THERAPEUTIC SIGNIFICANCE OF INDOLE SCAFFOLD IN MEDICINAL CHEMISTRYHTML Full Text
A COMPREHENSIVE REVIEW ON INDOLE NUCLEUS WITH THERAPEUTIC SIGNIFICANCE
Kashif Hussain 1, Md. Jahangir Alam 2, Afzal Hussain 3 and Nadeem Ahmad Siddique * 1
Bioactive Natural Compound 1, Laboratory (BNCL), Department of Pharmacognosy and Phytochemistry, Glocal School of Pharmacy, Glocal University, Saharanpur - 247121, Uttar Pradesh, India.
School of Medical and Allied Sciences 2, KR. Mangalam University, Sohna Road, Gurugram - 122103, Haryana, India.
Department of Pharmaceutics 3, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
ABSTRACT: Discovery of New Chemical Entities (NCEs) is the result of a series of high throughput screening process after the successful design and synthesis scheme. The indole nucleus is an important heterocyclic compound containing nitrogen, and it has been a source of vital therapeutic agents. It is noteworthy in recent advances of synthetic, medicinal chemistry; the last decade has been witnessed with a multitude of reports on several indole derivatives corroborating these chemical entities to be an eminent target for the discovery of new drugs. Global research investigations published has outstanding impact attention for the scientists working on indole derivatives which transformed into various commercially approved indole candidate in the commercial market and there are several in the pipeline. This review highlighted recent achievements of indole lead molecules in biological, chemical, and pharmacological activity having diverse perspectives on how this indole moiety as a privileged structure may be browbeaten for elucidating salubrious biological activities.
Indole, Biological activity, Drug discovery, In-vitro antimicrobial, Molecular derivatives
INTRODUCTION: Indole is a notable privileged lead scaffold that arises in several natural products such as alkaloids, peptides, and various synthetic compounds. Heterocyclic renders chemistry with a broad scope of pharmaceutical applications playing a pivotal part in synthetic chemistry and pharmacological activity. Indole and its derivatives have been employed as an exclusive platform in heterocyclic chemistry containing a nitrogen atom and it is an aromatic heterocyclic organic compound having a formula of C8H7N in which a bicyclic structure comprised of a benzene skeleton is merged with pyrrole moiety with derivatives possess various biological applications in medicinal chemistry 1, 2.
Indole is a hetero-atomic planar lead molecule 3. The chemistry of indole up to dates to the mid 19th century is due to wide-ranging research on a natural violet-blue dye named indigo through leads to the preparation of indole Fig. 1A in 1866 by zinc distillation of oxindole 4, 5, 6. Therefore, in this review, we emphasized the various synthetic route of the indole-based scaffold and their biological activity. This moiety is an important bioactive molecule which is an essential component of pharmacologically active natural products such as plant growth hormone, indole-3-acetic acid (IAA) (antibacterial), indole alkaloids like tryptophan (essential amino acid), reserpine, alstonine, ergo-tamine, vincristine and vinblastine and 5-hydroxy-tryptamine (serotonin), melatonin are generally known as the neurotransmitter, anti-psychotic, migraine, hypertension, cancer chemo-therapy and lowering blood pressure, correspondingly 7-12. Biological evaluation of indole-3-carbinol (I3C) along with 3, 30-di-indolylmethane (DIM), (a natural derivatives consequent commencing the digestion of I3C) are under research because of their anti-cancer, antioxidant as well as anti-atherogenic activity 13, 14, 15, 16. In addition, some of the important pharmaceutical lead-containing indole rings are roxindole, indalpine, ondansetron, tadalafil and fluvastatin, perindopril, reserpine, pindolol introduced by Novartis is an application intended in management of hypertension since 1982 17. Indapamide marketed by Servier, used in the treatment of heart failure and hypertension 18. Delavirdine and ateviridine are approved by the US FDA against HIV-1 19.
Indomethacin containing the most important promising lead drug molecule for anti-inflammatory and analgesic effects.20 Along with this, various other marketed indole derivatives such as apaziquone (anti-cancer), abridol (anti-cancer), zafirlukast (antihistaminic), indoleamine (antibiotic) and strychnine has been shown in Table 1 21-25.
TABLE 1: BIOACTIVE MOLECULE CONTAINING THE INDOLE FRAMEWORK:
FIG. 1: (A) DISCOVERY OF INDOLE, (B) PHARMACOLOGICAL PROFILE OF INDOLE NUCLEUS AND (C) DIFFERENT TYPES OF CONVENTIONAL INDOLE SYNTHESIS
In medical science, indole based therapeutic drugs possess valuable biologic activities such as anti-HIV (Human immunodeficiency virus), anti-microbial, anti-malarial, antiviral, anti-fungal, anti-leishmanial, anti-oxidant, and anti-tubercular Fig. 1B 26-33. Indole is a principal structural molecule which is explained as a privileged scaffold. Evans and co-workers introduced and define indole scaffolds that are proficient in performing as ligand meant for receptors diversity 34-36.
They have the special property of mimicking the structure of proteins and inversely binding with enzymes that offer great opportunities to discover novel drugs with a proliferation mode of action. Many of the marketed drugs containing indole (synthesized) have been reported as the “Best Retail” by USA37-41. In this review, an attempt has been made to summarize recent advances in the moiety with diverse biological and therapeutic functionality in the health care domain.
We designed to accumulate the details of synthetic form, in-vitro, in-silico, and in-vivo evaluation had been completely done on diverse indole molecules through collecting the different research articles survey during literature search from different scientific portals area. There are also a number of accepted indole based drug molecules in the market along with lead molecule presently obtainable through diverse clinical phases.
