36
7	5a₅	200	0.375	04.58	0.412	20.24	0.337	42.22	0.25	54.54
8	6a₁	200	0.301	23.40	0.340	34.18	0.255	56.28	0.170	69.09
9	6a₂	200	0.355	09.66	0.392	34.11	0.317	45.65	0.24	56.36
10	6a₃	200	0.202	48.60	0.25	50.32	0.177	66.65	0.088	84.00
11	6a₄	200	0.221	48.60	0.278	46.18	0171	70.68	0.092	83.27
12	6a₅	200	0.325	17.30	0.362	29.92	0.275	52.85	0.162	70.54

Animals: Albino rat, Route: P.O, Standard: Diclofenac, ROV- Reduction in paw oedema volume.

representative types of gram positive and gram-negative organisms respectively. The antibacterial activity of the compounds was assessed by disc-diffusion method.

All the synthesized compounds were screened for antibacterial activity studies at a concentration of 50 µg /ml & 100 µg /ml using DMSO as a control against B.substilis, B.pumillus, Escherchia coli and P.aeruginosa by disc-diffusion method on nutrient agar media, Ampicillin 50 µg /ml & 100 µg /ml used as standard against Gram positive and Gram negative bacteria.

The data in the Table 4 indicate that 5a_1,5a₅ and 6a₄ compounds was found to possess a broad spectrum activity. While compounds 5a₂, 5a₃, 5a_4,6a_1,6a_2,6a₃ and 6a₅ were found to exhibit moderate activities. Among the synthesized compounds the compounds 5a₁, 5a₅ and 6a₄ showed good activities.

Anti-inflammatory activity:(557/02/c/CPCSEA[)

Inflammation is a normal protective response to tissue injury caused by physical trauma, noxious chemicals or microbiologic agents. Inflammation is body’s response for tissue repair ^69. Inflammation is triggered by the release of chemical mediators from the injured tissues and migrating cells. The specific chemical mediators vary with the type of inflammatory process and include amines such as histamine, serotonin, and lipids such as prostaglandins and small peptides such as kinins ⁷⁰. The acute inflammatory response has 3 main functions.

1.A transient material called the acute inflammatory exudates occupies the affected area. The exudate carries proteins, fluid and cells from local blood vessels into the damaged area to mediate local defenses.

2. If an infective causative agent (e.g. bacteria) is present in the damaged area, it can be destroyed and eliminated by components of the exudates.

3. The damaged tissue can be broken down and partially liquefied, and the debris removed from the site of damage.

Mechanism of inflammation:

In and around the inflamed tissue, there is an accumulation of oedema fluid in the interstitial compartment which comes from blood plasma by its escape through the endothelial wall of peripheral vascular bed. In initial stage the escape of fluid i.e. due to vasodilatation and consequent elevation in hydrostatic pressure, the characteristic inflammatory oedema, and exudates appear by increased vascular permeability of microcirculation. Inflammatory diseases including different types of rheumatic diseases are a major cause of morbidity of the working force throughout the world. Many drugs produced a dramatic symptomatic improvement in rheumatic processes, but all of them shared the common undesirable effect i.e., gastrointestinal irritation⁷¹.

Procedure: ^{72 ,73}

Carrageenan induced rat paw oedema model:

Albino rats of either sex weighing 150 – 200gms were selected. They were maintained on standard pellet diet and free access to water.

The animals were divided into 6 groups each having six animals. The various groups were treated as follows:

Group 1 - Normal Control (treated with 0.2 ml of 5% gum acacia p.o.)

Group 2 - Diclofenac (20 mg / kg, p.o.)

Group 3 - Compound 5a₁ (200 mg/ kg, p.o.)

Group 4 - Compound 5a₂ (200 mg/ kg, p.o.)

Group 5 - Compound 5a₃ (200 mg/ kg, p.o.)

Group 6 - Compound 5a₄ (200 mg/ kg, p.o.)

Group 7 - Compound 5a₅ (200 mg/ kg, p.o.)

