Synthesis and Antimicrobial Activity of Some Indole Derivatives

 

Dhanashri Nimbalkar*, Pratik P. Maske, Sachin G. Lokapure, R. V. Heralagi, N. V. Kalyane

Department of Pharmaceutical Chemistry. B.L.D.E.A College of Pharmacy, Bijapur, Karnataka State. India

ABSTRACT:

Present work deals with the preparation of Ethyl 1H-indole-5-caboxylate by refluxing indole-5-carboxylic acid and ethyl iodide in the presence of DMF (dimethyl formamide). Further, Ethyl 1H-indole-5-carboxylate treated with hydrazine hydrate gives 1H-indole-5-carbohydrazide which is treated with various substituted aromatic aldehydes to form indole derivatives.Hydrazides were synthesized so as to increase intracellular concentration and so as to try and decrease the resistance developed due to decrease intracellular concentration of the drug. The synthesized aldehyde derivatives were characterized on the basis of physical, analytical and spectral (IR, ¹HNMR and Mass) data. Further, these were tested for anti-bacterial activity against S.aureus (ATCC 29213), E.coli (ATCC 25922),Pseudomonas aeruginosa (MTCC 741)andanti-fungal activity against Aspergilusniger, Candida albicans(ATCC 9025)in cup plate method. Evaluation of the compound revealed moderate to good antimicrobial activity.

 

 

 

1. INTRODUCTION:

In the past, the production of what we would now call “bioactive” substances was a mystery. A modern view is that these compounds have a role in protecting otherwise defenceless, stationary plant from attack by mammals, insects, fungi, bacteria and viruses.¹

 

Today’s developed medicines are results of relentless effort made by human civilization time to time. When the era of synthetic drugs began, it opened thousand doors for the development of various synthetic molecules with potential action. But developing a new molecule every time was neither easy nor a wise step too, so concept of derivatization came. It is always better to synthesize a derivative of known molecule with known properties rather than to synthesize a totally unknown new molecule. In fact it is a wise step, in minimizing the toxicity as well as improving potency of the parent molecule.

 

It is a rational approach towards the drug design and development, based upon the various physical and physiochemical parameters.

 

That’s why most of the drugs in practice are derivatives of known molecules, whether it is β-lactam antibiotics (Penicillin G, Penicillin V, and Ampicillin), Irreversible proton pump inhibitors (Omeprazole, Lansoprazole, Rabeprazole), or CNS drugs such as BDZ derivatives (Diazepam, Clonazepam etc.). Several diseases have been treated by administration of plant extracts based on traditional medicine.²

 

The synthesis of derivatives has been an important part and is aimed at modifying the action of drugs, particularly to reduce the side effects and to potentiate the drug action. Chemical modifications of drug molecules to locate the number of series having optimal effects, and will probably continue to be a factors necessary to drug discovery to establish the effect of drug molecules the new invention in physicochemical directions such as X-ray analysis, UV, IR, and NMR are immensely helpful for medicinal chemist.Silica gel thin-layer chromatography (TLC) has become a powerful technique in the purification, separation and possible identification of natural and synthetic indole derivatives : The advantages over paper chromatography are short developing times, inertness of the silica gel layer towards corrosive spray reagents and minimal zone spreading of the chromatographic compounds^3,4.

 

 

 

Table No. 1:- Physicochemical properties of compound 2D–a to 2D-l.

 

Table NO: - 2. Zone of inhibition of synthesized compounds [2D-a to 2D-l]

Note: - 15-20 mm poor activity, 20-25 mm moderate activity, above 25 good activity. Standard (S) = Ciprofloxacin;  Control (C) = DMF

 

Use of electrochemistry is animportant approach in drug discovery and research as well as quality control, drug stability, and determination of physiological activity. The indole nucleus is an essential element of a number of natural and synthetic products with significant biological activity. Indole derivatives are the well-known electro active compounds that are readily oxidized at carbon-based electrodes. ⁵

METARIAL AND METHOD:

Experimental work:

All the chemicals used were produced from Aldrich and purity of starting materials used for reactions was confirmed by checking their melting point or boiling point and by thin layer chromatography. All the reactions were monitored using thin layer chromatography. The appropriate mobile phases (solvent systems) as applicable were developed using ‘silica gel G’ as stationary phase. Melting points were determined in open capillary tube and are uncorrected. FT-IR (KBr) spectra were recorded on SHIMADZU FTIR-8400S Spectrophotometer. ¹HNMR spectra of synthesized compounds were recorded on Bruker Spectrophotometer at 300 MHz frequency in Deuterated chloride (CDCl₃) as well as dimethyl sulfoxide (DMSO) using tetramethylsilane (TMS)  as internal standard (chemical shift δ in ppm). Purity of the compounds was checked on ‘Silica Gel G’ coated on laboratory micro slide prepared by dipping method or pre-coated plates, eluent was the mixture of different polar and non-polar solvents in varying proportions and detections was done either by observing in ultraviolet (UV) light or exposure to iodine vapors as required. The absence of thin layer chromatography (TLC) spots for starting materials and appearance of new TLC spot at different R_f value ensured the completion of reaction. The products of all the reactions were purified initially by different workup processes to remove unreacted starting materials if any and then by recrystallization using suitable solvents. The absences of any impurity of starting material or possible bi-product were ensured by performing qualitative organic analytical tests for various functional groups. All the compounds were prepared by conventional method as outlined in the scheme.

 

Synthesis of Ethyl 1H-Indole-5-Carboxylate(I):

To a solution of indole-5-carboxylic acid (0.0015 mol), dry DMF and ethyl (or) methyl iodide (0.0015 mol) was added drop wise in 500 mL round bottom flask. Flask provided with a mechanical stirrer. The reaction mixture was stirred for 2-3 h at 20-25⁰C, reaction monitored by TLC technique up to completion. After the reaction completed, ice water was added and stirred for 30 min. The crude indole ester isolated by filtration technique was purified by recrystallization with methanol.^6,7

 

Synthesis of 1H-Indole-5-Carbohydrazide(II):

To a solution of methyl or ethyl 1H-indole-5-carboxylate 2 (0.001 mol) in a dry methanol in 500 mL round bottom flask, hydrazine hydrate (0.0015 mole) was added. Flask provided with a mechanical stirrer. The reaction mixture was stirred for 3-4 h at 55-60 ⁰C temperature, reaction monitored by TLC technique up to completion. After the reaction completed, methanol was removed by vacuum into that ice cold water was charged, solids collected by filtration technique, was recrystallized by methanol.^8,9,10

 

Synthesis of respective different indole derivatives (III):

A mixture of 1H-Indole-5-Carbohydrazide (0.01mol) and aromatic aldehyde (0.01mol) and 2-3 drops of glacial acetic acid in ethanol (30ml) was refluxed on water bath for about 5 hrs.⁸ The solvent was removed under vacuum and residue was stirred with ice cold water (50ml) filtered and dried to give products viz, 2D-a to 2D-lshown in table no. 1.

 

Antibacterial activity:

All the test compounds were evaluated for antibacterial activity against S.aureus (ATCC 29213) (gram-positive), E.coli (ATCC 25922) (gram-negative),Pseudomonas aeruginosa (MTCC 741) (gram-negative)following the agar diffusion method of assay. The specific method adopted in the present investigation was cup-plate method involving cups of standard diameter, the nutrient agar medium and containing standard bacterial inoculum.  The test compounds were introduced into the cups and the diameters of the zones of inhibition were measured.¹¹

 

The organisms were sub-cultured using nutrient agar medium.  The tubes containing sterilized medium were inoculated with respective bacterial strain.  After incubation at 37 ± 1°C for 24 hr. they were stored in a refrigerator.  Thus stock cultures were maintained.  Bacterial inoculum was prepared by transferring a loopfull of stock culture to nutrient broth (100ml) in a clean and sterilized conical flask (250 ml).  The flasks were incubated at 37 ± 1°C for 18 hr. before the experimentation.

 

Solutions of the test compounds were prepared by dissolving 5 mg and 10 mg of each in dimethylformamide (10ml AR).  Reference standards for gram-positive and gram-negative bacteria were made by dissolving accurately weighed quantity of Procaine Penicillin and Streptomycin, respectively in dimethylformamide solution, separately.

 

The nutrient agar medium was sterilized by autoclaving at 121°C (15 lb/sq. inch).  The petri-plates, tubes and flasks plugged with cotton were sterilized in hot air-oven at 160°C, for an hour.  Into each sterilized petri-plate (10cm diameter), about 30 ml each of molten nutrient bacteria (6 ml of inoculum to 300 ml of nutrient agar medium) was transferred, aseptically. The plates were left at room temperature to allow the solidification.  In each plate, four cups of 6 mm diameter were made with a sterile borer.  Then, 0.1 ml of the test solution was added to the cups, aseptically and labeled, accordingly.  The plates were kept undisturbed for at least 2 h at room temperature to allow diffusion of the solution properly, into nutrient 2 hr. at room temperature to allow diffusion of the solution properly, into nutrient agar medium.  After incubation of the plates at     37 ± 1°C for 24 hr. the diameter of the zone of inhibition surrounding each of the cups was measured with the help of an ‘antibiotic zone reader’. All the experiments were carried out in triplicate. Simultaneously, controls were maintained employing 0.1 ml of dimethylformamide to observe the solvent effects.^12,13

 

The extent diameter of inhibition after 24 hours was measured as the zone of inhibition in millimeters shown in fig no. 1 to 3 and the results were shown in table no. 2.

