INTRODUCTION:

In view of the general observation that pharmacological activity is invariably associated with a large variety of heterocyclic compounds, the present investigation of some heterocycles belonging to certain class of compounds was undertaken. We focused our attention on compounds like fluoroindole and their derivatives. These compounds are reported to possess a wide spectrum of biological properties which include antibacterial, antifungal, anti-inflammatory, antipyretic, CNS depressant and anticancer activities^1-19.

Indole can be produced by bacteria as a degradation product of the amino acid tryptophan. It occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell, and is a constituent of many flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar.

Indole plays an important role as biologically active compounds. Indole derivatives constitute an important family of compounds such as antifungal and antioxidant.

The compound 5-nitro-2-phenylindole is a promising lead in helping a wide range of antibiotics stay in bacterial cells. Other 2-aryl substituted indole derivatives are implicated in inhibition of bacterial histidine kinase

Therefore the synthesis of 2- and 3-substituted indoles and their pyran fused analogues are important targets for organic synthesis. These compounds can then be tested as potential bacterial and fungal inhibitors^20-28.

Indole nucleus is frequently found in medicinal chemistry and is considered as “privileged scaffolds”. Therefore the synthesis and selective fictionalization of indole have been focused of active research over years. Now a day’s cancer is also one of the causes of death. Recent research oriented toward the discovery of new generation anticancer agents has identified kinesin spindle protein as a possible cellular target. KSP is a mitotic spindle motor protein that plays an important role in centrosome separation and formation of the bipolar mitotic spindle. Inhibition of KSP function leads to cell cycle arrest during mitosis with a monopolar spindles.

Indoles are also important synthons for the preparation of biologically active derivatives. Synthesis of nitrogen-containing heterocyclic compounds has been a subject of great interest due to the wide application in agrochemical and pharmaceutical fields. Some indole derivatives which belong to this category have certainly been shown to exhibit biological activity. On the other hand, it is well accepted that selective introduction of fluorine to organic compounds often causes a marked effect on structure, stability, reactivity, and biological activity.

EXPERIMENTAL:

Synthesis of 2-Benzyl-3-oxo-butyric acid ethyl ester (3):

Accurately weighed 31.8 g of dry K₂CO₃and 70 ml of dry acetonitrile was taken in RBF fitted with reflux condenser on magnetic stirrer, 9.6 ml of ethylacetoacetate was added with stirring during 30 min. (i.e. ½ Hrs) then 8.6 ml of benzyl chloride was added. Reflux on steam bath for 6 Hrs. Remained solvent get evaporated and residue was cooled,

diluted with 100 ml of water. Oil separated was extracted with 50 ml of ether. Ether layer was separated.

(b.p. 240-260 °C).

Preparation of diazonium chloride solution (4a):

The diazonium chloride solution was prepared by adding drop wise 1.4 g (0.02mole) of sodium nitrite in 20 ml of water to a suspension of (0.02 mole) of substituted aniline in 100 ml of 1N HCl. The reaction mixture was stirred for 1 Hr at 0-5°C and filtered.

Synthesis of 3-[(3-Chloro-4-fluoro-phenyl)-hydrazono]-4-phenyl-butan-2-one (5):

To a vigorously stirred solution of 4.4 g (4.4ml) of ethyl–α– benzylacetoacetate in 5 ml of absolute ethanol, add a solution of 0.9 g of NaOH in 2.5 ml water. Immediately after precipitation of gelatinous mass, added 50 ml of water and continued stirring for 4 Hrs. Unreacted ester was removed by extracting with ether. To the above aqueous layer aryldiazonium chloride solution was added drop wise prepared from appropriate aniline. To the aqueous layer aryl diazonium salt solution was added drop wise and stirred maintaining temperature 0-5°C. After adding 10 g of crystalline sodium acetate stirred for 1 Hr. The phenyl hydrazone precipitates quickly with the evolution of CO_2. The solid product was filtered, washed with water, aqueous sodium carbonate solution and then again with water and dried. Brown crystals were obtained. Recrystallised it from cyclohexane. The m.p. of compound was found to be 210°C.