Group 8 - Compound 6a₁(200 mg/ kg, p.o.)

Group 9 - Compound 6a₂ (200 mg/ kg, p.o.)

Group 10 - Compound 6a₃(200 mg/ kg, p.o.)

Group 11 - Compound 6a₄(200 mg/ kg, p.o.)

Group 12 - Compound 6a₅(200 mg/ kg, p.o.)

The normal control, diclofenac and test compounds were administered to the rats 30 minutes before the injection of 0.1ml of 1% carrageenan suspension in normal saline. Carrageenan suspension was injected into the sub-planar region of the left hind paw, and the right hind paw served as reference. Immediately thereafter the oedema volume of the injected paws were measured plethysmographically by mercury displacement method ⁷⁴.

For comparison purpose, the volume of oedema at various prefixed time intervals was measured. The difference between paw volume of the treated animals was measured and the mean oedema volume was calculated.

Percentage reduction in oedema volume was calculated by using the formula,

Vo - Vt

Percentage reduction = x 100

Where, Vo = Volume of the paw of control at time ‘t’.

Vt = Volume of the paw of drug treated at time ‘t’.

From the data obtained, the mean oedema volume with standard error (SEM), standard deviation (S.D.), percentage reduction in oedema was calculated. The anti-inflammatory activity of synthesized compound is given in the Table No-5.

All the ten compounds 5a₁, 5a₂, 5a₃, 5a_4,5a₅, 6a_1,6a_2,6a_3,6a₄and 6a₅ at dose of 200mg/ kg exhibited significant anti-inflammatory activity in acute inflammatory models in rats. Results are tabulated in Table 5. Compounds 5a₁, 5a₂, 5a₃, 5a_4,5a₅, 6a_1,6a_2,6a_3,6a₄and 6a₅exhibited maximum inhibition of 84.18 %, 70.54 %, 81.81 %,86.36 %, 54.54 %,69.09 %, 56.36 %,84.00 %,83.27 %,70.54 % respectively where as standard Diclofenac sodium showed reduction in oedema volume by 90.90 % in carrageenan induced rat hind paw oedema model.

CONCLUSION:

From the antibacterial and anti-inflammatory screening it was found that the compounds showed significant activity and were found to be good with respect to the standard at the given concentration levels. Hence these compounds appear to be promising antibacterial, anti-inflammatory agents. Perhaps the substituent at 2^nd position of benzothiazole ring and which contains substituted 2-mercapto benzothiazole and 2-hydrazino benzothiazole ring may be largely responsible for the marked bactericidal and anti-inflammatory activity. The above results establish the fact that substituted benzothiazoles can be studied further to search for new anti-inflammatory and anti-microbial compounds.

The two moieties, i.e., 2-subtituted benzothiazoles and 2-chloroacetamido -6-substitued benzothiazole moieties independently are showing antibacterial activity. Here when the two moieties are fused and screened for antibacterial studies they showed a broad spectrum of antibacterial activity. They showed good activity against Gram positive and Gram negative bacteria. 2-subtituted benzothiazoles and 2-chloroacetamido -6-substitued benzothiazole are responsible for antibacterial activity, but it is interesting to note that benzothiazole moieties when fused with other moieties showed a broad spectrum antibacterial activity. Hence in search of new generation of antibiotics it may be worthwhile to explore the possibility in this area by fusing different moieties and increase potency.

ACKNOWLEDGEMENT:

The authors are thankful to Dr. S.M. Shantakumar for providing necessary infrastructural facilities and also to management of ASPM’s K.T. Patil college of Pharmacy for constant encouragement and support.

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Received on 14.10.2009 Modified on 29.11.2009

Asian J. Research Chem. 3(2): April- June 2010; Page 421-427

Synthesis and Biological Activities of Some Benzothiazole Derivatives

INTRODUCTION:

Table-5. Data showing anti-inflammatory activity of benzothiazole derivatives in Carageenan induced acute rat paw oedema model