 

Table no. 3 -Anti-bacterial activity data by Minimum inhibitory concentration method

Sl. No.	Compound code	S.aureus (ATCC 29213) (G+ve)	E.coli (ATCC 25922) (G-ve)	Pseudomonas aeruginosa (MTCC 741) (G-ve)
1	2D-a	200 µg/ml	50 µg/ml	200 µg/ml
2	2D-b	50 µg/ml	100 µg/ml	50 µg/ml
3	2D-c	100 µg/ml	200 µg/ml	100 µg/ml
4	2D-d	100 µg/ml	200 µg/ml	100 µg/ml
5	2D-e	200 µg/ml	400 µg/ml	50 µg/ml
6	2D-f	200 µg/ml	50 µg/ml	200 µg/ml
7	2D-g	50 µg/ml	100 µg/ml	50 µg/ml
8	2D-h	100 µg/ml	200 µg/ml	100 µg/ml
9	2D-i	100 µg/ml	200 µg/ml	100 µg/ml
10	2D-j	200 µg/ml	400 µg/ml	50 µg/ml
11	2D-k	50 µg/ml	100 µg/ml	50 µg/ml
12	2D-l	100 µg/ml	200 µg/ml	100 µg/ml

 

 

Fig.No:- 1 Zone of inhibition of synthesized compounds against E.coli.(ATCC 25922)

 

Fig No.:-2 Zone of inhibition of synthesized compounds against S.aureus.(ATCC 29213)

 

 

Fig. No:-3 Zone of inhibition of synthesized compounds against P.aeruginosa. (MTCC 741)

 

Determination of minimal inhibitory concentration:

The synthesized compounds were dissolved in DMF to prepare a stock solution of 1 mg/ml conc. with this stock solution different dilutions 800 ng to 5 µg/ml were prepared. The ciprofloxacin was also prepared in DMF to obtain a conc. of 800 ng/ml to 5 µg/ml.  The sterile test tube containing 1 ml of sterile media were added with 1 ml of different serially diluted test samples. To these tubes 0.1 ml of normal saline solution suspended with respective microorganisms were inoculated and incubated at 37 ± 2⁰C for 18 to 24 hrs.¹³The growth in the tubes were observed visually for turbidity and inhibition was determined by lowest concentrations of sample that prevented the development of turbidity. The procedure was repeated to confirm the MIC.

 

The antibacterial screening results for the determination of MIC are given in the Table No. 3.

 

Antifungal activity:

All those compounds screened for antibacterial activity were also tested for their antifungal activity. The fungi employed for screening were: Asperigillus niger and Candida albicans (ATCC 9025) The test organisms were sub-cultured using potato dextrose agar medium.  The tubes containing sterilized medium were inoculated with test fungi and after incubation at 25⁰C for 48 hr. they were stored 4°C in a refrigerator.

 

The inoculum was prepared by taking a loopful of stock culture to about 100 ml of nutrient broth; in 250 ml clean ad sterilized conical flasks. The flasks were incubated at 25⁰C for 24 hr. before use. The solutions of test substances were prepared by a similar procedure described under the antibacterial activity.  A reference standard (0.5 mg and 1 mg/ml conc.) were prepared by dissolving 5 mg and 10 mg of Ketoconazole in 10ml of dimethylformamide to obtain a solutions of 50 µg/ml and 100 µg/ml concentration.^14,15

 

The potato-dextrose-agar medium was sterilized by autoclaving at 121⁰C (15 lb/sq. inch), for 15 minutes.  The petri-plates, tubes and flasks plugged with cotton plugs were sterilized in hot air-oven at 150⁰C, for an hour.  Into each sterilized petri-plate (10 cm diameter), about 30 ml each of molten potato dextrose-agar medium inoculated with respective fungus (6 ml of inoculum to 300 ml of potato-dextrose-agar medium) was transferred, aseptically.  After solidification of the medium at room temperature four cups of 6mm diameter were made in each plate with a sterile borer.^18,19

 

Accurately 0.1 ml (100 µg/ml conc.) of test solution was transferred to the cups, aseptically and labeled, accordingly. The reference standard 0.1 ml (50µg/ml conc., 100 µg/ml  conc.) were also added to the cups in each plate.  The plates were kept undisturbed for at least two hours at room temperature to allow diffusion of the solution properly, into potato-dextrose-agar medium.^16,17,18,20 Then the plates were incubated at 25⁰C for 48 hr.  The diameter of the zone of inhibition was read with help of an ‘antibiotic zone reader’.  The experiments were performed in triplicate in order to minimize the errors.