Chemical Synthesis of the Indole Ring: Conventional synthesis of the indole nucleus by various methods have been reported in the literature. It involves a number of starting materials and different strategies as mentioned in scheme 1 which includes: Mori indole synthesis, Buchwald indole synthesis, Sundberg indole synthesis, Hemetsberger indole synthesis, Kanematsu indole synthesis, Van Leusen indole synthesis, Nenitzescu indole synthesis, Modeling indole synthesis, and Fischser indole synthesis Fig. 1C 42-50.
Pharmacological Evaluation of Indole Compounds: Due to the universal nature of indole derivatives, it has gained vast recognition among the organic and medicinal chemists.
Many lead drug molecules containing indole moiety are found to be under investigation and research to control various disease conditions such as bacterial, malaria, fungal, viral, tubercular, and HIV infections.
Antimicrobial Activity: In general, antibacterial action of clinically approved drugs and newly reported moiety are based on bactericidal or bacteriostatic mode of action. Antibiotic acts either acting directly on bacterial cell wall or enzyme based hacked systems. Bacterial cell wall is composed of complex polysaccharides which is targeted by antibiotics and caused cell wall degradation or fragmentation and thereby causing cytoplasmic content to be oozed or released. This may be a potential mechanism of bacteria death. Another aspect is enzyme mediated or nuclear mechanism. There are several enzymes responsible for a cell physiological normal process. However, bacterial cells are differentiated from mammalian cells in several terms which seek an attention for the drug discovery scientist. This was a basis new drug development such as rifampicin which primarily acts on bacterial mRNA dependent DNA polymerase.Rapid development of drug resistance has emerged as a serious challenge since the entry of the first agent into the clinical market in the 1940s. To curtail the development and spread of antimicrobial resistance, it requires the preservation of current antimicrobials through their appropriate use, besides the drug development and discovery of new lead molecules. A higher rate of mortality and cost are observed in the management of microbial disease and further is amplified to enhance its antimicrobial resistance 51.
The WHO's (World Health Organization) latest survey revealed that 0.5 million people are antibiotic-resistant across 22 countries 52. To combat the problem of anti-microbial resistance new indole derivatives targeting microorganism through different mechanism should be developed. Various indole derivatives are identified and evaluated as anti-microbial agents. Sanna and his colleagues mentioned the synthesis of indole-thiourea hybrids and evaluated it against a pool of microbes containing both Gram-positive and Gram-negative types. Compound (1) (minimum inhibitory concentration as MIC (minimum inhibitory concentration) < 12.5 μg/mL) was establish to be extremely potent as compared with standard drug ciprofloxacin (MIC < 1.0 μg/mL) 53.
Thiazolidine is also known for its activity as an antimicrobial agent and therefore researchers are trying to combine thiazolidine moiety with others to design potent antimicrobial agents 54. Abo-Ashour and coworker synthesized oxindole-thiazolidine conjugates. All the synthesized derivatives were evaluated against S. aureus, P. aerugenosa, E. coli, M. tuberculosis, A. fumigates and C. albicans. SAR (structural activity relationship) study concluded that chloro and methyl substitution are favorable for the activity. Compound (2) (MIC < 0.98 μg/mL) was established to be nearly all active with equal potency both as antifungal and as antimicrobial relative to ciprofloxacin (MIC < 3.90 μg/mL) and amphotericin B (MIC < 1.95 μg/mL), respectively 55. Recently, synthesized and evaluated various indole derivatives containing heterocyclic nucleus were explored as antimicrobial agents. The presence of thiophene and imidazole rings improved the antimicrobial evaluation of prepared new compounds. It was observed that compound (3) (MIC < 8 μg/mL) showed high antibacterial activity, whereas compound (4) (MIC < 6 μg/mL) showed high antifungal activity 56. Various 5-hydroxy-indole moieties were prepared and measured next to C. albicans, A. niger, E. coli and B. cirroflagellosus. Compounds (5) (zone of inhibition = 28 mm) showed maximum potency as compared with standard drug griseofulvin (zone of inhibition ~ 30 mm) 57.
Mane et al., 2016 evaluated and prepared various indole-2-carboxamide derivatives having research that various ester derivatives and amide moieties of indole-2-carboxylic acid was found to be potent antioxidant and antibacterial properties. New synthesized derivatives were assessed against K. pneumonia, E. coli, P. aeruginosa, S. typhi, C. albicans, C. neoformans, A. fumigatus and C. parapsilosis. SAR studies suggested that the alkyl and halogen-substituted phenyl and cyclohexyl carboxamide derivatives are favorable for the activity. Compound (6) (MIC < 6.25 μg/mL) exhibited maximum antimicrobial activity compared with standard drug gentamicin (MIC < 3.0 μg/mL) 58.
It is found that pyrazole and imidazole have the wide spectrum of antimicrobial evaluation owing to because the existence of nitrogen atom in five-membered rings which acts by inhibiting cell wall synthesis or DNA (Deoxyribose nucleic acid) damage 59-61. The antimicrobial activity of these heterocyclics attracted various scientists to attach pyrazole and imidazole rings with the indole nucleus to prevent the problem of microbial resistance. In 2017, Quazi et al., prepared and assessed different indole-pyrazole derivatives.
All the new derivatives, (7) (zone of inhibition < 0.5 cm) showed good activity against Gram-positive bacteria and compound (zone of inhibition < 0.1 cm), has good activity against fungal strain Macrophominaphaseolina and Sclerotiumrolfsii 62. A new class of imidazole-based indole moities were prepared and evaluated against bacterial strains S. aureus, S. pyogenes, Shigella flexneri, Proteus mirabilis, Vibrio cholera and on fungal strains such as Candida albicans, C. glubrate, and C. crusei Fig. 2A.
