Review Article Thai Journal of Pharmaceutical Sciences

Recent advancements on biological

activity of indole and their
derivatives: A review
Punet Kumar1 , Md Iftekhar Ahmad2 , Sangam Singh3 ,
Mohammad Rizki Fadhil Pratama4 , Arun K. Mishra1
1
Department of Pharmaceutical Chemistry, SPS, IFTM University, Moradabad, Uttar Pradesh,
India, 2Department of Pharmaceutics, Shri Gopichand College of Pharmacy, Baghpat,
Uttar Pradesh, India, 3Department of Pharmaceutical Chemistry, Oxford College
of Pharmacy, Hapur, Uttar Pradesh, India, 4Department of Pharmacy, Universitas
Muhammadiyah Palangkaraya, Palangka Raya, Central Kalimantan, Indonesia

Corresponding Author:
Punet Kumar, Department ABSTRACT
of Pharmaceutical
Chemistry, SPS, IFTM Indole, a versatile outstanding heterocyclic compound, engaged in numerous pharmacological
University, Moradabad, properties due to their multiple biochemical processes. The remarkable indole moiety resembles
Uttar Pradesh, India with numerous protein structures. The fascinating molecular framework of indole makes its
E-mail: punetkumar987@ suitable for drug development. Indole derivatives mimic the peptides structure and bind reversibly
[Link] to several enzymes, which contribute enormous opportunities to develop novel drugs with distinct
mechanism of action. The presence of nitrogen-based heterocycles in several compounds has
Received: January 27, 2021 been investigated enormously as the core structures comprise several biologically appropriate
Accepted: April 14, 2021
molecules found active in different diseases. The investigations conducted worldwide have
Published: May 27, 2022
shown outstanding impact for scientists, working on indole derivatives to formulate commercially
approved indole derivatives. Numerous drug molecules having indole moiety are under
investigation to control disease. The explicit characteristics with the rationale and foundation of
the research topic are to establish and assist the formulator. In this review, we summarized various
studies reported on anticancer, antifungal, antiplatelet, antidiabetics, antimalarial, antimicrobial,
antidiabetic, antiviral, antifungal, anticonvulsant, antifertility, anti-inflammatory, antidepressant,
antioxidant, antiestrogenic, and antitubercular of past several decades. This review article would
provide a platform for researchers in tactical outline of novel indole derivatives having numerous
encouraging biological activities with decreased toxicity and side effects.

Keywords: Anticancer, Anticonvulsant, Antimicrobial, Antitubercular, Indole derivatives

INTRODUCTION 10 π electrons resonate in a heteroaromatic planar molecule. The

T
delocalization of a lone pair of a nitrogen atom in the π electron
he most remarkable scaffold which arises in several in
system which resonates in an indole ring makes indole a weak
alkaloids, peptides, and various synthetic compounds
base. Consequently, nitrogen’s lone pair of an electron does not
is from those which have indole ring in their nucleus.
undergo protonation but attain protonated at C-3 carbon meta
The heterocyclic property of any phytochemicals nucleus
provides a broad scope in pharmaceutical applications such position. This place allows the withholding of aromaticity and
as pharmacological activity and synthetic chemistry. Indole provides thermodynamic stability. Because of this, indole takes
and its derivatives have been utilized as an absolute platform part in numerous chemical synthesis, that is, cycloaddition,
in heterocyclic chemistry containing a nitrogen atom.[1] Indole carbon lithiation, oxidation, electrophilic substitution, and
having a formula of C8H7N comprised a bicyclic structure organometallic indole anion complexes, etc.[4] The indole exists
containing benzene merged with pyrrole moiety with derivatives as solid at 23–25°C temperature. Indole exists naturally in the
possesses various biological applications in medicinal feces of human beings which gives it a peculiar smell. Although
chemistry.[2] The indole was synthesized by reducing oxindole at lower concentrations, it has a flowery smell and is the main
which has suggested by Adolf Von Baeyer in 1866.[3] In indole, component of flower scents, coal tar, and perfumes. Besides

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 Kumar, et al.: An updated review on indole and its derivatives

