INTRODUCTION:

Stilbenes are biologically active secondary metabolites found in numerous families of plants and derived from the greek word stilbos , which means shining. Stilbenes are chemically derivatives of trans 1, 2-diphenylethylene.

STILBENES

Stilbene is generally used in manufacture of dyes and optical brighteners and also as a phosphor and a scintillator. Stilbene itself does not occur in nature but hydroxylated or methoxylated stilbenes are found in a multitude of medicinal plants.Early types of antimicrobial substances ¹ were not specifically antimicrobial but were usually toxic to all living cells and were of the value only in so far as they could be employed without serious damage to the host.

Antimicrobial drugs are the greatest contributions of 20^th century to therapeutics. Their advent changed the outlook of the diseases. They are one of the few curative drugs. Many stilbene derivatives are present naturally in plants e.g.; resveratrol. Some of these such as trans-resveratrol,² the cis-stilbene combrestatin A-4 and stilbene based vitamin-A analogs have shown unique potentialities for treatment of cancer.^3,4

Trans-resveratrol

Combrestatin A-4

Natural products play a major role as therapeutic agents, but all products themselves, cannot be used as such. It may either be due to insufficient level of activity, bad distribution properties or poor stability.⁵

Trans-combrestatin

cis-combrestatin

Stilbenes produced by several plants in response to pathogen attack are known to act as toxins. Some of the stilbene compounds elicit strong anti-fungal properties and are therefore included under the broad class of plant antibiotics known as phytoalexins.⁶

Examples of stilbenes:

Resveratrol a natural product with a stilbene structure exerts profound proapototic activity in human cancer cell by triggering the accumulation of ceramide, ^7,8 a bioactive sphingolipid.^9,10

Resveratrol a natural product with a stilbene structure has shown an inhibitory effect on human CYP-1A1 and CYP-1B1.^11,12Resveratrol a naturally occuring phytoalexins(trans-3,4,5-trihydroxystilbene) present in grapes peel, peanut and red wine has been reported to produce chemoprevensive activity and exerting antiproliferative and proapoptotic effect in human cancer cell.^13,14,15

Recently rhapontigen a natural hydroxy stilbene showed strong selectivity of CYP-1A1 inhibition.¹⁶

Rhapontigen

Resveratrol shown antimicrobial activity against bacteria and dermatophytes that are major etiologic agent of human skin infection. So resveratrol and its analogs may have wide application to skin condition afflict, a significant portion of our population, and also have promising clinical potentials in diabetic wound.¹⁷

Another stilbene derivative like ptero-stilbene occuring naturally in blueberries and has preventive activity against colon carcinogenesis.

Pterostilbene

In addition, some stilbenoids( stilbenes and bibenzyls) have shown properties more strictly related to cancer chemo-prevention and treatment, such as inhibition of tubulin polymerization and anti estrogenic activity.¹⁸

Chemotherapy is a new term that applies to the use of both natural and synthetic chemicals to interfere with the functioning of foreign cell populations. A current use makes no distribution between chemotherapeutic agent of synthetic origin and the antibiotics. Intially the term “ chemotherapeutic agent” was restricted to synthetic compounds but now snce many antibiotics and their analogs have been synthesized, this criterion has become irrelevant, but synthetically and microbiologically produced drugs need to be included together. However it would be more meaningfull to use the term antimicrobial agent (AMA) to designate synthetic as well as naturally obtained drugs that attenuate microorganisms. Infectious studies is as old as life itself. Bacteria and fungi efffect mellions of people worldwide. The treatment of those bacterial and fungal infection diseases with the help of chemical substances is known as chemotheraphy and these chemicals are knows as chemotherapeutic agent. Antibiotics are chemical compounds produced by living microorganisms ( bacteria, fungi, actinomycetes ), which are at high dilution capable of inhibiting or killing bacteria and other microorganisms.

Synthetic anti-infective drug differ from naturally derived antibiotics only their origin, in that they are synthetic. Basically the molecules of these entire agents react with microbial cell molecules in a way interferes with the normal metabolic processes of the microorganisms.