Considering another context, density functional theory, computational method, X-ray crystallo-graphic analysis and molecular docking study were also used to evaluate indole compounds and its derivative for physicochemical properties by several authors. Compound (8) (MIC < 12.5 μg/mL) showed good chemical stability, reactivity and bond parameters due to the presence of negative charges on oxygen and nitrogen atoms as compared to methicillin standard drug (MIC < 6.25 μg/mL) 63. In the same year, Yadav et al., 2016, reported the role antibacterial activity of 1, 2, 3, 5 substituted indole derivatives and evaluated against S. aureus, S. pyogenes, E. coli, and P. aerugenosa. Compounds (9) (MIC = 37.5 μg/mL) was establish to be active 64.
Choppara et al., 2015, have designed and synthesized bis-indole derivatives and evaluated against B. subtilis, E. coli, K. pneumonia, and P. aerugenosa. SAR study concluded the role of prenyl system for the activity. Compound (10) (zone inhibition < 24 mm), (zone of inhibition < 21 mm) (8) (zone of inhibition < 20 mm) were establish to be the main active as compared to reference ciprofloxacin (zone of inhibition < 27 mm) 65. Gali et al., 2015 investigated the synthesis of thiazolylcoumarins substituted indole derivatives and further evaluated against B. subtilis and E. coli. SAR highlighted that the occurrence of unsubstituted thiazolylcoumarins was favorable for the evaluation. Compound (11) (zone inhibition < 18 mm) was initiate highly potent as compared to reference drug streptomycin (zone of inhibition < 30 mm) 66.
Hydrazone is another moiety having immense antimicrobial activity due to inhibition of microbial cell wall synthesis described in a large literature data 67-68. Based on this, Shirinzadeh et al., synthesized and evaluated various indole-hydrazone derivatives to cope with the problem of multidrug-resistant bacteria. SAR studies suggested that activity increased with the introduction of halogen atoms into the phenyl ring especially at the ortho position. (12) (3, 5-difluoro) (MIC < 100 μg/mL), showed the highest activity when compared to standard drugs sultamicillin (MIC < 25 μg/mL), ampicillin (MIC < 50 μg/mL), fluconazole (MIC < 0.78 μg/ml) and ciprofloxacin (MIC < 0.19 μg/mL) 69. Nassar et al., 2010, also prepared pyrazoline, pyridine, pyrimidine substituted indole compounds as antibacterial agents. All the new prepared compounds were assessed against S. aureus, E. coli, P. aerugenosa, Fusarium A. niger, and C. albicans. SAR study indicated the role of methoxyphenyl substitution. Compound (13) (zone inhibition < 34 mm) showed promising antimicrobial potency when compared to reference drug ciprofloxacin (zone of inhibition < 44 mm) and nystatin (zone of inhibition < 44 mm) Fig. 2B 70-71.
FIG. 2: ANTIMICROBIAL ACTIVITY OF INDOLE DERIVATIVES (A) AND (B)
El-Sayed, et al., 2015, bisindolyl-substituted cycloalkane-anneallated indoles as a new series of antibacterial activity. The new active derivatives (14) was containing cyclohexane indole moiety when evaluated against S. aureus and MRSA (methicillin resistance S. aureus) 72. Choppara, et al., 2015, synthesized two classes of new analogues bis (indole) and selected for their antimicrobial, antitumor activities, and the SAR. Compound (15) N (-((5-bromo-1H-indol-3-yl) methylene)-2-(1H-indol-3-yl) acetohydrazide) was establish to be active potent.
Shi et al., 2015, reported the new synthesis and antibacterial evaluation of new indole containing 1, 2, 4-triazole, and 1, 3, 4-oxadiazole moieties during ultrasound irradiation. In the present series two optimized drugs (16) 3-(1H-indol-3-yl)-5-[[2-[[5-(4-methoxy-phenyl)-1, 3, 4-oxadiazol -2-yl]thio] ethyl]thio]-4H-1, 2, 4-triazol-4amine and (17) 3-(1H-indol-3-yl)-5-[[2-[[5-(4-aminophenyl)-1, 3, 4-oxadiazol-2-yl] thio] ethyl]t hio] -4H-1, 2, 4-triazol-4-amine exhibited tremendous intrinsic effectiveness Fig. 3A 73.
Anti-tubercular Activity: Tuberculosis is global and deadly air borne infectious disease caused by Mycobacterium tuberculosis affecting lungs as well as other parts of the body 74. According to WHO report 2019, 10 million new cases of TB were estimated globally 75. Tuberculosis is considered the most life-threatening disease that causes about 100 million deaths worldwide 76.
A number of indole derivatives are mentioned here having advanced anti-tubercular activity 77. In 2018, Abo-Ashour et al., 2018, synthesized and evaluated various oxindole-thiazolidine conjugates active against M. tuberculosis bacterial strain RCMB 010126. The methoxy, ethoxy, and alkyl groups were found to be favorable for the activity. Compounds (18) (MIC = 0.39 μg/mL) were more and equally potent compared to standard drug isoniazid, (MIC = 0.78 μg/mL) 78.