 

The antifungal screening results are given in the Table No. 4. And the zone of inhibition in millimeters has shown in fig no .4 to 5.

 

Table NO: -4 Zone of inhibition synthesized compounds [2D-a to 2D-l].

Sr.No	Compound	Zone   of   inhibition diameter in (mm)
		C.albicans (ATCC 9025)	A.niger
1	2D-a	24	22
2	2D-b	20	28
3	2D-c	28	38
4	2D-d	32	36
5	2D-e	24	30
6	2D-f	25	32
7	2D-g	20	26
8	2D-h	22	28
9	2D-i	12	18
10	2D-j	24	29
11	2D-k	-	-
12	2D-l	-	-
	S	33	44
	C	-	-

Note: - 0-15 mm poor activity, 15-25 mm moderate activity, above 25 good activity.

Standard(S) = Ketoconazole Control (C) = DMF

 

Fig No. 4 Zone of inhibition of synthesized compounds against fungi A.niger.

 

Fig No. 5 Zone of inhibition of synthesized compounds against fungi C.albicans (ATCC 9025)

 

Characterization of synthesized compound:

2D-a= N'-benzylidene-1H-indole-5-carbohydrazide, IR (KBr) 1663 (Ar-CH),3296-3416(NHstr.), 2925(C-H) 1262(C-N). 1H NMR ( DMSOd6) 2.4 (2H, R-NH₂), 7.1 to 8.3H, (Ar-H)10.5(1H, -CHO).m/z1752D-b= N'-(4-bromobenzylidene)-1H-indole-5-carbohydrazide, IR(KBr) 1688 (Ar-CH), 3345(NHstr.), 2924 (C-H) 1256 (C-N), 583 (C-Brstr.)  1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO)4.5(2H, -CH=CH-), 7.1 to 8.3H, (Ar-H)10.5 (1H, -CHO).m/z263. 2D-c = N'-[4-(dimethylamino)benzylidene]-1H-indole-5-carbohydrazide.,IR(KBr) 1266(Ter.Amine C-N)1689 (Ar-CH), 3345 (NHstr.), 2924 (C-H) 1256 (C-N), 1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO) 4.5(2H, -CH=CH-)3.1 to 3.6(6H, N-R₂ ), 7.1 to 8.3H, (Ar-H)10.5 (1H, -CHO).m/z 343. 2D-d = N'-(4-hydroxybenzylidene)-1H-indole-5-carbohydrazide, IR(KBr) 3366(O-Hstr)1689 (Ar-CH), 2960 (C-H) 1286 (C-N), 1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO) 4.5(2H, -CH=CH-)3.1 to 3.6(6H, N-R₂ ), 7.1 to 8.3H, (Ar-H)10.5 (1H, -CHO).m/z243. 2D-e =N'-(4-methoxybenzylidene)-1H-indole-5-carbohydrazide., IR(KBr) 3366 (O-Hstr)1689 (Ar-CH), 2960 (C-H) 1286 (C-N), 1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO) 4.5(2H, -CH=CH-)3.1 to 3.6(6H, N-R₂ ), 7.1 to 8.3H, (Ar-H)10.5 (1H, -CHO).m/z 343. 2D-f = N'-(4-methoxybenzylidene)-1H-indole-5-carbohydrazide, IR(KBr) 3366 (O-Hstr)1689 (Ar-CH), 2965 (C-H) 1186 (C-N), 1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO) 4.5(2H, -CH=CH-) 3.6(6H, N-R₂ ), 7.1 to 8.3H, (Ar-H)10.5 (1H, -CHO).m/z 234. 2D-g = N'-(1,3-benzodioxol-5-ylmethylidene)-1H-indole-5-carbohydrazide, IR(KBr) 3366 (O-Hstr)1689 (Ar-CH), 2965 (C-H) 1186 (C-N), 1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO), 3.6(6H, N-R₂ ), 7.1 to 8.3H, (Ar-H)10.5 (1H, -CHO).m/z534. 2D-h = N'-(2,3-dichlorobenzylidene)-1H-indole-5-carbohydrazide., IR(KBr) 3366 (O-Hstr)1689 (Ar-CH), 2965 (C-H) 1123 (C-N), 1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO) 4.5(2H, -CH=CH-) 3.6(6H, N-R₂ ), 7.1 to 8.3H, (Ar-H)10.5 (1H, -CHO).m/z 254. 2D-i= N'-(4-nitrobenzylidene)-1H-indole-5-carbohydrazide., IR(KBr) 3366 (O-Hstr)1689 (Ar-CH), 2965 (C-H) 1186 (C-N), 1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO) 4.5(2H, -CH=CH- 3.6(6H, N-R₂ ), 7.1 to 8.3H, (Ar-H)10.5 (1H, -CHO).m/z434. 2D-j= N'-(2-nitrobenzylidene)-1H-indole-5-carbohydrazide, IR(KBr) 3366 (O-Hstr)1689 (Ar-CH), 2930 (C-H) 1186 (C-N), 1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO) 4.5(2H, -CH=CH-) 3.6(6H, N-R₂ ), 8.3H, (Ar-H)10.5 (1H, -CHO).m/z334. 2D-k= N'-(4-chlorobenzylidene)-1H-indole-5-carbohydrazide, IR(KBr) 3366 (O-Hstr)1689 (Ar-CH), 2965 (C-H) 1186 (C-N), 1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO) 4.5(2H, -CH=CH-) 3.6(6H, N-R₂ ), 7.1 t3H, (Ar-H)10.5 (1H, -CHO). m/z134.