this, indole is associated with numerous biological reactions in It encompasses indole synthesis (Fischer indole synthesis,
humans. Indole modulates the physiology of bacteria, which Kanematsu indole synthesis, Mori indole synthesis, Buchwald
is associated with the stability of plasmid, formation of spore, indole synthesis, Madelung indole synthesis, Sundberg indole
virulence, biofilm formation, and drug resistance.[5] synthesis, Van Leusen indole synthesis, Nenitzescu indole
synthesis, and Hemetsberger indole synthesis).[42-50]
Indole is a heteroatomic planar lead molecule. The history
of indole use in the chemical industry goes back to dates to
the mid-19th century on a wide-ranging investigation on indigo THE PHARMACOLOGICAL ACTIVITY
dyes which guides in preparation of indole by zinc distillation INVOLVED WITH INDOLE COMPOUNDS
of oxindole in1866.[6,7] Hence, in this review, we focused on
Due to the wide distribution of indole derivatives in nature,
the various synthetic routes of indole-based scaffold and
it has got acceptability among the organic and medicinal
their pharmacological activity. This moiety is a key bioactive
industries. Numerous drug molecules having indole moiety
molecule which is a vital part of the pharmacological
are under investigation to control disease conditions such as
activity of natural products such as plant growth hormone,
bacterial, malaria, fungal, viral, tubercular, and HIV infections.
5-hydroxytryptamine (serotonin), vincristine, vinblastine,
indole-3-acetic acid (IAA) (antibacterial), and indole alkaloids
such as tryptophan (essential amino acid), reserpine,
Antimicrobial Activity
alstonine, and ergotamine. Melatonin is generally used as The rapid development of drug resistance has emerged as a
the neurotransmitter, antipsychotic, migraine, hypertension, serious challenge since the entry of the first agent into the
cancer chemotherapy, and lowering blood pressure.[3,8-12] clinical market in the 1940s. To avoid microbial resistance,
Indole-3-carbinol along with 3,3-diindolylmethane’s there is a need to preserve the current antimicrobials through
biological assessment is under-investigated because of proper use besides developing new lead molecules. The World
their antioxidant, anticancer as well as anti-atherogenic Health Organization in its latest survey report has confirmed
activity.[13-16] Besides, some of the important pharmaceutical that more than 0.5 million people have developed antibiotics
lead-containing indole rings are roxindole, indalpine, resistance across 22 countries.[51] To control the antibiotics
ondansetron, tadalafil, and fluvastatin, perindopril, reserpine, resistance problem, new indole derivatives with a different
and pindolol introduced by Novartis in an application mechanism of action must be evolved. Nemours derivatives
intended for hypertension management since 1982.[17] of indole are identified and study as an antimicrobial agent.
Heart failure and hypertension are treated by indapamide Sanna et al., 2018, synthesized hybrids of indole-thiourea and
marketed by Servier.[18] The US FDA approved delavirdine treated it on a group of Gram-positive and Gram-negative
and ateviridine against HIV-1.[19] Indomethacin containing microbes. The synthesized compound 1 (minimum inhibitory
the most important promising lead drug molecule for anti- concentration <12.5 μg/ml) has reported higher potency
inflammatory and analgesic effects.[20] Besides this, numerous compared to reference drug ciprofloxacin (minimum inhibitory
marketed indole derivatives such as apaziquone (anticancer), concentration <1.0 μg/ml).[52] Since thiazolidine has been
abridol (anticancer), zafirlukast (antihistaminic), indolmycin reported for its antimicrobial activity, therefore, the scientists
(antibiotic), and strychnine are shown in Table 1.[21-25] tried to combine thiazolidine moiety with other indole derivatives
to form a potent antimicrobial agent.[53] Oxindole thiazolidine
In medicinal science, indole-based therapeutic drugs conjugates were synthesized by Abo-Ashour et al., 2018, and
encompass valuable pharmacological activities such as were treated against C. albicans, S. aureus, E. coli, A. fumigatus,
antimalarial, antimicrobial, antiviral, anti-leishmanial, M. tuberculosis, and P. aeruginosa. The compound 2 (minimum
antifungal, antioxidant, anti- human immunodeficiency virus inhibitory concentration < 0.98 μg/ml) has been reported very
(HIV), and antitubercular.[26-33] Indole is a key structural effective in potency as compared to ciprofloxacin (minimum
molecule that elucidates as an affluent scaffold. Evans inhibitory concentration <3.90 μg/ml) and amphotericin B
et al. suggested and explained scaffolds of indole which are (MIC <1.95 μg/ml), reciprocally.[54] In recent times, many
accomplished by performing as ligand meant for receptors indole derivatives with heterocyclic were synthesized and
diversity.[33-36] Indole and their derivatives exhibit the special
evaluated and examined for antimicrobial properties. The newly
attribute of imitating the structure of proteins and inversely
synthesized compounds containing thiophene and imidazole
binding with enzymes that offer great scope to discover
ring enhanced the antimicrobial properties. The compound
novel drugs with a propagation mode of action. Various
3 (minimum inhibitory concentration < 8 μg/ml) having
drugs available in the market containing indole have been
demonstrated high antibacterial activity whereas compound
reported as the “Best Retail” by the USA.[37-41] In this review,
4 (minimum inhibitory concentration< 6 μg/ml) displayed
we tried to summarize recent advances in the moiety with
higher antifungal activity.[55] Gani et al., 2017, synthesized and
diverse biological and therapeutic functionality in the health-
evaluated 5-hydroxy indole analogs and treated on A. niger, B.
care domain. We outline to gather the details of indole and
cirroflagellosus, and C. albicans for their antimicrobial properties.
their derivatives synthetic form, in vitro, in silico, and in vivo
The compound 5 shows a higher potency (zone inhibition =
evaluation. It had been completely done on diverse indole
28 mm) compared to griseofulvin (zone inhibition = 30 mm).
molecules by collecting the different research articles survey. [56]
Mane et al., 2017, synthesized and evaluated numerous
5-substituted indole-2-carboxamide derivatives treated against
Synthesis of Indole Ring A. fumigatus, C. albicans, C. neoformans, C. parapsilosis,
Various methods have been reported in the literature and E. coli for antioxidant and antimicrobial activity. The
regarding the conventional synthesis of the indole nucleus. compound 6 with MIC<6.25 μg/ml revealed higher microbial

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 Kumar, et al.: An updated review on indole and its derivatives

Table 1: Bioactive molecule containing the indole framework

Name Chemical Structure Indication References
Delavirdine Antiviral [19]

Ateviridine Antiviral [19]

Abridol Antiviral [22]

Indole-3-Acidic acid Antibacterial [29]

Sumatriptan Antimigrain [10]

Serotonin Antipsychotric [11]

Apaziquone Anticancer [21]

Zafirlukast Antihistaminic [23]

Indomethacin Anti-inflammatory [20]

Indolmycin Antibiotic [24]

Pindolol Antihypertensive [17]

(Contd...)