Various indole derivatives were synthesized using Knoevenagel and Michael reaction mechanism, and in-vitro activity was conducted to assess the anti-tubercular activity against M. tuberculosis bacterial strain (MTCC 300). Docking study was also performed to further detect the affinity between the synthesized compound and enoyl-acyl carrier protein reductase using Auto Dock-Vina software (Los Angeles, USA).79 SAR studies concluded that chloro and nitro substituent at the para and ortho positions of phenyl ring were favorable for the activity. Compound, (19) has comparable activity (MIC = 40 μg/mL) to standard drug isoniazid (MIC = 10 μg/mL) and good binding affinity (-11.6) with the target protein 80. Based on reported literature, piperazine is also goog anti-tubercular agents 81-82. Naidu et al., 2016, reported various indole-piperazine derivatives and evaluated against Mycobacterium tuberculosis (H37 Rv). The introduction of electron-withdrawing groups such as Br, CF3 leads to an increase in anti-tubercular activity. Compounds, (20) (MIC = 6.16 μM) showed highly potent anti-tubercular activity compared to standard drug isonicotinic acid hydrazide (MIC = 91.14 μM) 83. In the same year, Stec J et al., designed and synthesized various indole-carboxamide derivatives targeting MmpL3 protein and were further evaluated for anti-tubercular activity by conducting in-vivo and in-vitro studies.
Lipophilic compounds exhibited higher activity compared to hydrophilic derivatives. The compound, (21) was of potential activity (MIC = 0.012 μM) against multidrug-resistant and extensively drug-resistant M. tuberculosis strains. Apart from this, docking studies were also conducted, showing the maximum binding of 21 (MIC = 0.29 μM) with MmpL3 protein 84.
Some new pyridine and indole based 1, 3, 4-oxadiazole derivatives having anti-tubercular activity was reported. The in-vitro studies were conducted to evaluate the anti-tubercular activity against M. tuberculosis H37 Ra and M. bovis BCG. However, the anti-proliferative activities of synthesized derivatives were also evaluated using three cell lines- HeLa, A549, and PANC-1. According to SAR, the substitution pattern at the phenyl ring of chalcone significantly modulates the activity. At the 2nd position of the phenyl ring, –OH and –NO2 functional group is favorable for the activity. Compound, (22) were recognized as the better active derivatives amid MIC ranging with 0.94 to 5.17 μg/mL compared to isoniazid (MIC = 0.037 μg/mL) and rifampicin (MIC = 0.017 μg/mL). Docking studies were also conducted using Grid-Based Ligand Docking 85.
Compounds (23) exhibited maximum docking in the active area of mycobacterial enoyl reductase (InhA) 86. Khan et al, 2016 have synthesized novel 3-alkylated indole derivatives using mp CuO as a heterogeneous catalyst having high catalytic efficiency, maximum surface area, and recyclability. Among all the synthesized compounds, (24) (MIC = 15 μg/mL) containing p-methoxy phenyl derivative at the 3rd position of indole exhibited significant anti-tubercular activity against M. tuberculosis bacterial strain (MTCC 300) in comparison to the isoniazid taken as a standard drug (MIC = 10 μg/mL). Docking studies were also conducted using enoyl-acyl carrier protein reductase and the binding score was calculated for each derivative. Among all the synthesized derivatives, 24 showed maximum binding score 87.
Various organic moieties containing a hetero atom, the double bond between carbon and nitrogen, are found to be the most potent inhibitor of DNA gyrase enzyme causing the bacterial death. Hydrazone and thiazolidinones falling under this category are found to be potent anti-tubercular agents 88-90.
Because of this, Ustundag et al., 2016 investigated and designed indole-based hydrazide-hydrazone, 4-thiazolidinones and evaluated for anti-tubercular evaluation against M. tuberculosis H37 Rv. SAR studies concluded that substitutions on the phenyl ring have a major impact on the activity. Substitution with F, CN, NO2, CF3 and COOCH3 at the para position were favorable for the activity. Compound, (25) (MIC = 25 μg/mL) demonstrated notable anti-TB activity ranging from 6.25 to 25 mg/mL compared to rifampicin as standard drug (MIC = 25 μg/mL). However, anticancer activity is also evaluated using the colon cancer cell line COLO 205 91.
Various indole-2-carboxamide derivatives were also established. SAR studies revealed that -Cl, -F, -CN substituents at the 4th and 6th position of indole and methyl substitution on phenyl ring attached with indole leads to increase in potency. All the synthesized derivatives were tested against M. tuberculosis H37 Rv strain. The compound (MIC50 = 0.23 μM) was found to be highly effective as compared to the reference isoniazid drug (MIC50 = 0.33 μM) 92.
Later in 2014, Tehrania and colleagues synthesized and evaluated various Schiff' base based indole derivatives. All the synthesized compounds are further evaluated using a microtitre plate on the Gram-positive and Gram-negative strain. SAR studies concluded that urea-based derivatives were highly potent. Compounds (26) (MIC = 3.91 μg/mL) exhibited maximum potency as compared with standard drug ethambutol (MIC = 0.75 μg/mL) Fig. 3B 93.
FIG. 3: ANTIMICROBIAL ACTIVITY OF INDOLE DERIVATIVES (A) AND ANTI-TUBERCULAR ACTIVITY OF INDOLE DERIVATIVES (B)
Anti-malarial Activity: Malaria is the most infectious ailment infected by Plasmodium parasite. Malaria is a chronic disease that leads to thousands of deaths annually 94. As per WHO 2016 report, among the 216 million reported cases of malaria, 731000 patients died worldwide. Maximum cases were reported from African 95. It is required to develop anti-malarial drugs at a fast pace to combat this problem. A few of indole derivatives as antimalarial agents are discussed below that have shown potential to encounter malaria. Yadav et al., 2016, synthesized and evaluated various novel indole derivatives and evaluated against P. falciparum.
SAR studies explained that alkyl substitution with carboxylate at 1st and 2nd position and aryl at the 3rd position of indole was favorable for the activity. Compounds (27) showed high potency, having MIC value not more than 0.70 μg/mL on comparing to the standard drugs quinine (MIC = 0.270 μg/mL) and chloroquine (MIC = 0.02 μg/mL) 96. Various indole-based piperidine derivatives were prepared, and in-vitro studies were conducted in P. falciparum culture, and activity was measured in terms of EC50. Lipophilicity was also calculated in terms of the partition coefficient (logP), to further assess the activity of synthesized derivatives.
