A manifold implications of indole and its derivatives: A brief Review

P. K. Das¹, R. Sahu², P. K. Behera², B.K.Garnaik^2*

¹Department of Chemistry, Kendrapara Autonomous College, Kendrapara, Odisha, India

²P. G. Department of Chemistry, Berhampur University, Bhanja Bihar 760007, Odisha, India

 

ABSTRACT:

Indole, a privileged heterocyclic nucleus has diverse biological activities and inspired chemists to utilise this skeleton as bioactive moiety to synthesize new compounds possessing pharmacological and biological properties. The beauty of indole moiety is that it provides a privilege scaffold for the discovery of different kinds of more active, less toxic novel drugs with different modes of action. Now it is found  an abiding interest in the use of indole derivatives against cancer cells, microbes and different kinds of disorder in the  human body. Extensive researches on manifold implication of indole and its derivatives have been going on since long specifically in the field of agrochemicals and pharmaceuticals. The review is intended to give a general overview of the various research activities in this expanding field. Here we have mode of attempt in highlighting the synthetic routes and characteristics of indole and its derivatives along with their recent developments in pharmacological potential values.

 

 

 

1. INTRODUCTION:

Indole finds an important place in chemistry because of its relationship to the natural occurring dye, indigo. Indigo can be converted to isatin, then to oxindole. In 1866, A.V. Bayer reduced oxindole to indole by using zinc dust.^[1]

 

It is an aromatic bicyclic heterocycle consisting of a six membered benzene ring fused to α and β positions of a five membered pyrrole ring. It is known as 1H benzo[b] pyrrole, it being the b face benzo fused isomer.

 

It is a planar molecule with a conjugated system of 10π electrons, two from nitrogen and eight from carbon atoms and is thus a π excessive molecule. In 1930s, interest in indole intensified when it is known that indole nucleus is present in many important alkaloids as well as in tryptophans (essential aminoacid), auxin (plant hormone) and it remains an active area of research today. Although indole motif is very small, it is an attention grabbing molecule and captured the attention of scientists and researchers over the years. It is found that this moiety is an important pharmacophore and serves as precursors in many pharmaceuticals. It has been reported that substitution of different heterocyclic or aromatic nuclei at α or β position of indole nucleus modulates the biological activity of such substituted indole derivatives. Thus indole derivatives occupy a unique place in medicinal chemistry due to their wide range of pharmacological activities such as anti-inflammatory, anti fungal, antimicrobial, antioxidant, antiviral, anti-tubercular, anticancer, anticonvulsant, antihistaminic and antagonistics, etc^[2-11]. Many of the synthesized indole containing commercial drugs are now readily available in the market. while some are in clinical trials. Besides the biological activities it also finds its use in the field of agrochemicals. The discovery of some indole derivatives help to control the phytopathogenic fungi that cause damage to crops. Anyway, the biological profiles of this new generation of indoles represent much progress with regard to the older compounds.

 

2. PROPERTIES OF INDOLE:

2.1- Physical properties

It is a colourless crystalline solid at room temperature. It is soluble in most organic solvents, pure indole has a very pleasant smell & is used as a perfume base while impure one has unpleasant odour.

Chemical formula – C₈H₇N

Molar mass - 117.15 g/mol

Appearance – White solid

Density – 1.1747g/ml

Melting Point – 52-55⁰C

Boiling Point – 253-255⁰C

Solubility in water – 0.19 gm/100ml (25⁰C)

Acidity (P_ka) – 16.2

Basicity (P_kb) – 17.6

Structure - Planner

Odour – Flowery

Dipole Moment – 2.11D in benzene

Related compound – isatin, methyl indole

 

2.2 - Chemical Properties :

The most reactive position on indole for electrophilic aromatic substitution is C – 3, which is 10¹³ times more reactive than benzene. Since the pyrrollic ring is the most reactive portion of indole, electrophillic substitution of the carbocyclic(benzene) ring can take place only after N-1, C-2, & C-3 are substituted. If both C-2 and C-3 positions are blocked then substitution occurs in benzene ring at position 6. Some of the electrophillic substitution reactions of indole are outlined below.

 

3. Synthetic routes of indole and its derivatives:

(A)          Indole and its derivatives can be synthesized by a variety of methods. The main industrial routes start from aniline via vapour phase reaction with ethylene glycol in the presence of catalyst.

 

Fischer – Indole Synthesis

This is the most reliable and widely investigated synthesis of indole, which involves an acid catalyzed rearrangement of phenyl hydrazone of a carbonyl compound with the removal of a molecule of ammonia.

 

Madelung synthesis

This involves the cyclic dehydration of an acyl o-toluidine in the presence of a strong base at a high temperature.

 

Bartoli Indole Synthesis

It involves cyclization of ortho (trimethyl silyl methyl) N - methyl anilides in presence of LDA (Lithium Diiso Propylamide).

 

Nenitzescu Synthesis

It involves the condensation of p- benzoquinone with 3- aminocrotonate in reflux condition with acetone.

 

Bischler Synthesis

 

Reissert Synthesis

It involves a base catalysed condensation of o- nitro toluene with oxalic acid ester. The resulting compound after hydrolysis serves as the starting material. This on reductive cyclization gives indole.