4-amino-α:β-diethyl stilbene

4-hydroxy-α:β-diethylstilbene

4-sulpanilamido-α:β-diethylstilbene

4-hydroxy-4’-amino-α:β-diethyl stilbene

The mode of action of 3,5-dihydroxy-4-ethyl-trans-stilbene (ES), an antibiotic produced by xenorhabdus luminescence symbiotically associated with an entomopathogenic nematode, was investigated. 3, 5-Dihydroxy-4-ethyl-trans-stilbene was active against gram-positive and a number of gram-negative bacteria. In susceptible bacteria this antibiotic caused the inhibition of total RNA synthesis and, to a lesser extent, protein synthesis.¹⁹

3,5-dihydroxy-4’-ethyl-cis-stilbene

In agreement with their role as antifungal, ²⁰ antioxidant, ²¹ anti-inflammatory, ^{22, 23} anti-cancer, ²⁴ anti-platelet aggregating and anti-HIV agents, ²⁵ our interest in the field of substituted stilbenes is the total synthesis of the stilbene and its several analogous and their evaluation for different biological activities. Using the base structure of stilbene, many synthetic and or semi synthetic compounds will be synthesized with the aim of optimizing the pharmacology of the base molecule as a potential antimicrobial agent with minimum toxicity or adverse effect.

EXPERIMENTAL:

The compounds synthesized were identified and characterized by following methods:

· Melting point determination

· Solubility

· Thin layer chromatography

· Infra red spectroscopy

· Nuclear magnetic resonance spectroscopy.

Melting Point Determination: The melting point of an organic compound was determined by Thiel’s melting point apparatus (capillary tube method). The determination of melting point is the most important and easy way of differentiating this physical constant of one compound from other.

Thin Layer Chromatography (TLC): TLC is an important method for synthetic chemistry to infer the formation of compound based on the R_f value since different compound will have different R_f values. It also helps in confirming the progress of the reaction.

Infra Red Spectroscopy (IR): IR is the most important tools for determining the various functional groups and the possible chemical structure. The important advantage of IR over other technique is that it gives fingerprints (1300-650 cm^-1) information about the structure (functional group, bonding with each other) of molecules easily. No two compounds have identical fingerprint region. This technique is based upon the molecular vibration of the compound such that each and every bond will vibrate at the different frequency and these vibration frequencies correspond to the IR frequency. FTIR spectra were recorded in KBr powder on a Jasco V410 FTIR spectrometer by diffuse reflectance technique.

Nuclear Magnetic Resonance Spectroscopy: NMR spectroscopy enables us to record differences in magnetic properties of the various magnetic nuclei present and to deduce in the large measure about the position of these nuclei within the molecule. We can deduce how many different kinds of environments are there in the molecules and also which atoms are present in neighboring groups. The proton NMR spectra enable us to know different chemical and magnetic environments corresponding to protons in molecules. This technique is useful in assuming the structure of the molecule.¹H- NMR spectra were measured in CDCl₃and d₆-DMSO on a Bruker Ultraspec AMX400MHz spectrometer.

SCHEME-1

1) Synthesis of p-substituted benzyl(chloro)triphenyl phosphorane from p-substituted benzyl chloride²⁶.

A stirred solution of benzyl chloride (2.88 g, 31.7 mmol) in methyl cyanide (20 ml) was treated with triphenyl phophene (8.57 g, 32.7 mmol) and the mixture was vigorously stirred and refluxed for 12 hrs and then evaporated. The crude product was purified by crystallization from chloroform/di-ethyl ether, affording 75% yield as a white solid.

2) General procedure for the preparation 1-(substituted phenyl)-2-(substituted phenyl) ethene²⁷.

Sodium hydride (72 mg, 3 mmol) was added in potion to a well stirred suspension of phosphonium chloride (2 mmol) and aryl aldehyde (2 mmol) in benzene (20 ml) at 0-5⁰C, and the mixture was allowed to come to room temperature, after the additional stirring for 16 hrs, excess sodium hydride was quenched by the addition of methanol (1 ml), then added 30 ml of chloroform and water. Separate the organic and aqueous layer. Aqueous layer contain the phophonium oxide as an impurity and discarded. Distilled off the organic layers and the residue were purified by preparative TLC using 5% ethanol in hexane as the eluent or by recrystallization with ethanol. The crystal formed is Z-isomer and the mother liquor containing E-isomer.