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 Kumar, et al.: An updated review on indole and its derivatives

Table 1: (Continued)
Name Chemical Structure Indication References
Reserpine Antihypertensive [9]

Strychnine Antidot [25]

Indapamide Antihypertensive [18]

Alstonine Antipsychotic [2]

Ergotamine Migraine and [10]

uterine muscle
Contraction

Vincristine Anticancer [2]

Roxindole Schizophrenia [2]

((EMD-49,980)

Indalpine Antidepressant [2]

Ondansetron Anti-nausea and [2]

vomiting

Tadalafil To improve erectile [2]

dysfunction

Fluvastatin Anti-hyperlipidemia [2]

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 Kumar, et al.: An updated review on indole and its derivatives

potency as equated to reference drug gentamicin MIC<3.0 aureus.[72] The indole nucleus-based antimicrobial compound
μg/ml.[57] The pyrazole and imidazole expressed maximum structures (1-17) are mentioned in Figure 1.
antimicrobial properties because of nitrogen atom presence
in their nucleus which functions by restraining DNA synthesis. Antitubercular Activity
[58-60]
The numerous indole-pyrazole by-products synthesized
Abo-Ashour et al., 2018, prepared and investigated numerous
and investigated for antimicrobial activity by Quazi et al.,
oxindole-thiazolidine conjugates treated on bacterial strain
2017. The compound 7 (zone of inhibition< 0.5 cm) showed
(RCMB 010126) of M. tuberculosis. The synthesized compound
higher potency against Gram-positive bacteria.[61] Rajaraman
18 (minimum inhibitory concentration of 0.39 μg/ml) has been
et al., 2017, synthesized and performed molecular docking
found equally potent against reference drug isoniazid, which
studies of numerous indole derivatives for antimicrobial
has shown its minimum inhibitory concentration at 0.78 μg/
activity. The compound 8 (minimum inhibitory concentration
ml.[54] Trott et al., 2010, prepared and investigated numerous
< 12.5 μg/ml) showed considerable stability bond parameter
indole derivatives and treated on bacterial strain (MTCC
reactivity due to the existence of negative charges on nitrogen
300), which was further subjected to docking study using
and oxygen atom as compared to standard drug methicillin
AutoDock Vina software (Los Angeles, USA). The compound
(minimum inhibitory concentration < 6.25 μg/ml).[62] Yadav et
19 has shown MIC of 40 μg/ml, which is equivalently effective
al., 2016, synthesized and evaluated 1,2,3,5-substituted indole
equated to reference drug isoniazid (MIC = 10 μg/ml). The
derivatives for antimicrobial activity and treated against E.
compound 19 has shown good binding interaction with target
coli, P. aeruginosa, S. aureus, and S. pyogenes. The compound
protein.[73,74] Based on reported literature, piperazine is also good
9 (minimum inhibitory concentration < 37.5 μg/ml) revealed
antitubercular agents.[75,76] Naidu et al.,2016, synthesized and
higher potency as equated reference drug gentamicin.
investigated numerous indole-piperazine analogs and treated
[63]
In another study, bis-indole derivatives were prepared
on Mycobacterium tuberculosis (H37Rv). The compound 20 has
and treated on E. coli, P. aeruginosa, and K. pneumoniae
shown the MIC of 6.16 μM which is an appropriately robust
by Choppara et al. in 2015. The compound 10 (zone of
antitubercular agent equated to reference drug isonicotinic
inhibition <24 mm) showed higher potency as equated to
acid hydrazide (MIC= 91.14 μM).[77] In another study, the
reference drug ciprofloxacin (zone of inhibition <27 mm).[64]
numerous indole-carboxamide derivatives were synthesized
Gali and their colleagues, 2015, synthesized and investigated
by Stec et al., 2016. The compound was investigated by
the thiazolyl coumarins substituted indole derivatives and
targeting at MmpL3 protein and investigated for antitubercular
treated on E. coli and B. subtilis. The compound 11 (zone of
activity through in vitro and in vivo study. The compound 21
inhibition < 18 mm) initiates higher potency as equated to
(MIC= 0.012 μM) has shown tremendous potency against
reference drug streptomycin (zone of inhibition < 30 mm).[65]
multidrug-resistant and extensively drug-resistant strains of M.
Hydrazone derivatives are widely present in several biological
tuberculosis.[34] The indole-based 1,3,4-oxadiazole derivatives
moieties and display innumerable pharmacological actions like
and pyridine have been reported for antitubercular activity.
anticonvulsant, antiviral, antibacterial, anti-tubercular, and
The evaluation of antitubercular activity on microbial strain M.
anticancer action.[66,67] Shirizadeeh et al., 2011, synthesized
tuberculosis (H37, Ra, and M. bovis) was performed by in vitro
and investigated many indole-hydrazone derivatives to combat
studies. The compound 22 (MIC= 0.094 to 5.17 μg/ml)
multidrug-resistant bacteria problems. The compound 12 (MIC
acknowledged for better activity as equated to reference drug
< 25 μg/ml) showed higher potent as compared to reference
isoniazid (MIC ranging 0.037 μg/ml) and rifampicin (MIC
drug fluconazole (MIC < 0.78 μg/ml) and ciprofloxacin
ranging 0.017 μg/ml). The compound 23 revealed higher
(MIC < 0.19 μg/ml).[68] Nassar et al., 2010, synthesized
potency.[78,79] Novel 3-alkylated indole derivatives were
and evaluated pyridine, pyrimidine, and pyrazoline indole-
synthesized by utilizing CuO (heterogeneous catalyst) by
substituted derivatives for antibacterial activity against A. niger,
Khan et al., 2016. The compound 24 having MIC of 15 μg/
C. albicans, E. coli, P. aeruginosa, and S. aureus. Compound 13
ml revealed remarkable antitubercular activity on bacterial
(zone of inhibition < 34 mm) exhibits higher antimicrobial
strain (MTCC 300) as compared to reference drug isoniazid
potency as compared to ciprofloxacin (zone of inhibition
(MIC = 10 μg/ml).[80] Ustundag and his colleagues, 2016,
< 44 mm) and nystatin (zone of inhibition < 44 mm).[69]
prepared and investigated indole-based hydrazide-hydrazone,
A new series of indole derivatives (bisindolyl-substituted 4-thiazplidinones treated against tubercular strain (H37 Rv). The
cycloalkane indoles) synthesized and evaluated against MRSA compound 25 (minimum inhibitory concentration ranging from
(methicillin resistance S. aureus) and S. aureus for antibacterial 6.25 to 25 μg/ml) showed remarkable antitubercular activity
activity by El-Sayed and colleagues, 2015. The new active as equated to reference drug rifampicin (minimum inhibitory
derivative 14 was containing cyclohexane indole moiety when concentration of 25 μg/ml).[81] Numerous Schiff base indole
evaluated against S. aureus and MRSA (methicillin resistance derivatives synthesized and investigated using a microtiter plate
S. aureus).[70] Choppara, et al., 2019, synthesized two classes on Gram-positive and Gram-negative bacterial stain by Tehrania
of new analogs indole and selected for their antimicrobial and et al., 2014. The compound 26 having MIC of 3.91 μg/ml shown
antitumor activities. The synthesized compound 15 has shown higher potency as equated to reference drug ethambutol (MIC
higher potency.[71] The numerous indole derivatives were of 0.75 μg/ml).[82] The indole derivatives based antitubercular
prepared and evaluated for antibacterial activity by Shi et al., active compound structure (18-26) are mentioned in Figure 2.
2015. Ultrasound irradiation was used to synthesize thirteen
novel indole derivatives by using 2-mercapto-5-substituted-
Antimalarial Activity
1,3,4-oxadiazoles and 4-amino-5-(1H-indol-3-yl)-4H-[1,2,4]
trizole-3thiol out of which two compounds 16 and 17 exhibited Yadav et al., 2016, designed and investigated numerous indole
exceptional anti-microbial activity against E. coli and S. derivatives and treated P. falciparum for antimalarial activity. The