Piperidinyl moiety was found to be critical for the activity. Compound (28) was obtained having selectivity for malaria parasites without drug resistance and better activity (EC50 ~ 3 μM, cLogP = 2.42 and MW = 305) as compared to most of the standard drugs such as chloroquine, atovaquone, amodiaquine and artesunate with EC50 value of 285 ± 58 μM, 0.35 ± 0.14 μM, 12.30 ± 4.21 μM and 1.97 ± 0.43 μM, respectively 97. Melatonin is an indole-derived hormone secreted by the pineal gland. It is involved in various signaling pathways involving the Plasmodium cell cycle and a major role in the replication of Plasmodium. Inhibition of this hormone can be used to inhibit the growth of Plasmodium. Keeping this in mind, Schuck and coworkers have investigated various melatonin-based indole derivatives.
They synthesized derivatives having an inhibitory effect on the cell cycle of P. falciparum. The in-vitro studies were conducted in P. falciparum culture, and a flow cytometer was used for activity calculation. SAR studies explained that carbo-xamide at the C-3 position of indole was decisive for the activity. Compounds (29) (IC50 = 2.93 μM) exhibited maximum antimalarial activity. Alkyl and aryl substitution with carboxamide at the C-3 and methoxy group at the C-5 gave maximum potency 98. Amongst the entire major heterocyclic nucleus, quinoline derivatives are the well known antimalarial agents acting through the inhibition of DNA synthesis of microorganism 99.
Assuming it to be a wonderful idea to combine this moiety with indole. Teguh et al., 2013 to synthesized various quinoline-indole conjugates and tested against P. falciparum using K1 strain. SAR studies concluded that the amino group and alkyl-substituted amino group were favorable for the activity. Compound (30) (IC50 < 0.4 ± 0.2 μg/mL) demonstrated promising antimalarial activity 100. Meridianin G, is an indole alkaloid obtained from marine invertebrate Aplidium meridianum. It is found to be the inhibitor of cyclin-dependent protein kinase, involved in the progression of malaria. Based on this fact, Bharate et al., 2013 reported various meridianin G-based indole derivatives and evaluated against chloroquine-sensitive and resistant clones of P. falciparum through plasmodial LDH (lactate dehydrogenase) activity. Compound, (31) (IC50 < 4.01 μM) was found to be most effective as compared to standard drug artemisin (IC50 < 0.09 μM) and chloroquine (IC50 < 0.72 μM) 101. Santos et al., 2015, reported, in their project a class of 3-piperidin-4-yl-1H-indoles containing on a hit with an HTS whole-cells evaluates against Plasmodium falciparum and assess for anti-parasitic evaluation. SAR report was done which exhibited that 3-piperidin-4-yl-1H-indole is prejudiced to new N-piperidinyl modifications. New compounds (32) (4-(1H-indol-3-yl) piperidin-1-yl) (pyridin-3-yl) methanone showed prospective anti-malarial activity 102. Schuck et al., 2014 have reported two series of melatonin analogues compounds which were evaluated in P. falciparum culture and their anti-malarial potencies were studies new technique flow cytometry. Among the melatonin analogue, derivative (33) was able to inhibit the P. falciparum development and thereby found be active Fig. 4 103.
FIG. 4: ANTI-MALARIAL ACTIVITY OF INDOLE DERIVATIVES
Antiviral Activity: A viral infection spreads by pathogenic viruses and infectious virus particles when enters inside the body. Various antiviral drugs are available in the market against HIV, Herpes viruses, hepatitis B and C viruses. Among all the infections, viral infection is the fastest spreading, creating about 60% illness in developed countries 104. Due to the fast replication rate, it is required to design safe and efficacious antiviral drugs. Researchers are working to design novel antiviral drugs with a wide range of activities 105. Scuotto et al., 2016 designed a new class of novel multi-target indole-3-carboxylate analogues as antiviral activity. All the new synthesized derivatives were evaluated against Chikungunya virus in vero cell culture through a CPE reduction method. SAR studies reported that the hydroxyl group at the 5th position is found to be most favorable. Compounds, (34) was active compounds (EC50 = 6.5 ± 1) which is 10-times more active as compared to the reference drug arbidol. Further docking studies were also performed by using the crystal structure of CHIKV glycoprotein complex. Maximum derivatives inserted into the lateral sites of the active site indole got deeply inserted into the cavity and thiophenol ring occupy solvent-exposed portions showing maximum bonding. The antiviral effect is due to the inhibition of an earlier viral life cycle 106.
Spiroindolines, like indole, has the property to inhibit the viral protein synthesis, nucleic acid synthesis and receptor recognition. With these diversified mechanisms, spiroindoline and indole combination can be the best strategy to control viral action 107. Based on these facts, Chen et al., 2017, designed synthesized and evaluated fused indoles and spiroindolines. All the synthesized compounds were further evaluated by in-vivo and in-vitro method against Tobacco mosaic virus. SAR studies concluded that in the case of fused indole derivatives, phenylsulfonyl, 4-tert-butylsulphonyl, 4-chlorophenylsulphonyl groups are favorable for the activity whereas C ring is crucial for the activity. In the case of spiroindolines, electron-withdrawing groups such as -Cl, -CN and -CF3 on quinolone phenyl ring were vital for activity.