SCHEME-2

1) General procedure for the preparation of compounds E-3-(phenyl)-2-(phenyl)prop-2-enoic acid²⁸.

A mixture of substituted phenyl acetic acid (2 mmol), substituted benzaldehyde (2 mmol) and triethyl amine (0.5 ml) in acetic anhydride (5 ml) was heated under reflux for 12 hrs, poured into hot saturated sodium carbonate solution (50 ml) and left overnight. The mixture was extracted with ether (2 x 50 ml), and the ether extracts were discarded, the aqueous solution was acidified with dilute HCl and the precipitated product was filtered and dried. Recrystallization from ethyl acetate-hexane gave pure compound.

SCHEME-3

1) General procedure for the preparation of the substituted benzylidene-(substituted phenyl)amine.

A solution of aldehyde(1 mmol) and substituted anilines(1 mmol) in toluene(5 ml) was heated to reflux, in a dean stark apparatus for 16 hrs. After the solvent was removed in vacuum the crude product was recrystallized from ethanol to give 50% yield.

ANTIMICROBIAL ACTIVITY

The following two are the methods available for screening of the antimicrobial agent:

1. Turbidimetric/photometric/tube dilution method.

2. Agar diffusion/cup-plate/cylinder plate method.

Turbidimetric method:

In this method a graded concentration of the antimicrobial substance in sterile fluid nutrient media is prepared. All of them are inoculated with a loop of specific microorganism. A positive control, a negative control and a blank is also maintained. They are incubated at 37° C for 24 hours or necessary conditions depending on the organism chosen. Among the different concentrations of the substance, the least one, which inhibits the growth of the microorganism, is noted visually or by measuring the percentage transmittance or absorbance at 530 nm against a blank. By this method minimum inhibitory concentration (MIC) for the newly synthesized compound is determined.

Agar diffusion method:

This method gives the extent of growth of the microorganism, inoculated into a solid nutrient agar bed by the antimicrobial substance. The test substance is kept in a cup made-up of agar bed and diffuses to inhibit the growth of microorganism. The diameter of zone of inhibition measured in comparison with suitable drug substance is considered as potency of that substance. The diameter of zone of inhibition is directly proportional to the concentration of the drug substances added into the cup, thickness of the agar bed, and diffusion coefficient of the antimicrobial substance into the agar cup, sensitivity of the microorganism to the test substance and temperature. The appropriate media is sterilized and cooled to 42 °C, incubated with the test organism, mixed uniformly and poured into Petri dishes and cooled to room temperature. Bores are made into it specified test solution is added and left at room temperature for 30 minutes, then incubated at 37 °C for 24 hours. The zone of inhibition is measured in mm after 24 hrs.

Material and method:

Method followed: - Agar diffusion method.

Requirements: - Petri dishes, glass syringes, cork borers, inoculation loop, cotton.

Working procedure: Stock solution of the synthesized compounds and standard drug used were prepared in dimethyl sulfoxide taken in the concentration of 100mg/ml.

Micro organism used: Standard cultures of Bacillus subtilus, Staphylococci and Protease vulgaris species were obtained from Microbiology Department, K.L.E.S. College of Pharmacy, Bangalore. The microorganisms were maintained by sub-culturing, and used at regular intervals in nutrient agar medium.

Preparation of Inoculum: The suspensions of all the organisms were prepared as Mac-Farland Nephelometer standard. A 24 hours old culture was used for the preparation of bacterial suspension. Suspensions of organisms were made in sterile isotonic solution of sodium chloride and turbidity was adjusted.