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 Kumar, et al.: An updated review on indole and its derivatives

Figure 1: Antimicrobial activity of indole derivatives

compound 27 exhibited higher potency with MIC restricted to 12.30±4.21 μM, consequently.[83] Numerous melatonin-based
0.70 μg/ml as compared to reference drug quinine (minimum indole derivatives were prepared and evaluated by Singh et al.
inhibitory concentration of 0.270 μg/ml) and chloroquine (2014) which has an inhibitory effect on P. falciparum cell
(minimum inhibitory concentration of 0.02 μg/ml).[63] cycle. The compound 29 revealed higher antimalarial activity
Schuck et al., 2014, designed and investigated 1H-indole and (IC50= 2.93 μM).[84] The different quinoline-indole conjugates
melatonin derivatives treated against P. falciparum which were prepared by Teguh and colleagues, 2013, and investigated
revealed antimalarial activity. The synthesized compound for antimalarial activity by treating against bacterial strain
28 has shown maximum potency (EC50 ~ 3 μM, cLogP = K1 of P. falciparum. The compound 30 has shown increasing
2.42 and MW = 305) for malaria parasites without showing antimalarial activity (IC50 <0.4±0.2 μg/ml).[85] Numerous
any resistance compared to reference drug-like chloroquine, meridianin G-based indole derivatives were prepared and
artesunate, atovaquone, and amodiaquine with EC50 evaluated by Bharate et al., 2013, treated against chloroquine-
values of 285±58 μM, 1.97±0.43 μM, 0.35±0.14 μM, and sensitive P. falciparum by plasmodial. The synthesized

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 Kumar, et al.: An updated review on indole and its derivatives

18
19 20

22
21 23

24 25 26
Figure 2: Antitubercular activity of indole derivatives

compound 31 (IC50 <4.01μM) has revealed higher efficacy as (CC50 = 39 μM) has revealed higher potency as compared
compared to reference drug chloroquine (IC50 <0.72 μM) and to reference drug briuvudine (CC50 = 160 μM) and acyclovir
artemisinin (IC50 <0.09 μM).[86] Santos and colleagues, 2015, (CC50 = 191 μM).[90] In 2009, Giampieri et al. form indole-
prepared 3-piperidin-4-yl-1H-indole containing treated against naphthyl derivatives by fusing indole with naphthalene
bacterial strain P. falciparum for antiparasitic activity. The new nucleus. Further, all prepared indole derivatives were
synthesized compound 32 has shown prospective antiparasitic treated on a variety of viruses like yellow fever virus (YFV),
activity.[87] Schuck and colleagues, 2014, synthesized and coxsackievirus B-2 strain (CVB-2), bovine viral diarrhea
reported a new series of melatonin analogs that were treated virus (BVDV), and HIV-1. The synthesized compound 37
against bacterial strain P. falciparum culture. Although the (CC50 => 57 μM, SI=<5) has relatively effective as equated
analog of melatonin, derivative compound 33 was found to to reference drug acyclovir, mycophenolic acid, and ribavirin
be active against P. falciparum and inhibits its development.[83] (CC50 => 100 μM, SI=<50).[30] Sanna and his colleagues,
The indole derivatives based antimalarial active compound 2018, synthesized and novel-indole thiourea hybrids
structures[26-32] are mentioned in Figure 3. derivatives investigated on HIV-1. The prepared compound 38
(EC50 = 8.7 ± 0.4 μM) has revealed higher potency against
Antiviral Activity standard drug efavirenz (EC50 = 0.002 ± 0.0002 μM).[82] A
A new class of novel indole-3-carboxylate analogs was further study conducted by Dussan et al., 2016, designed and
synthesized and investigated against the chikungunya investigated numerous indole derivatives against HIV activity.
virus by the CPE reduction method. The compound 34 The compound 39 (EC50 < 0.011 μM) has been reported as
(EC50 =65±1) shown higher potency as equated to highly potent anti-HIV activity.[27] Ravichandran et al., 2016,
reference drug arbidol.[88] Chen et al., 2017, synthesized and synthesized and investigated numerous indole-7-carboxamide
investigated on integrated indoles and spiroindolines. The derivatives for anti-HIV activity. The compound 40 has revealed
prepared compounds were, furthermore, investigated by in higher potency.[91] Numerous indole-pyrido derivatives were
vitro and in vivo method tobacco mosaic virus. The compound synthesized and investigated for anti-HIV activity. Ashok and
35 (% inhibition of 56±2% has shown higher potency as his colleagues, 2015, indole-pyrido derivatives, molecular
equated to reference drug ribavirin (% inhibition of 36±1%) properties were also studied to monitor HIV-infected cells.
and harmine (% inhibition of 45±1%) at the concentration of The synthesized compound 41 (EC50=0.53 μM) has revealed
500 μg/ml.[89] Musella et al., 2016, designed and synthesized higher potency equated to reference drug zidovudine
amide substituted indole derivatives and treated on the human with EC50=0.002 μM.[92] Jiang and colleagues, 2014, have
alphaherpesvirus-3 (HHV-3). The synthesized compound 36 synthesized trifluoromethyl-indole analogs which have