Synthesis of 1-(6-Chloro-5-fluoro-3-phenyl-1H-indol-2-yl)-ethanone by cyclization (6):

To the above 3-[(3-Chloro-4-fluoro-phenyl)-hydrazono]-4-phenyl-butan-2-one, dry HCl gas was passed for 2 Hrs. After passing gas the solution was kept aside for 4Hrs at R.T. and precipitate was obtained. The solution was filtered and dried well. The crude product was recrystallised with super dry ethanol to get the desired product having m.p. 200°C.

Synthesis of 1-(6-substituted-5-fluoro-3-phenyl-1H-indol-2-yl)-ethanone 6(a-h):

To the above 1-(6-Chloro-5-fluoro-3-phenyl-1H-indol-2-yl)-ethanone derivative (1M), different types anilines ( 3-Nitro aniline, 4-chloro aniline) or piperazine or piperidine or morpholine (1M) were attached. 1,4-dioxane 10 ml and 1-2 drops of triethylamine was taken in a 100 ml RBF fitted with a reflux condenser. Refluxed the reaction mixture 10-12 Hrs and monitored by TLC, then transferred to ice cold water and filtered the solution to get the desired products.

Synthesis of 1-(6-Chloro-5-fluoro-3-phenyl-1H-indol-2-yl)-3-substituted-propenone 6 (i-p):

To the above 1-(6-Chloro-5-fluoro-3-phenyl-1H-indol-2-yl)-ethanone derivative (1M), different types of aromatic aldehydes ( 2-nitro benzaldehyde, 4-hydroxy -3-methoxy benzaldehyde, 3,4,5-trimethoxy benzaldehyde) were hooked. 8ml of 10 % alcoholic NaOH solution and 25ml solution of main compound was taken in 100ml RBF and stirred it at RT for 24 Hrs. Then the solvent was poured in ice cold water, filtered, thoroughly washed with water and recrystallised from acetone-water mixture.

In vitro evaluation of Antibacterial activity:

All the newly synthesized fluoro-indole derivatives (6, 6c, 6d, 6f, 6g, 6i, 6j, 6k and 6m) were evaluated for their Antibacterial activity against Staphylococcus aureus and Escherichia coli at the concentration of 50μg/ml and 100μg/ml by Agar Diffusion method using DMF as a solvent. After 24 Hrs of incubation at 37 ⁰C ± 1⁰C, zones of inhibition were measured in mm. The activity was compared with Ampicillin at the same concentration. Among the compounds tested 6f, 6i and 6k were found to be the most potent against both the microorganisms used³⁰.

RESULTS AND DISCUSSION:

Synthesis of novel substituted fluoroindole derivatives was carried out firstly by the reaction of ethylacetoacetate(1) with benzyl chloride (2) to form 2-Benzyl-3-oxo-butyric acid ethyl ester (3) in presence of dry K₂CO₃ and dry acetonitrile and reaction of the corresponding 2-Benzyl-3-oxo-butyric acid ethyl ester (3) with fluoro-chloro aniline (4) to form the intermediate 3-[(3-Chloro-4-fluoro-phenyl)-hydrazono]-4-phenyl-butan-2-one(5) in presence of 1N HCL, NaNO₂and CH₃COONa. The intermediate is then cyclized by passing dry HCl gas using super dry alcohol as a solvent to give the final compound, 1-(6-Chloro-5-fluoro-3-phenyl-1H-indol-2-yl)-ethanone(6). Electrophilic substitution group is removed from the final compound, and 6(a-p) derivatives have been synthesized. All the synthesized compounds were characterized by physical data (M.P. and TLC) (Table No. 1). 3-Chloro-4-fluoro-benzenediazonium; chloride (4a) was synthesized in good yield by diazotization of fluorochloro aniline(4) in presence of sodium nitrite and 1N HCl. 3-Chloro-4-fluoro-benzenediazonium; chloride(4a) was then treated with 2-Benzyl-3-oxo-butyric acid ethyl ester(3), sodium acetate and ethanol to give 3-[(3-Chloro-4-fluoro-phenyl)-hydrazono]-4-phenyl-butan-2-one (5) which was then cyclized to give 1-(6-Chloro-5-fluoro-3-phenyl-1H-indol-2-yl)-ethanone(6) (Scheme No.1). 3-[(3-Chloro-4-fluoro-phenyl)-hydrazono]-4-phenyl-butan-2-one(5) was then cyclized with dry HCl gas in super dried ethyl alcohol as a solvent to give the final compound 1-(6-Chloro-5-fluoro-3-phenyl-1H-indol-2-yl)-ethanone(6). Here, the final compound (6). The ¹H NMR spectrum of this compound has been showed its characteristic peak at 9.35 (s, 1H, Ar-NH), 7.92-7.32 (d, 5H, Ar-H), 7.19-7.14 (d, 2H, Ar-H), 6.99 (d, 1H, Ar-H ortho to fluorine), 2.17 (s, 3H, CH₃) which is of (N-H def) group was confirmed by peak at 1602 cm^-1 in their IR spectra. The keto group was shown in the IR spectra at 1641 cm^-1(Tabel No. 2). The resultant compound is treated with five different aniline and aromatic aldehyde in presence of 1, 4-dioxane,triethyl amine and 10% alcoholic NaOH solution to give different derivative compounds (6a-p).