 

Synthesis of Oxindole

 

Synthesis of Dioxindole (Isatin)

The most general method of its synthesis are given bellow,

(a) Aniline and chloral hydrate first form iso-nitroacetanilide in the presence of hydroxyl amine. This subsequently cyclizes in the presence of sulphuric acid to give isatin.

 

(b) O-nitro benzoyl chloride on treatment with AgCN gives Nitro benzoyl cyanide which on hydrolysis and subsequent reduction gives o- amino phenyl oxalic acid. This on acidification gives isatin

 

4. Pharmacological activities of indole derivatives

4.1- Anti- inflammatory activity

 A series of substituted indole derivatives were synthesized by Ashok kumar et al ^[12] (2010) and evaluated for their in vitro anti-inflammatory activity. It was seen that the compound 2-(p-chlorophenyl)-1-{4^I-(4-chlorobenzylidene)amino-5^I-(2-aminothiazol-4-ylthio)-[1^I, 2^I, 4^I]-triazol-3^I-yl-methyl-3-(4^II6^II-dibromo-2^II-carboxyphenyliminomethyl}-5-methoxy indole had exhibited promising anti-inflammatory activity at the three graded dose of 25, 50 and 100 mg/kg.

 

R = Chlorobenzylidene amino

the compound 6-(3-(2-oxopropyl)-1H-indole-2-carbonyl)-2H-benzo[b][1, 4]oxazin-3(4H)-one was synthesized by Dubey et al ^[13](2006). It was found that the compound exhibited significant COX-2 inhibitor characteristics.

 

 

Indol-3-aceticacids were synthesized by Kalaskar et al ^[14](2007) and assessed them for their in vivo anti-inflammatory activity. The compound, 2-(1-benzyl-5-methoxy-2-phenyl-1H-benzo[g]indol-3-yl) acetic acid showed remarkable anti-inflammatory activity.

 

The anti-inflammatory activity of various isatin semicarbazide derivatives were evaluated by Prakash C.R., Raja S, Saravanan G (2012). They found that the compound (E)-N-(1-(4-chlorobenzyl)-2, 3-dioxoindolin-5-yl)-2-(-4(trifluoromethyl)benzylidene) hydrazinecarboxamide containing trifluoro methyl substituent displayed promising anti inflammatory activity. ^[15]

 

A series of novel 1, 3, 4-oxadiazole and 1, 2, 4-triazole moieties substituted in the indole ring at C-3 position was synthesized by Gadegoni H, Manda S (2013) and was evaluated for anti-inflammatory activity. The compound, 3-(3-((1H-indol-3-yl)methyl)-4-amino-5-thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl)propanenitrile was reported with excellent anti-inflammatory activity.^[16]

 

4.2 Anti fungal activity:

A series of 1-aryl-2-methyl-3-carboetoxy-5-hydroxy indole derivatives were synthesized by Mehta D S et al ^[17](2005) and evaluated their anti fungal activity against A.arogens and A.awamori. Some of the synthesized compounds had shown significant anti fungal activity.

 

Synthesis of Schiff bases of isatin and 5-methyl isatin with sulphadoxine was carried out by Pandeya et al ^[18](1998) and these were evaluated for their in vitro anti fungal activity against various fungal strains viz. Candida albicans, candida neoformis etc. It aws found that the piperidino methyl compounds had shown considerable anti fungal activity.

 

→ Some of the indole oximes were synthesized by Abele et al ^[19](2003). Particularly 3-substituted indoles were found to be exhibiting potent fungicidal activity.

 

4.3 Antimicrobial activity:

Some substituted 3-aryl indoles i.e. 3-(2-nitro-4-(trifluoromethyl)phenyl)-1H-indole was synthesized by Hiari et al ^[20](2006). The synthesized compound demonstrated significant anti microbial activity.

 

5-chloro-2-phenyl-1H-indole derivative was synthesized by Kumar Dharmendra et al ^[21] (2010). The compound had shown promising antibacterial activity particularly against P. Aeruginosa and S. Thermonitrificans bacteria

 

Substituted azetidonyl- 1, 3, 4-thiadiazino[6, 5-b] indole was synthesized by Panwar et al ^[22] (2006). The compound was found to exhibit most inhibitory effect against some gram negative bacteria like E. Coli and some gram positive bacteria like S. Aureus.

 

The compound, 2, 3, 4, 9-tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxylic acid was synthesized by Ramninder Kaur et al ^[23] (2013) and they examined its antimicrobial activity. It was found to be exhibiting considerable antimicrobial activity

 

4.4 Antioxidant activity :

A series of indole derivatives were synthesized by Enein et al ^[24] (2004) and were biologically evaluated. They found that indole-2 and indole-3-carboxamide exhibited excellent antioxidant properties and have strongest scavenging effect on hydroxyl radicals.

 

Indole-2-carboxylicacid-aryl amine conjugates that is 1-(2-((2-hydroxyphenyl) amino)acetyl)-1H-indole-2-carboxylic acid synthesized by Nagaraja Naik et al ^[25] (2013) was found to exhibit remarkable anti oxidant properties.