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 Kumar, et al.: An updated review on indole and its derivatives

Hepatitis C Virus Activity

Zhang et al., 2005, reported and prepared a new series
of indole derivatives (2-(4-sulfonamidophenyl)-indole
3-carboxamides) and evaluated on the HCV genotype 1b
27 28 29 replicon. The synthesized compound 51 exhibits good potency
[Figures 5 and 6].[102] The indole derivatives based hepatitis
C virus active compound structure is mentioned in Figure 5.

Anti-leishmanial Agents
Porwal et al., 2017, designed, synthesized gem-dithioacetylated
30 31 32
indole analogs, and investigated against Leishmania Donovan.
The compound 52 (% inhibition of 96–99%) revealed higher
potency.[103] In 2016, Felix and colleagues designed and
investigated thiophene-indole hybrids and treated them on
33 L. donovani. The prepared compound 53 (IC50=3.2 μg/mL,
Figure 3: Antimalarial activity of indole derivatives SI>124.6) has shown good potency as equated to reference
drug amphotericin B (IC50=0.2 μg/mL, SI>124.5).[104] Sharma
and colleagues, 2014, synthesized and investigated triazine
shown better drug resistance against anti-HIV-1 NNRTIs. The indole-quinoline hybrid derivatives and treated them against
compound 42 (EC50<133.33 μM) has shown better potency L. donovani. The compound 54 (IC50=0.36μM) has revealed
as compared to reference drug nevirapine with EC50=0.4 higher potency as equated to reference drug miltefosine
μM and efavirenz with EC50=0.08 μM.[93] Ferro et al., 2014, (IC50=8.10 μM).[105]
developed and investigated the indole derivatives for HIV-1 Bharate and colleagues, 2013, synthesized and
integrase through a docking study. The compound 43 (IC50 evaluated 3.3-diindolylmethane for anti-leishmanial
= 0.4 mM) has shown maximum potency.[94] Hassam and activity on L. donovani. The synthesized compounds 55
colleagues, 2012, synthesized and investigated cyclopropyl (IC50<7.17 μM) and 56 (IC50<8.37 μM) have shown higher
indole analog for HIV-1 activity. The compounds 44 (IC50= potency as equated to reference drug amphotericin B (IC50<
0.065 μM) and 45 (IC50= 0.069 μM) have revealed higher 0.17 μM) and pentamidine (IC50<8.39 μM).[106] Singh et al.,
potency as compared to reference drug nevirapine (IC50= 2012, synthesized and investigated azetidine-indole analogs
0.087 μM).[95] Balupuri and colleagues, 2014, prepared and and screened for L. promastigotes. The compound 57 (056
investigated 1H-indole-piperazine derivatives and screened ± 0.06 μg/mL) has revealed higher potency as equated to
it through numerous molecular computational techniques reference drug amphotericin B (056 ± 0.001 μg/mL).[107] The
(molecular dynamics, combined docking, and 3D-QSAR) indole derivatives based anti-leishmanial active compound
study. The compound 45 ((IC50n= 0.005 nM) has revealed structures[51-56] are mentioned in Figure 6.
higher potency and shown a better binding affinity to the HIV
cells receptor.[96] Yeung et al., 2013, synthesized the indole-7- Antifungal Activity
carboxamide derivatives and investigated by cell-based assay
against pseudotype virus. The compound 46 found to be very In recent times, indole derivatives have an achieved
potent (EC50 +0.29 nM).[97] Indole-2-carboxamide derivatives acknowledgment due to their exceptional role as an antifungal
were synthesized, investigated, and treated against HIV-1 agent. Kumar et al., 2020, synthesized and investigated
Strain (G190A, IRLL98, K101Q, K103N, Y181C, and Y188L) 1H-Indole derivatives on fungi, Aspergillus niger, and Candida
by Regina et al., 2012. The compound 47 with EC50 = 2.0 albicans. The compound 58 (zone of inhibition 16±2 mM)
±0.2 nM has shown higher potency as compared to reference has revealed better potency as compared to reference drug
drug efavirenz with EC50 = 6.3 ±3.2 nM and zidovudine with ampicillin (zone of inhibition 25±2 mM).[108] In 2015, Zhang
EC50 = 2.0 ±0.2 nM.[98] Regina and colleagues, 2011, prepared and colleagues prepared and investigated the antifungal
activity of streptochlorin analogs. The compound 59 has
and investigated indole-2-carboxamide derivatives and treated
shown remarkable potency of 81–100% in controlling the
against HIV-1 strain (L100I and K103NRT).
disease.[109] Jia et al., 2018, performed an investigation on
The compound 48 with EC50 = 1.3 ±0.0 nM has streptochlorin. The investigation of analogs was performed
revealed higher potency as compared to reference drug on Pythium dissimile, Alternaria solani, Gibberella zeae,
nevirapine with EC50 = 19.2 ±0.2 nM) and efavirenz with Botrytis cinerea, Rhizoctonia solani, Alternaria blotch, and
EC50 = 21.5 ±0.3 nM.[99] Further study in the same year Collecteri chumcapsica. The compound 60 was established
Tichy et al. designed and investigated indole-2-carboxylate highly potent.[110,111] Mishra et al., 2018, conducted a study to
derivatives for anti-HIV activity. The compound 49 exhibited improve the antifungal activity of the indole triazole-amino
good anti-HIV activity.[100] Xue et al., 2014, synthesized and acid conjugates. The prepared compound 61 has shown
investigated indole-2-carboxylate derivatives for antiviral better activity equated to reference drugs.[112] Sandmeyer
potencies. The compound 50 exhibiting a good potency for reaction in the presence of tert-butyl nitrite was used to
antiviral effect.[101] The indole derivatives based antiviral active prepare a new class of indole [1,2-c]-1,2,4-benzotriazine
compound structures (34-50) are mentioned in Figure 4. analog. A commercial fungicide, hymexazol, and two