Derivatives (35) (% inhibition = 56 ± 2%) exhibited maximum potency as compared to reference drug ribavirin (% inhibition = 36 ± 1%) and harmin (% inhibition = 45 ± 1%) at the 500 μg/mL concentration 108. Musella et al., 2016 reported the synthesis of amide substituted indole derivatives and tested against human Varicella zoster virus (VZV). SAR studies concluded that substitution of biphenyl ethyl moiety and acetylation at the amino group of tryptamine is required for the activity against VZV. Compound, (36) (CC50 =39 μM) was found to be highly potent as compared to standard drug acyclovir (CC50 = 191 μM) and biuvudin (CC50 = 160 μM) 109. Naphthalene derivatives are also observed against a variety of viral disease conditions. Inhibition of viral replication is the main mechanism used by these derivatives 110. Prompted by these, Giampieri et al., 2009 fused the indole with naphthalene nucleus to form indole-naphthyl derivatives. All the synthesized derivatives were screened against a variety of viruses i.e., HIV-1 (human immune-deficiency virus-1), BVDV (bovine viral diarrhea virus), YFV (yellow fever virus), CVB-2 (coxsackievirus B-2 strain). The presence of carboxylate, indole and naphthol were found to be imperative for the antiviral activity. Compound (37) (CC50 = >57 μM, SI = <5) was quite active among all the compounds and compared to the standard drugs acyclovir, mycophenolic acid, ribavirin, 6-azauridine (CC50 = > 100, SI = < 50) 111. AIDS is a very dreadful disease occurring due to the infection by human immunodeficiency virus (HIV) 112.
According to 2016 Census, 36.7 million people are diagnosed with HIV worldwide 113. Thus, the advancement of anti-HIV drugs should emphasize on the favorable structural modifications and its mechanism of action. Some novel indole derivatives as anti-HIV agents are mentioned here. In 2018, Sanna et al., mentioned the synthesis of novel indole-thiourea hybrids and evaluated against HIV-1. SAR studies reported the importance of 4-bromophenyl moiety. All the compounds, (38) (EC50 = 8.7 ± 0.4 μM) was found to be highly potent as compared to standard drug efavirenz (EC50 = 0.002 ± 0.0002 μM) 114. In 2016, Doussan et al., reported synthesis and evaluation of various indole derivatives for anti-HIV activity. Compounds, (39) (EC50 < 0.011 μM) was found to be highly potent as compared 115.
Various indole-7-carboxamide analogue were also showed by Ravichandran et al., 116. Computational techniques were used to screen the synthesized derivatives, thereby calculated various properties to evaluate the indole-7-carboxamide analogues i.e., electrostatic, steric physicochemical and hydro-phobic properties. SAR studies revealed that bulky and electronegative groups were favorable at the 3rd position of indole-7-carboxamide groups present on benzamido and pyrazine nucleus contribute hydrogen acceptance property which facilitates binding with HIV-1. Compound (40) was highly potent 116. Ashok et al., 2015, reported the synthesis and evaluation of various indole-pyrido derivatives. In-vitro study was conducted on HIV-1 infected cells and molecular properties were also calculated to further screen the synthesized analogues. SAR studies were conducted on the basis of substitutions present on the phenyl ring attached to piperazine, which is further attached with indole. The studies concluded that ortho and para directing substitutions on 4th position of phenyl ring lead to no anti-HIV activity. Whereas, the 2-3rd position of phenyl favors the activity. Replacement of phenyl with benzyl moiety leads to increase impotency.
The compound (41) (EC50 = 0.53 μM) was found to be highly potent, whereas others have moderate activity compared to reference drug zidovudine (EC50 = 0.002 μM).117 In the same year, trifluoromethyl-indole derivatives having improved drug resistance with anti-HIV-1 NNRTIs were reported by Jiang and coworkers. All the synthesized derivatives were screened against WT (wild-type) HIV-1 strain. SAR studies revealed that the presence of Cl or Br at C-5 improved the activity and presence of nitro at C-7 reduced the activity. Substitution of alkyl chain substituted with halogen at C-3 leads to potent compound (42) (EC50 < 133.33 μM) on the basis of the comparison with standard drug nevirapine (EC50 = 0.4 μM) and efavirenz (EC50 = 0.08 μM).
Further docking analysis gave the idea about the binding mode of various derivatives with HIV reverse transcriptase enzyme 118. Ferro et al., 2014 designed, synthesized and evaluated indole derivatives by performing the docking study with HIV-1integrase. Docking studies concluded that bulkier substituent on the benzyl group, i.e. tert-butyl, trifluoromethyl group, is favourable for the interaction with HIV-1 integrase protein. Compound, (43) (IC50 = 0.4 mM) was highly potent 119. Hassam and coworkers report and assessed cylopropyl indole analogue as HIV non-nucleoside reverse transcriptase analogue. All the new derivatives were evaluated by using HIV-1 retroviral vector system. SAR studies concluded that the C-1 position of propanoic acid and amides were favourable for the activity. At the C-2 position, cyclic groups, i.e., phenyl and thiophene enhance the activity and finally, at the C-3 position, Cl and Br groups are favorable. Compound (44) (IC50 = 0.065 μM) were highly potent on the basis of the comparison with standard drug nevirapine (IC50 = 0.087 μM). Docking studies were also conducted to further evaluate the activity using HIV non-nucleoside reverse transcriptase enzyme which confirmed that compound (45) well accommodated within the active site 120.
Various indole-piperazine derivatives were also synthesized and screened using various molecular computational techniques, i.e., combined docking, molecular dynamics and 3D-QSAR study. SAR studies suggested that small bulky substituents were required for the activity and also smaller substituents having balanced steric and electrostatic properties are highly desirable at 7 positions of the indole ring. However, activity reduced in the order of primary>secondary>tertiary amine. Compounds (45) (EC50 = 0.005 nM) were found to be highly potent, having good binding affinity with receptor 121. In the same year, indole-7-carboxamide derivatives were synthesized by Yeung and coworkers.