Table -1: Composition of Nutrient broth medium

Sl. No	Ingredients	Weight in gm.
1.	Beef extract	1.50
2.	Peptic digest of animal tissue	5.00
3.	Yeast	1.50
4.	Sodium chloride	5.00
Final pH at 25  C 7.4 ± 0.2

Table-2: Composition of Nutrient Agar medium

Sl. No	Ingredients	Weight in gm.
01	Beef extract	1.50
02	Peptic digest of animal tissue	5.00
03	Yeast	1.50
04	Sodium chloride	5.00
05	Agar	15.00
Final pH at 25 ° C 7.4 ± 0.2

The above-mentioned quantities of different ingredients were accurately weighed and dissolved in appropriate amount of distilled water. Prepared media was sterilized by autoclaving technique at 121° C for 15 minutes.

Procedure:

The Petri dishes were washed thoroughly and sterilized in hot air oven at 160° C for one hour. 30 mL of sterile nutrient agar medium was poured into sterile Petri dishes and allowed to solidify. The petri dishes were incubated at 37° C for 24 hours to check for sterility. The medium was seeded with the organism by spread plate method using sterile cotton swabs. Bores were made on the medium using sterile borer and 0.1 mL of the Norfloxacin at a concentration of 100mg/mL was taken as standard reference. A control having only DMSO in the cup was maintained in each plate. The petri dishes were kept in refrigerator at 4° C for 15 minutes, allowing diffusion to take place. Agar diffusion and the petri plates were incubated at 37 °C for 24 hours and zone of inhibition were observed and measured using a scale. Antimicrobial activities of all the compounds were carried out against all 3 species of microorganisms²⁹.

RESULTS:

Results are summarized in tables (3-7) and Fig 1-3 of schemes (1-3), show the details of the synthetic strategy adopted for the synthesis of these compounds. The product Benzyl (chloro) triphenyl phosphorone versatile starting material for a number of syntheses. Firstly we prepared substituted benzyl (chloro) triphenyl phosphorone by reacting the substituted benzyl chloride in methyl cyanide according to the literature. After preparing substituted Benzyl (chloro) triphenyl phosphorone, it was reacted with various substituted aldehyde in the presence of the benzene and sodium hydride to get the specific stilbenes (SS-2, SS-15, SS-18, SS-22). After completion of the reaction we collected the compound by extracting with chloroform. After getting two isomer of the product we separated the compound by preparative TLC and recrystalize method with suitable solvent.

In second method we used substituted phenyl acetic acid as a starting material by reacting with different aldehyde to get desired product (SS-27).

In third method we replaced the carbon from C=C with N to produce C=N as a bioisosteric replacement of the stilbenes (SR-2).

All the compounds were confirmed by TLC, melting point, IR, NMR and MASS Spectroscopy.

In (Z)-2-styryl thiophene (SS-2) IR vibrations were seen at 3060 cm^-1 for Aromatic C-H (stretching), 2920 cm^-1 aliphatic C-H, 1517 cm^-1 for –C=C-. In ¹H NMR there are well-resolved peaks from 7.50-7.10 (8H, Ar-H) ppm for aromatic hydrogen.

In (Z)-1-methoxy-3-styrylbenzene (SS-15) IR vibrations were seen at 3055 cm^-1 for aromatic C-H, 2962 cm^-1 for aliphatic C-H, 1600 cm^-1 for –C=C-, 1440 cm^-1 for –C=O-. In ¹H NMR there are well-resolved resonance peak at 7.50-7.10 for aromatic hydrogen.

In (Z)-1-chloro-3-(4-methyl styryl)benzene (SS-18) IR vibrations were seen at 3020 cm^-1 for aromatic C-H, 2915 cm^-1 for aliphatic C-H, 1675 cm^-1 for –C=C-. In ¹H NMR there are well-resolved peak at 7.50-7.10 for aromatic hydrogen.

In (Z)-1-(4-chlorostyryl)-3-nitro benzene(SS-22) IR vibrations were seen at 3057 cm^-1 for Aromatic C-H, 2968 cm^-1 for aliphatic C-H, 1655 cm^-1 for –C=C- and 1521 cm^-1 for –N=O. In ¹H NMR there are well-resolved resonance peak at 7.47-7.10 for aromatic hydrogen.