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 Kumar, et al.: An updated review on indole and its derivatives

Figure 4: Antiviral activity of indole derivatives

indoles [1,2-c]-1,2,4-benzotriazines at a concentration of revealed better antifungal activity as compared to reference

50 mg/ml have shown promising and prominent antifungal drug Fluconazole.[115] Pooja et al., 2014, synthesized amino
activity against phytopathogenic fungi. It concluded that the acid appended indole moiety and investigated against Candida
substitution on indolyl moiety of [1,2-c]-1,2,4-benzotriazines albicans. The compound 67 exhibited proficient antifungal
(compound 63) would form a potent antifungal agent.[113] activity.[116] The indole derivatives based antifungal activity
compound structures[57-66] are mentioned in Figure 7.
Based on the principle of combination of new structural
rings, a bespoke and proficient synthetic technique for
three classes of new indole-based 1,3,4-oxadiazoles 64 was Anticancer Activity
explained. Biological assay conducted at Syngenta exhibited Coriglino et al., 2018, synthesized numerous
that more than a few prepared compounds revealed good 2,4-thiazolidinedione indole analogs as an anticancer agent.
potency as compared to standard drug pimprinine, the The synthesized compound was analyzed upon human breast
natural compounds which stimulated this synthesis. Two cancer cells (MCF-7) and PC3 human prostate cancer cells. The
main structural modifications were found to make wider the compound 68 (IC50=5 µM) showed high potency.[117] Ustundag
spectrum of biological activity in most belongings.[114] Song et al., 2016, synthesized and biological investigation of
et al., 2015, synthesized 2-(Indole-3-yl)-thiochroman-4-ones 1H-indole hydrazide-hydrazone, thiazolidinones derivatives .
65 and 6-chloro-2(5-chloro-1H-indole-3-yl)-thiochroman- In compound 70 has revealed the IC50 values of colo-38
4-one by ionic liquid and investigated for antifungal study (IC50<0.83 ± 0.09) and K562 (IC50 < 0.63 ± 0.05 µM).[81]
through in vitro experiment. The compounds 65 and 66 have Demurtas et al., 2019, prepared indole hydrazone derivatives

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 Kumar, et al.: An updated review on indole and its derivatives

and analyzed for erythroleukemia (K562) and melanoma cell prepared and investigate reciprocated heteroannulated indole
lines (Colo-38). In compound 70 (IC50 < 0.63 ± 0.05 µM) derivative for their cervical anticancer activity was performed
has revealed higher potency for anticancer activity.[118] The by Parkash et al., 2018. The electron-withdrawing group
present at the 8th position of carbon showed good association
at the target site because of the hydrogen bonding and Van
der Waal’s interaction, observed in the docking study. The
compound 71 (IC50 = 13.41 µM) and IC50 = 14.67 µM)
revealed exceptional anticancer activity, which is equipotent
to reference drug cisplatin (IC50 = 13.20 µM) activity.
[119]
Tocco et al., 2017, prepared and investigated Bis-Indole
against hepatocarcinoma cell. Compound 72 (IC50 = 20-100
Figure 5: Hepatitis C virus genotype activity of indole derivatives µM) was observed to have better activity than the standard
drug indole 3-carbinol.[120] Romagnoli et al., 2017, prepared
and evaluated several 3-substituted-2-oxindole hybrid
analogs. The prepared compound 73 has shown the highest
potency (IC50< 5500 µM) on human leukemia-60 cells. The
human leukemia-60 cells showed better interaction with
cellular nucleophiles than standard drugs.[121] Lafayette
and colleagues, 2017, prepared and investigated indole
derivatives as encouraging DNA-binding sites for antitumor
and anti-topoisomerase activity. The compound 74 revealed
remarkable antitumor activity on cell lines T47D (IC50 =1.93
µM).[122] Chang et al. (2016), synthesized a series of bis-
(hydroxymethyl) idolizing [8,7-b] indole hybrids compound
of β-carboline and bis(hydroxymethyl)pyrrole to evaluate
antitumor and lung cancer cell investigation.. The compound
75 (IC50 = 0.49 µM) exhibited higher anticancer activity
treated equated to the growth of small cell lung cancer (SCLC)
H526 cells in xenograft against cisplatin (IC50 = 0.63 µM).
[123]
Bakherad and colleagues, 2019, prepared and investigated
numerous thiosemicarbazone indole derivatives on MCF-7
(breast cancer), A-549 (cancer of the lung), and Hep-G2 (liver
cancer) cell lines. The compound 76 has shown the potency
treated on A-549 (IC50 = 12.5 µM) and Hep-G2 (IC50 = 56±
Figure 6: Anti-leishmanial activity of indole derivatives 6.30 µM) cell lines equated to reference drug etoposide A-549