All the new derivatives were assessed by cell-based assay against a pseudotype virus expressing a JRFL envelope. SAR studies concluded that 4-fluoro substitution is favourable for the activity. All the new compounds, (46) (EC50 = 0.29 nM) was found to be highly potent 122. Regina et al., 2012 synthesized and evaluated nitrogen-containing indole 2-carboxamide derivatives. All the synthesized derivatives were evaluated against mutant Y181C, Y188L, K103N, K101Q, IRLL98 and G190A HIV-1 strain.
SAR studies concluded that pyridine-4-yl methyl substituent is favourable for the activity. Compound (47) (EC50 = 2.0 ± 0.2 nM), as compared with standard drug zidovudine (EC50 = 2.0 ± 0.2 nM) and efavirenz (EC50 = 6.3 ± 3.2 nM) was found to be highly potent 123. Regina et al., 2011 reported synthesized and evaluated indole 2-carboxamide derivatives with different substitutions.
All the synthesized compounds were further evaluated against mutant L100I and K103N RT HIV-1 strains. SAR studies concluded that nitro and pyrrole substituted carboxamide is favourable for the activity. Compound (48) (EC50 = 1.3 ± 0.0 nM) was found to be highly potent than standards, nevirapine (EC50 = 19.2 ± 0.2 nM) and efavirenz (EC50 = 1.5 ± 0.3 nM) 124. Tichy et al., 2012 was report some new indole-2-carboxylate analogue which was evaluated for antiviral agents. Their relation with potency was done through SAR report and performed to get the pharmacological activity. Compound (49) 2-(6-chloro-4-(furan-2-yl)-9H-pyrimido [4, 5-b] indol-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3, 4-diol exhibited good inhibitory activity 125.
Xue et al., 2014, reported a series of new indole-2-carboxylate analog and were evaluated to determine their in-vitro wide spectrum antiviral potencies. SAR report was also conducted 126. Compounds tested against influenza A virus was analog (50) methyl 6-amino-1H-indole-2-carboxylate exhibiting good potent inhibitory effect Fig. 5.
FIG. 5: ANTIVIRAL ACTIVITY OF INDOLE DERIVATIVES
Hepatitis C Virus Activity: Zhang et al., 2005 reported and prepared a new series of 2-(4-sulfonamidophenyl) -indole 3-carboxamides derivatives and evaluated against the HCV genotype 1b replicon. Compound (51) 6-(difluoromethoxy)-2-(4-(1,1-dimethyl ethyl sulfonamido) phenyl)-5-fluoro-1-hexyl-1H-indole-3-carboxamide exhibit good potency Fig. 6 127.
FIG. 6: HEPATITIS C VIRUS GENOTYPE ACTIVITY OF INDOLE DERIVATIVES
Anti-leishmanial Agents: Leishmaniasis is a parasitic disease spread by female sand-fly belonging to genus Leishmania, which can appear in the visceral, cutaneous, diffuse and mucocutaneous form 128. According to the recent data by WHO, nearly 88 developing and developed countries are affected by leishmaniasis. Every year, nearly 1.5-2.0 million new cases are reported 129. Leishmania causes a wide range of health problems, it is imperative to develop effective drugs. Recently, Porwal et al., 2017 synthesized and evaluated gem-dithioacetylated indole derivatives.
All the new derivatives were evaluated through in-vivo study against Leishmania donovani. SAR report showed that the presence of H2S at the C-3 and p-cyanophenoxy, N-phenyl, pentyl chain at nitrogen atom and dimethyl-sulphoxide at 3rd position of indole was most important for the activity. Compound, (52) (% inhibition = 96-99 %) showed maximum activity 130. Felix et al., 2016, also reported the synthesis of thiophene-indole hybrids and evaluation against L. donovani. SAR study concluded the role of 5-cyano, 5-methyl were found to be favorable for the activity.
Compounds (53) (IC50 = 3.2 μg/mL, SI >124.6) was good potent with as compared to reference drug amphotericin B (IC50 = 0.2 μg/mL, SI >124.5) 131. In 2014, Sharma et al., reported triazino indole-quinoline hybrid analogue were prepared and assessed. All the reported analogue were evaluated through in-vitro study against L. donovani. SAR studies suggested that at the nitrogen atom of indole hydrogen, methyl, ethyl, isopropyl, isobutyl, allyl and benzyl were favorable for the activity. Alkyl chain length connecting triazino indole andquinoline should contain a maximum of two carbons. Compounds, (54) (IC50 = 0.36 μM) were found to be highly potent as compared with standard drug miltefosine (IC50 = 8.10 μM) 132. The anti-leishmanial activity of 3, 3-diindolylmethane was investigated by Bharat and coworkers. All the synthesized compounds were screened through in-vitro study against L. donovani. Pharmacophore model was also developed for diindolyl methane derivatives (55) showed excellent statistical parameters.
SAR studies concluded that 4-nitroaryl substitution was favorable for the activity. Compound (56) (IC50 < 8.37 μM) was found to be highly potent as compared with pentamidine (IC50 <8.39 μM) and amphotericin B (IC50 < 0.17 μM) 133. Leishmania cysteine protease is essential for the growth, differentiation, and multiplication of parasite. Azetidine derivatives are one of the prominent inhibitors of this enzyme. Based on this fact, Singh et al., synthesized and evaluated azetidine-indole derivatives and screened them through an in-vitro study using Leishmania major promastigotes.
SAR studies concluded that methyl substitution to the imine attached to the indole enhanced the activity. Conversion of imine intoazetidin-2-one resulted in a drastic increase in the activity. Compound (57) (0.56 ± 0.06 μg/mL) was found to be highly potent as compared with standard drug amphotericin B amongst them (0.56 ± 0.001 μg/mL) Fig. 7 134.