To investigate the SAR of synthesized fluoroindole derivatives, we have selected the 6^th and 2^ndposition for the preparation of derivatives (6a-h) and (6i-p) respectively.

The compounds were evaluated for anti- bacterial activity. Anti-bacterial activity was performed by agar diffusion method. Among 6, 6c, 6d, 6f, 6g, 6i, 6k and 6m compounds 6f, 6i and 6k demonstrated good anti- bacterial activity. Here it shows that the synthesized compound possessing electron withdrawing group at meta or para position showed better anti-bacterial activity (Table No. 3).

Sl. NO.	C.C.*		Molecular Formula	Mol. wt.	% Yield	m.p. (°C)	R_f Value	Solvent System
1.	5		C₁₆H₁₄ClFN₂O	304.75	78.85	210	0.59	EA:HE*1:4
2.	6		C₁₆H₁₁ClFNO	287.05	84.40	195	0.61	EA:HE1:4
3.	6a	-NC₅H₁₀(piperidine)	C21H21FN₂O	336.40	53.28	124	0.49	EA:HE1:4
4.	6b	-NOC₄H₈(morpholine)	C₂₀H₁₉FN₂O₂	338.38	59.95	165	0.57	EA:HE1:4
5.	6c	-NH-C₆H₄-4-NO₂	C₂₂H₁₆FN₃O₃	389.38	45.85	112	0.58	EA:HE1:4
6.	6d	-NH-C₆H₄-2-NO₂	C₂₂H₁₆FN₃O₃	389.38	39.25	142	0.53	EA:HE1:4
7.	6e	-NH-C₆H₄-3-NO₂	C₂₂H₁₆FN₃O₃	389.38	60.29	148	0.61	EA:HE1:4
8.	6f	-N₂C₄H₉(piperazine)	C₂₀H₂₀FN₃O	337.36	56.73	172	0.66	EA:HE1:4
9.	6g	- N₂C₅H₁₁(N-CH₃-piperazine)	C₂₁H₂₂FN₃O	351.35	49.30	135	0.58	EA:HE1:4
10.	6h	-NH-C₆H₄-3-Cl	C₂₂H₁₆ClFN₂O	378.82	42.45	85	0.50	EA:HE1:4
11.	6i	R₁- NOC₄H₈(morpholine) R₂-CH-C₆H₃-4-OH-3-OCH₃	C₂₈H₂₅FN₂O₄	472.41	49.64	245	0.58	EA:HE1:4
12.	6j	R₁- NOC₄H₈(morpholine) R₂-CH-C₆H₄-2-NO₂	C₂₇H₂₁FN₃O₄	470.12	49.32	274	0.46	EA:HE1:4
13.	6k	R₁- NH-C₆H₄-4-Cl R₂-CH-C₆H₃-4-OH-3-OCH₃	C₃₀H₂₂ClFN₂O₃	512.42	65.45	244	0.49	EA:HE1:4
14.	6l	R₁- NH-C₆H₄-3-Cl R₂-CH-C₆H₃-4-OH-3-OCH₃	C₃₀H₂₂ClFN₂O₃	512.42	54.65	140	0.68	EA:HE1:4
15.	6m	R₁- NH-C₆H₄-4-NO₂ R₂-CH-C₆H₃-4-OH-3-OCH₃	C₃₀H₂₂FN₃O₅	523.82	53.50	260	0.54	EA:HE1:4
16.	6n	R₁-NH-C₆H₄-3-NO₂ R₂-CH-C₆H₃-4-OH-3-OCH₃	C₃₀H₂₂FN₃O₅	523.82	67.36	280	0.62	EA:HE1:4
17.	6o	R₁-NH-C₆H₄-2-NO₂ R₂-CH-C₆H₃-4-OH-3-OCH₃	C₃₀H₂₂FN₃O₅	523.82	56.45	235	0.57	EA:HE1:4
18	6p	R₁-NH-C₆H₄-3-NO₂ R₂-CH-C₆H₄-2-NO₂	C₂₉H₁₈FN₄O₅	521.96	58.12	285	0.51	EA:HE1:4