Figure 7: Antifungal activity of indole derivatives

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 Kumar, et al.: An updated review on indole and its derivatives

Figure 8: Anticancer activity of indole derivatives

(IC50 = 38.23 ± 1.89 µM) and Hep-G2 (IC50 = 33.17 ± 3.19

µM), and colchicine A-549 (IC50 = 1.9 ± 0.23 µM), Hep-G2
(IC50 = 6± 0.49 µM).[124] Jiang and colleagues (2016) prepared
and investigated numerous indole derivatives treated on HeLa,
A-549, and ECA-109 cell lines. The compound 77a (IC50
< 16.65 µM) and (77b) (IC50 <14.74 µM) has revealed
higher potency than reference drug cisplatin (IC50 < 30.89
µM).[125]
Kumar et al., 2016, prepared and investigated numerous
rosuvastatin-based indole derivatives for anticancer activities
on against A549 and TZMBL cell lines. Compound 78
(IC50<12 µM) has revealed higher potency in comparison to
reference drug gemcitabine.[126] Hu and colleagues prepared
and investigated numerous new series of 2,5-disubstituted
indole derivatives for their anticancer properties. The Figure 9: Anticonvulsant activity of indole derivatives
compound 79 (IC50 < 8.70 ± 0.11 µg/mL) has revealed higher
potency as compared to reference drug cisplatin (IC50 < 6.10 has revealed higher potency as compared to reference drug
± 0.09 µg/mL).[127] The indole derivatives based anticancer phenytoin (100%).[130] Indole-1,2,4-triazine analogs were
activity compound structures[54,67-77] are mentioned in Figure 8. synthesized, evaluated against maximal electric shock (MES),
and subcutaneous pentylenetetrazole (scPTZ), by Ahuja and
Anticonvulsant Activity Siddiqui. The compound (83) (% protection=100%) revealed
higher potency upon study due to the presence of nitro
Dialkylaminoalkoxy-oxindole analogs were prepared and
groups binding with the receptor.[131] The indole derivatives
investigated by Swathi and Saragapani in 2017. Synthesized
based anticonvulsant activity compound structures[34,78-80] are
compounds were investigated for anticonvulsant activity by
mentioned in Figure 9.
the pentylenetetrazole (PTZ) induced convulsion method and
maximal electroshock seizure (MES). The compound 80 has
shown (IC50 < 67.18 ± 0.23 µg/mL) better anticonvulsant
Antidiabetic Activity
activity compared to the standard drug Phenytoin.[128] Madhira The novel indole-triazole derivatives were prepared and
et al., 2017, prepared and evaluated benzohydrazide-oxindole investigated for antidiabetic properties by Rajan and
derivatives to anticonvulsant activity. The compound 81 colleagues in 2018. Syrian Golden Hamster model was used
(%protection=83.19%) [Figure 9] showed higher potency for evaluating all the synthesized compounds. The compound
equated to reference drug phenytoin (%protection=100%).[129] 84 [Figure 10] showed maximum potency.[132] Nazir
Raju and colleagues, 2016, prepared and investigated novel and colleagues, 2018, prepared and investigated indole-
indole carboxylate derivative for anticonvulsant activity by the oxadiazole hybrids analogs for inhibiting α-glucosidase
MES method. The compound 82 (108.3 ± 0.7) [Figure 10] activity. The compounds 85 (IC50 = 9.46 ± 0.03 µM)

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 Kumar, et al.: An updated review on indole and its derivatives

[Figure 10] and 86 (IC50 = 9.37 ± 0.03 µM) [Figure 10] analogs. The prepared compound 88 (IC50=2.00 ±
revealed high potency as compared to acarbose (IC50 = 0.001mM) [Figure 10] revealed high potency as compared
37.38 ± 0.12 µM).[133] The diabetes-induced chick model was to reference drug acarbose (IC50=895.09 ± 2.04 mM).[135]
investigated in the in vivo study, for the synthesized indole The indole derivatives based antidiabetic activity compound
derivatives by Srividya and Reddy, 2017. The compound structures (84-88) are mentioned in Figure 10.
87 (29.6-38.6%) [Figure 10] demonstrate very good
antidiabetic activity against standard drug glibenclamide Anti-inflammatory Activity
(57.10%).[134] Taha et al., 2017, combined indole and
oxadiazole to attain a new chain of tris-indole-oxadiazole 1H-indole capsaicin derivatives and nitro-indole derivatives
were synthesized and investigated on the pro-inflammatory
cytokinase TNF-α by Mukhtung et al., 2018. The compound
89a showed a value % relative inhibition of 47.65% and 89b
% relative inhibition of 51.95%) [Figure 11] revealed high
potency in comparison to standard drug capsaicin (relative
% inhibition = 65.55%).[136] Bhat and colleagues, 2018,
prepared and investigated acetohydrazide-indole hybrid
derivatives COX-2 inhibitory activity. The docking study of
compound (90) (potency 0.79%) [Figure 11] revealed potent
selective inhibition as equated to reference drug Indomethacin
(potency = 1.0%).[137] In the same year, Shaker et al.
conducted the prepared and investigated of indole derivatives
containing methyl sulfonyl and aryl-substituted derivative for
COX-2 inhibition activity. The compound 91a (IC50=0.11 µM,
SI=107.63) and (91b) (IC50=0.15 µM, SI=76.6) [Figure 11]
Figure 10: Antidiabetic activity of indole derivatives demonstrates higher potency as equated to reference drug