2D-l= N'-[(2E)-3-phenylprop-2-en-1-ylidene]-1H-indole-5-carbohydrazide., IR(KBr) 3366 (O-Hstr)1689 (Ar-CH), 2965 (C-H) 1186 (C-N), 1H NMR ( DMSO d6) 1.1, 2.5(1H, CH-CO) 4.5(2H, -CH=CH-) 3.6(6H, N-R₂ ), 7.1 to 8.3H, (Ar-H)10.5 (1H, -CHO).m/z224.

 

RESULT AND DISCUSSION:

Various Schiff’s Base derivatives 2D-a–l were prepared using different aromatic aldehyde and ethanol which gaveN'-benzylidene-1H-indole-5-carbohydrazide derivative 2D-a-l. (Scheme 1).The synthesis followed is outlined in scheme. The derivatives synthesized and subjected it for its antimicrobial evaluation. The antimicrobial screening followed according to the literature survey and it mentioned in Table no.2, 3 and 4. The synthesized derivative compounds of 1H-indole-5-carbohydrazide were assayed in vitro for their antibacterial activity shown in Table no.2 and 3.

 

CONCLUSION:

The obtained results revealed that the nature of substituent and substitution pattern on the benzene ring may have a considerable impact on the antibacterial and antifungal activities of the synthesized compounds have particular importance, a nitro group hasa considerable impact on antibacterial and antifungal activity. The compounds 2D-b, 2D-c, 2D-d, 2D-e, exhibited Good activity against S. aureus (ATCC 29213), P. aeruginosa (MTCC 741)and E. coli (ATCC 25922)and 2D-c, 2D-d, 2d-f exhibited Good activity against A. niger, C. albicans (ATCC 9025)and other  have shown moderate activity against S. aureus (ATCC 29213), E. coli (ATCC 25922), P. aeruginosa(MTCC 741), A. niger, C.albicans (ATCC 9025).

 

For minimum inhibitory concentration (MIC) method 2D-a, 2D-b, 2D-i, 2d-j were found moderately active while, 2D-c, 2D-d, 2D-e, 2D-h, and 2D-f were found to have an average activity compared with standard. Test compounds were found to be more sensitive towards S. aureus (ATCC 29213) and Escherichia coli (ATCC 25922) and 2D-a, 2D-e and 2D-g was found moderately active, while 2D-c, 2D-d,2D-f_, 2D-h, and 2D-j, were found to have an average activity compared with standard. Test compounds were found to be more sensitive towards Aspergillus niger and Candida  albicans (ATCC 9025).

 

ACKNOWLEDGEMENT:

We are also thankful to the Principal Prof Dr. N. V. Kalyane and Management of B.L.D.E.A college of Pharmacy, Bijapur for providing the necessary facilities to carry out this work.

 

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Received on 14.05.2012        Modified on 18.06.2012

Accepted on 20.06.2012        © AJRC All right reserved