In (E)-3-(3-hydroxy-4-methoxy phenyl)-2-phenyl acrylic acid (SS-27) IR vibrations were seen at 2942 cm ^-1 for aromatic C-H, 2624 cm^-1 for aliphatic C-H, 3516 cm^-1 for OH, 1673 cm^-1 for C=O and 1597 cm^-1 for –C=C-. In ¹H NMR there are well-resolved resonance peak at 7.92-7.15 for aromatic hydrogen. The Mass spectroscopy of the compound (SS-27) shows molecular ion peak at m/z 270 by which we have confirmed for its authenticity.

In (Z)-2-chloro-N-(4-nitrobenzylidene)aniline (SR-2) IR vibrations were seen at 3070 cm ^-1 for aromatic C-H, 2914 cm^-1 for aliphatic C-H, 1627 cm^-1 for –C=C- and 1517 cm^-1 for –N=O- by which we have confirmed for its authenticity.

The anti-bacterial and Anti-fungal activity of synthesized compounds was shown in Table 8, Fig (4A-4D) and Table 9, Fig 5A-5B respectively.

TABLE-3: Analytical data of synthesized compounds

Sl NO.

Molecular structure

Nature of compound

% Yield

Molecular Formula

Molecular Weight

SS-2

Yellow

powder

60%

C₁₂H₁₀S

186

SS-15

White

powder

65%

C₁₅H₁₄O

210

SS-18

Light

Yellow

powder

50%

C₁₅H₁₃Cl

228.5

SS-22

Yellow

Crystals

67%

C₁₄H₁₀NO₂Cl

259.5

SS-27

White

powder

70%

C₁₆H₁₄O₄

270

SR-2

Brown powder

57%

C₁₃H₉N₂ClO₂

250.5

TABLE-4: Physical properties of Synthesized Compounds:

CODE	SOLUBLITY	MOBILE PHASE FOR TLC	Rf Value	MELTING POINT (^oC )
SS-02	Chloroform	Hexane-Ethyl acetate (0.7:0.3)	0.58	170-175
SS-15	Chloroform	Hexane-Ethylacetate (0.7:0.3)	0.49	190-195
SS-18	Chloroform	Hexane-Ethylacetate (0.7:0.3)	0.76	250-255
SS-22	Chloroform	Hexane-Ethylacetate (0.7:0.3)	0.65	210-215
SS-27	Chloroform	Hexane-Ethylaceate (0.7:0.3)	0.45	120-125
SR-02	Chloroform	Hexane-Ethylacetate (0.7:0.3)	0.77	90-95

TABLE-5: Spectral data

Infra red spectral studies of the synthesized compounds:

COMPOUNDS

SPECTRAL SPEAKS (Cm^-1 )

MOLECULAR NATURE

SS-02

3028

2920

1517

-C-H Str ( aromatic )

-C-H (aliphatic )

-C=C-

SS-15

3055

2962

1600

1440

-C-H Str ( aromatic )

-C-H (aliphatic )

-C=C-

-C=O

SS-18

3020

2915

1675

-C-H Str ( aromatic )

-C-H ( aliphatic )

-C=C-

SS-22

3057

2968

1655

1521

-C-H Str ( aromatic )

-C-H ( aliphatic )

-C=C-

-N=O

SS-27

3516

2942

2624

1673

1597

-OH

-C-H Str ( aromatic )

-C-H ( aliphatic )

-C=O-

-C=C-

SR-02

3070

2914

1517

1627

-C-H Str ( aromatic )

-C-H ( aliphatic )

-N=O

-C=C-

TABLE-6: H¹ NMR Spectral data of synthesized compounds:

COMPOUNDS

CHEMICAL SHIFT VALUE

PROTON NATURE

SS-2

7.50-7.20

7.19

7.10

8H, -Ar-H

1H, -CH

SS-15

7.50-7.25

7.10

7.05

3.91

9H, Ar-H

1H, -CH

1,H, -CH

3H, -OCH₃

SS-18

7.50-7.25

7.21

7.19

2.38

8H, -Ar-H

1H, -CH

1H –CH

3H, -CH₃

SS-22

7.47-6.90

7.23

7.10

8H, -Ar-H

1H –CH

1H, -CH

SS-27

7.92-7.25

7.98

7.25

6.98

3.43

8H, -Ar-H

1H, -COOH

1H, -CH

3H, -OCH₃

SR-02

8.52-8.06

7.22

7.08

8H, Ar-H

1H, -CH

TABLE-7: Mass spectral data of synthesized compounds

COMPOUND	MOLECULAR ION PEAK
SS-27	270 [ M⁺]

Spectral Data

Fig-2: NMR spectrum of (E)-3-(3-hydroxy-4-methoxyphenyl)-2-phenylacrylic acid.