 

4.5 Antiviral activity

Indole oxime carbamoyl derivatives of indole-3-oxime synthesized by Abele et al ^[19] (2003) exhibited the most potent antiviral activity.

 

Ethyl 6-bromo-5-hydroxy-1H- indole-3-carboxylate was synthesized by Wang Dun et al ^[26] (2004) and they examined its in-vitro antiviral activity against human influenza A3 and respiratory syncytial virus respectively MDCK cell culture with virus cytopathic effect assay in comparison with Amantadine and Abidol. The minimum inhibitory concentration (MIC) for the tested compounds against the above two virus were calculated and it was found that the compounds exhibit significant antiviral activity.

 

The Drug, Arbidol i.e. ethyl 6-bromo-4-((dimethylamino)methyl)-5-hydroxy-1-methyl-2-((phenylthio)methyl)-1H-indole-3-carboxylate, synthesized by Leneva et al ^[27](2009) was found to exhibit excellent antiviral property.

 

4.6 Anti-tuberculosis activity :

Oxime derivatives of 2-indolenone, synthesized by Abele et al ^[19] (2003) was found to exhibit a profound anti-tuberculosis activity against M. Tuberculosis.

 

Some indolizine derivative i.e. N-(2-ethylpyridine-4-carbonothioyl)indolizine-1-carboxamide was synthesized by Srikanth Lingala et al ^[28] (2011) and it was evaluated for in-vitro anti-tuberculosis activity against Mycobacterium Tuberculosis. It was found to exhibit significant inhibitory activity with MIC value ≥ 75%.

 

4.7 Anticancer activity :

A series of various tricyclic and tetracyclic indoles were synthesized by Hong et al ^[29] (2006). These were evaluated for their anticancer activity. The compounds I, II, III, IV were found to exhibit remarkable in-vitro activity against human nasopharyngeal carcinoma and gastric adenocarcinoma cell lines.

 

The compound (Z)-1-(2, 6-dichlorobenzyl)-3-(((3-methylbutanoyl)oxy)imino)indolin-2-one synthesized by Abele et al ^[19] (2003) was found to show significant anticancer activity.

 

Halogenated indole-3-acetic acid i.e. 2-(5-chloro-1H-indol-3-yl)acetic acid synthesized by Rossiter et al ^[30] (2002) was reportedly showing potent anticancer activity and it was the suitable drug for targeted cancer therapy.

 

The inhibitory activity of phenyl benzothieno indole on the growth of human tumour cell lines was studied by Queiroz et al ^[31] (2008). The result showed that the compound methyl 3-(dibenzo[b, d]thiophen-3-yl)-1H-indole-2-carboxylate had most potent growth inhibitory activity in all the tumour cell lines(breast adenocarcinoma).

 

4.8 Anticonvulsant activity :

A series of various 3-(1, 3-benzothiazol-2-ylimino) derivatives were synthesized by Sharma Prince P et al ^[32] (2009)and it was found that the compound (Z)-3-(benzo[d]thiazol-2-ylimino)indolin-2-one exhibited significant Anticonvulsant activity.

 

The compound, 2-(((H-indol-3-yl)oxy)methyl)-1, 3, 4-oxadiazole synthesized by Harish Rajak et al ^[33] (2009) was found to exhibit a more potent anticonvulsant activity.

 

4.9 Antihistaminic Activity :

A series of indole amide derivatives having a side chain were prepared and examined for Antihistaminic activity by Battaglia et al ^[34] (1999). The compounds V and VI were found to exhibit better Antihistaminic activity.

 

 V vi                       

 

 

4.10. Antagonistics activity

A 3-substituted indole i.e. N-(2-acetamido-3-(1H-indol-3-yl)propyl-N-(2-methoxy benzyl)acetamide was synthesized by J.E. Fritz et al ^[11] in 2001 and it was found to exhibit most effective antagonistic activity.

 

4.11 Anti-anxiety activity :

The compound 1^I-(2-(4-bromophenyl)-2-oxoethyl)spiro[[1, 3]dioxolane-2, 3^I-indolin]-2^I-one synthesized by Athina Geronikaki et al ^[35] (2004) showed most remarkable Anti-anxiety activity.

 

4.12 Antidiabetic Activity:

Some of the indole derivatives were evaluated for their insulin sensitizing and glucose lowering effects by Li et al ^[36] (2007) The derivative, (5-(benzyloxy)-1H-indol-1-yl)(4-chlorophenyl)methanone showed decreased serum glucose and contributed to Antidiabetic Activity.

 

4.13 Antihypertensive activity :

A series of novel 7-azaindole-3-acetamidoxime and 7-azaindole-1-acetamidoxime were synthesized by Bell MR et al ^[37](1967) and evaluated for hypertensive activity. These compounds had shown significant Antihypertensive properties.

 

5. CONCLUSION:

Indole based Pharmaceutical constitute an weighty class of therapeutic molecules which may replace many currently running Pharmaceutical in near future. Many researches should be carried out to evaluate the therapeutic efficacy of indole derivatives for many other dreadful diseases like AIDS, hepatitis and cancer.

 

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