C.C. * = Compound Code, EA:HE* = Ethyl Acetate: n-hexane

Table-2: Spectral data of synthesized compounds:

Compound Code	IR Data (cm^-1)	NMR data (ppm)
[6]	3311cm^-1 (NH str secondary amine);1641 cm^-1(C=O); 860 cm^-1(Ar- Cl); 1259 cm^-1(C-F); 1242 cm^-1(C-C); 1452 cm^-1(CH₂).	peak at 9.35 (s, 1H, Ar-NH), 7.92-7.32 (d, 5H, Ar-H), 7.19-7.14 (d, 2H, Ar-H), 6.99 (d, 1H, Ar-H ortho to fluorine), 2.17 (s, 3H, CH₃)
Compound Code	IR Data (cm^-1)
[6a]	3341 cm^-1 (NH str secondary amine),2246(CN); 1680 cm^-1(C=O); 860 cm^-1 (Ar- Cl); 1272 cm^-1(C-F); 1491 cm^-1(CH₂).
[6b]	3311 cm^-1 (NH str secondary amine), 1643(C=O); 827cm^-1 (Ar- Cl); 1259(C-F); 1533 (Ar C=C); 1452(CH₂); 1161 cm^-1(C-O); 1201(C-Cstr).
[6c]	3481(NH₂); 2984 cm^-1 (C-H str aromatic); 3362 cm^-1 (NH str secondary amine); 1643 (C=O str amides); 1203cm^-1( C-C str);1259 (C-F).
[6d]	3481(NH₂); 2984 cm^-1 (C-H str aromatic); 3362 cm^-1 (NH str secondary amine); 1203cm^-1( C-C str); 1259 (C-F);1643 (C=O str amides).
[6e]	3362 cm^-1 (NH str secondary amine); 1203cm^-1( C-C str); 1259 (C-F); 3481(NH₂); 2984 cm^-1 (C-H str aromatic);1643 cm^-1 (C=O str amides).
[6f]	3311cm^-1 (NH str secondary amine); 1261 cm^-1 (C-C str ); 1652(C=O); 1458(CH₂).
[6g]	3311cm^-1 (NH str secondary amine); 1263cm^-1(C-F); 1261 cm^-1 (C-C str ); 1652 cm^-1(C=O); 1458 cm^-1(CH₂).
[6h]	1645 (C=O str amides); 1203 cm^-1( C-C str); 1288 cm^-1(C-F); 3402(NH₂); 2978 cm^-1 (C-H str aromatic); 3273 cm^-1 (NH str secondary amine); 690 cm^-1(C-Cl).
[6i]	3311cm^-1 (NH str secondary amine); 1259 cm^-1(C-F); 1203 cm^-1 (C-C str ); 1643 cm^-1(C=O); 1452 cm^-1 (CH₂); 1533 cm^-1 (Ar C=C);2928cm^-1( CH); 1152 cm^-1(C-O).
[6j]	1230 cm^-1 (C-C str ); 1643 cm^-1(C=O); 1452 cm^-1 (CH₂); 3290 cm^-1 (NH );1261 cm^-1(C-F); 1438 cm^-1(CH₂); 1502 cm^-1(Ar C=C); 2918 cm^-1(CH).
[6k]	3313 cm^-1 (NH); 1259 cm^-1 C-F); 838 cm^-1(Ar- Cl); 1641 cm^-1 (C=O); 1484 cm^-1(CH₂); 1159 cm^-1(C-O).
[6l]	1641 cm^-1 (C=O); 1484 cm^-1(CH₂); 1159 cm^-1(C-O);3313 cm^-1 (NH); 1259 cm^-1 C-F); 838 cm^-1(Ar- Cl )
[6m]	3383 cm^-1 (OH); 3313 cm^-1 (NH); 1643 cm^-1 (C=O); 1259 cm^-1(C- F); 1452 cm^-1(CH₂); 1533 cm^-1(Ar C=C); 1508 cm^-1(NO₂); 1103(C-O), 1230(C-C).
[6n]	1259 cm^-1(C- F); 1452 cm^-1(CH₂); 3383 cm^-1 (OH); 3313 cm^-1 (NH); 1643 cm^-1 (C=O); 1533 cm^-1(Ar C=C);1508 cm^-1(NO₂); 1103 cm^-1(C-O), 1230(C-C).
[6o]	3383 cm^-1 (OH); 3313 cm^-1 (NH); 1643 cm^-1 (C=O); 1259 cm^-1(C- F); 1452 cm^-1(CH₂); 1533 cm^-1(Ar C=C); 1508 cm^-1(NO₂); 1103 cm^-1(C-O), 1230 cm^-1(C-C).
[6p]	3336 cm^-1 (NH); 1650 cm^-1 (C=O); 1250 cm^-1(C- F); 1491 cm^-1(NO₂)_; 1452 cm^-1(CH₂); 1512 cm^-1(Ar C=C);1508 cm^-1(NO₂); 1151 cm^-1(C-O), 1203 cm^-1 (C-C).