Figure 11: Anti-inflammatory activity of indole derivatives

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 Kumar, et al.: An updated review on indole and its derivatives

indomethacin (IC50=0.49 µM, SI=0.079).[138] The novel higher potency.[147] Farani et al., 2013, synthesized numerous
indolyl-pyrazoline derivatives were prepared and investigated indole derivatives by investigating in vitro and docking study
to inhibit inflammation using the Carrageenan-induced paw for anticholinergic activity. The compound 101 (IC50=1.1 ±
edema method by Shroff and Daharwal in 2017. The compound 0.25 μM) has revealed high potency against the reference drug
92a (% of inhibition=63.90%) and 92b (% of inhibition = donepezil (IC50=0.41 ± 0.12 μM).[148] The indole derivatives
57.46%) [Figure 11] showed higher potency as compared to based anticholinergic active compound structures (100-101)
reference drug indomethacin (% of inhibition=61.36%).[139] are mentioned in Figure 13b.
Numerous indole derivatives were prepared and investigated
for an anti-inflammatory property using the paw edema Antifertility Agents
method by Fatahala et al. in 2017. The highest potency was
Bhowalet al., 2008, synthesized and evaluated
shown by compound (93) (%inhibition = 92%) [Figure 12]
2-(2’’-chloroacetamidobenzyl)-3-(3’-indolyl) quinoline as a
in comparison to ibuprofen (% of inhibition=69.84%)
contraceptive agent by measuring the level of sexual hormones
and indomethacin (% of inhibition = 78.58%).[140] Xu and
and spermatogenesis. The compound 102 [Figure 14a] has
colleagues, 2019, prepared and investigated indole-2-
demonstrated good potency.[149]
carboxamide derivatives for the identification of potent anti-
inflammatory agents. The compound 94a (% of inhibition
< 2.90 ± 0.73%) and 94b ((% of inhibition < 2.67 ±
0.76%) has revealed better potency.[141] Numerous chromone-
substituted oxindole was synthesized by Shaveta and
colleagues in 2014 and investigated on COX-1, COX-2, and
5-LOX. The compound 95a (IC50 = 9.5 ± 0.8 µg/mL) and
95b (IC50= 10.0 ± 4.2 µg/mL) [Figure 11] has shown higher
potency in comparison to reference drug indomethacin (IC50
= 0.7 ± 0.2 µg/mL).[142] The indole derivatives based anti-
inflammatory activity compound structures (89a-95b) are
mentioned in Figure 11.

Antidepressant Activity
Oxindole derivatives having azetidinone moiety were synthesized
and analyzed by Kerazare et al. in 2018 which further undergone
animal study using a forced swim test. The compound 96a
showed a reduction in immobility to 66.82% and compound 96b
to 65.61% [Figure 12] has revealed high potency as compared to Figure 12: Antidepressant activity of indole derivatives
reference drug fluoxetine reduction in immobility to 70.93%.[143]
The numerous indole derivatives having dihydropyrazole moiety
were synthesized and investigated for antidepressant activity
using a forced swim test by Patil and Bari 2013. The compound
97a (116.3 ± 1.54) and 97b (109.8 ± 2.86) [Figure 12]
demonstrated higher potency as equated to reference drug
fluoxetine reduction in immobility to 77.4% and imipramine to
75.5%.[144] The indole derivatives based antidepressant activity
compound structures (96a-97b) are mentioned in Figure 12.
a
Antioxidant Activity
Melatonin analogs with indole moiety were synthesized and
investigated for antioxidant and protective effects against
damage induced β-amyloid by Orhan et al., 2016. The compound
b
98a (IC50 = 38.3 ± 8.9 µM) and 98b (IC50 = 37.0 ± 2.0 µM) was
Figure 13: (a) Antioxidant activity of indole derivatives and
screened against ROS-induced oxidation and it was found very
(b) anticholinergic activity of indole derivatives
effective against the standard drug melatonin.[145] Silveira et al.,
2013, conducted a study on C-3 sulfenyl indoles for antioxidant
activity. The compound 99 (activity <96.8%) showed higher
potency.[146] The indole derivatives based antioxidant active
compound structures (98a-99) are mentioned in Figure 13a.

Anticholinergic Activity
Parveen et al., 2018, demonstrated that the synthesized indole a b
analogs on molecular docking and in vitro study showed Figure 14: (a) Antifertility activity of indole derivatives and
anticholinergic activity. The compound 100 has revealed (b) antiestrogenic activity of indole derivatives

245  [Link] TJPS 2022, 46 (3): 233-250

 Kumar, et al.: An updated review on indole and its derivatives

Antiestrogenic Activity FINANCIAL SUPPORT

Ji et al., 2005, synthesized and evaluated benzothieno[3,2-b] All authors are declared no financial support or otherwise.
indole derivatives which were effective estrogen receptor
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