Fig-3: MASS spectrum of (E)-3-(3-hydroxy-4-methoxyphenyl)-2-phenylacrylic acid.

Fig-4A: SR-2 and SS-2 showing zone of inhibition against S.aureus and klebsiella

Fig-4B: SS-15 and SS-18 showing zone of inhibition against S.aureus and klebsiella

Fig 4C: SS-18 and SS-22 showing zone of inhibition against S.aureus and klebsiella

Fig 4D: SS-27 showing zone of inhibition against S.aureus and klebsiella

TABLE-8: Anti bacterial activity of synthesized compounds

Code No	Dose (µg/ml)	Zone of inhibition in mm
Code No	Dose (µg/ml)	*S.aureus*	*K.pneumonia*
SS-2	75	20	16
SR-2		12	R
SS-15		R	14
SS-18		12	14
SS-22		R	14
SS-27		14	R
SS-2	50	14	R
SR-2		12	R
SS-15		R	R
SS-18		12	R
SS-22		R	14
SS-27		12	R

R= Resistant Standard for Bacteria-Ciprofloxicin 10µg-28mm

TABLE-9: Anti fungal activity of synthesized compounds

Code No	Dose (µg/ml)	Zone of inhibition in mm
Code No	Dose (µg/ml)	*C.albicans*
SS-2	75	20
SR-2		14
SS-15		20
SS-18		R
SS-22		14
SS-27		20
SS-2	50	18
SR-2		12
SS-15		16
SS-18		R
SS-22		12
SS-27		18

R= Resistant Standard for fungus-fluconozole 30 µg-22mm

Fig 5A: SS-2, SR-2 and SS-15 showing zone of inhibition against C. albicans

Fig 5B: SS-18, SS-22 and SS-27 showing zone of inhibition against C. albicans

DISCUSSION:

Hydroxylated, methoxylated and halogenated stilbenes are known to show good antimicrobial properties. Antimicrobial studies were carried out and the results obtained are discussed below. Antimicrobial activities for all synthesized compounds were carried out by agar diffusion method and the average radius of the zone of inhibition was recorded³⁰. Among the other derivatives screened the following observations were made and compared with the standard Ciprofloxicin (10µgm)

· SS-02, SS-22, SR-02 derivatives have shown moderate degree of antimicrobial activity.

· SS-15, SS-18, SS-27 derivatives have shown mild antimicrobial activity.

Antifungal activities for all synthesized compounds were carried out by agar diffusion method and the average radius of the zone of inhibition was recorded. Among the other derivatives screened the following observations were made and compared with the standard fluconozole (10µgm/ml).

· SS-02, SS-15, SS-27 derivatives have shown moderate degree of antifungal activity.

· SR-02, SR-22 derivatives have shown mild antifungal activity.

CONCLUSION:

The objective of the present work was to synthesize, characterize and evaluate for antimicrobial activity of some stilbene derivatives. The yield of different synthesized compounds was found to be in the range of 65-70% and the characterization was done by Melting Point and TLC (R_f value). The synthesized compounds were also characterized by IR, ¹HNMR, and Mass spectral studies.

All the synthesized derivatives showed antibacterial activity against both Gram positive and Gram negative bacteria at a concentration of 100 mg. Moderate results in terms of antimicrobial activity, best result in terms of antibacterial activity were shown by (SS-02), (SS-22), (SR-02). Some of the compounds have shown mild antibacterial activity such as (SS-18), (SS-15), (SS-27). Best result in terms of antifungal activity were shown by (SS-02), (SS-15), (SS-27). Some of the compounds have shown mild antifungal activity such as (SR-02), (SS-22).

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Received on 31.10.2011 Modified on 10.11.2011

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