Table-3: Antibacterial evaluation data of the synthesized compounds:

Sl.No.	Comp. Code	Zone of Inhibition (Diameter in mm)
		*Staphylococcus aureus* (+ve)		*Escherichia coli(-ve)*
		50 μg/ml	100 μg/ml	50 μg/ml	100 μg/ml
01.	6	5.7 mm	5.9 mm	4.3 mm	4.7 mm
02.	6c	5.1 mm	5.8 mm	3.9 mm	4.6 mm
03.	6d	4.1 mm	4.8 mm	4.5 mm	4.9 mm
04.	6f	6.0 mm	6.4 mm	6.2 mm	6.5 mm
05.	6g	5.1 mm	5.6 mm	4.9 mm	5.1 mm
06.	6i	6.1 mm	6.5 mm	5.5 mm	6.1 mm
07.	6j	5.7 mm	5.9 mm	4.9 mm	5.1 mm
08.	6k	6.0 mm	6.8 mm	5.4 mm	5.9 mm
09.	6m	5.6 mm	5.8 mm	5.0 mm	5.5 mm
10.	Control	3.9 mm	4.5 mm	3.5 mm	3.8 mm
11.	Ampicillin	7.4 mm	8.3 mm	7.9 mm	8.1 mm

Standard: Ampicillin = 7.5 mm at 50 μg/ml and 8.1 mm at 100 μg/ml

CONCLUSION:

A series of targeted compounds was synthesized by Scheme No.1 and were screened for anti-bacterial activity in-vitro by using Bovine serum albumin. The electron withdrawing groups at ortho or para position needs to be investigated pharmacological activity to develop a class of anti-bacterial agents. Among 6, 6c, 6d, 6f, 6g, 6i, 6k and

6m Compounds 6f, 6i and 6k were found to possess good anti-bacterial activity. In this connection, fluoroindole derivatives bearing electron withdrawing group gives better anti-bacterial activity.

ACKNOWLEDGEMENTS:

The authors wish to express their thanks to management of Nargund College of Pharmacy Dattatreya Nagar, II main,100Ft Ring Road, BSK III stage, Bangalore, for providing necessary facilities.

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Received on 08.06.2012 Modified on 04.07.2012

Research J. Pharm. and Tech. 5(11):November, 2012; Page 1446-1451