FIG. 7: ANTI-LEISHMANIAL ACTIVITY OF INDOLE DERIVATIVES
Anti-fungal Activity: Recently, indole subunits have gained wide-spread concern due to their remarkable role as antifungal agents. In this perspective, Zhang et al., 2012 have reported noticeable work in the area of antifungal drug development. In 2012, analogues of pimpirinine, an indole alkaloid obtained from streptomyces species, were synthesized and bioassay was conducted on Pythium dissimile, Alternaria solani, Botyyotinia fuckeliana and Gibberellazeae by Zhang et al., 2012. SAR study concluded that bromo and acetyl chloride substitutions were favorable for the activity. All of them were found to be highly potent 135. Furthermore, Zhang et al., 2013 synthesized and studied the oxadiazole derivatives of indole.
All the newly prepared compounds were tested against Pythium dissimile, Septoriatritici and Uromyces viciaefabae and compared with pimpirine alkaloid. SAR study concluded that halogen substitution is favorable for the activity. Compounds (58) were found to be potent 136. Motivated by the promising results, this study was further extended with streptochlor in an indole alkaloid obtained from marine actinomycetes. Synthesized streptochlor in analogs were evaluated against Pythium dissimile, Alternaria-solani, Uromycesviciaefabae, Gibberel-lazeae, Alternariasolani, Phyto-phthorainfestans, Zymo-septoriatritici and A. Solani.
The introduction of chloro and bromo substitution at the 4th position of oxazole ring increases the activity. Compounds (59) were found to be highly potent analogues showing 81-100% control of the disease 137. Similarly, novel derivatives of streptochlorin were synthesized with more active heterocycles having improved antifungal activity. All analogues were studied against Pythium dissimile, Alternariasolani, Uromycesviciae-fabae, Gibberellazeae, Alternariasolani, Phytophth-orainfestans, Zymoseptoriatritici. The compound was found to be highly potent on Alternaria solani.
SAR study marked the importance of indole moiety in streptochlorin. Due to the high potency of streptochlorin as an antibiotic, extensive study on the derivatization of streptochlorin was also conducted by other researchers. Recently, Jia et al., 2018 also conducted the study on streptochlorin, natural antifungal constituents extracted from marine streptomyces species. Evaluation of analogues was conducted on Pythium dissimile, Alternariasolani, Gibberellazeae, Botrytis cinerea, Rhizoctorziasolani, Alternaria blotch, and Collecteri chumcapsica. Chloro and bromo substitution were favorable for the activity. Compounds (60) were establishing highly potent 138-139. 1H-Indole-4, 7-diones were reported and evaluated for in-vitro antifungal activity. The analogue 1Hindole-4, 7-diones generally exhibit good antifungal activity against Candida krusei, Cryptococcus neoformans, and Aspergillus niger. The results commented that 1H-indole-4, 7-diones would be better potent antifungal activity.
The modification of lead compounds that were recognized as highly effective in the back report could significantly improve the pharmacological activity of the resulting analog. While targeting lanosterol 14-α demethylase, the molecular modeling technique persuaded that the addition of the phenyl moiety of new derivatives deep into the hydrophobic pocket of the enzyme might raise the enzyme-ligand linked and hence get better the anti-fungal outline of the new molecules. As a result, the recently designed new compounds (61) were prepared and tested for their anti-microbial activity and these compounds were found to display considerably good activity than the previous compounds.
Some of the analogues in this class showed MIC90 16 μg mL-1 and 32 μg mL-1 against Candida albicans and Aspergillus Niger, respectively, at 312 μg mL-1 for analogue 140. A class of new indole [1, 2-c]-1, 2, 4-benzotriazine analogue was prepared by a Sandmeyer reaction in the presence of tert-butylnitrite (t-BuONO). As a result of hymexazol, a commercial agricultural fungicide, at the concentration of 50 mg/mL, two indoles [1, 2-c]-1,2,4-benzotriazines, (62) showed the more promising lead and prominent antifungal efficacy in in-vitro against five phytopathogenic fungi.
It clearly confirmed that the beginning of appropriate substituent on the indolyl moiety of indole [1,2-c]-1,2,4-benzotriazine (63) would lead to the large potent analogues 141. On the basis of the principle of combination of new structural rings, a bespoke and proficient synthetic technique for three class of new indole-based 1, 3, 4-oxadiazoles (64) was explained. Biological assay conducted at Syngenta exhibited that more than a few of the prepared compounds exhibit good antifungal activity than pimprinine, the natural compounds which stimulated this synthesis. Two main structural modifications were found to make wider the spectrum of biological activity in most belongings 142. 2-(Indole-3-yl)-thiochroman-4-ones (65) were prepared via ionic liquid and evaluated for in-vitro antifungal profile. The contribution of ionic liquid to Michael addition reaction is noteworthy. Structures of whole compounds are optimized by 1H NMR, 13C NMR and HRMS. Most of this analogue gives better antifungal profile than fluconazole drugs. The output of 2-(indole-3-yl) -thiochroman-4-ones would be proficient antifungal activity 143. Song et al., 2015 reported and prepared 2-(Indole-3-yl)-thiochroman-4-ones and assessed them for in-vitro antifungal profile.
The analog showed the best activity than fluconazole. Compound (66) 6-chloro-2-(5- chloro-1H-indol -3-yl) thiochroman-4-one exhibit potent antifungal activity 144. Pooja et al., 2014 reported the synthesis of amino acid appended indoles moiety and evaluated against Candida albicans with their MIC80 in µg/ml assortment. Compound (68) (2R)-2-(2-(1-(4- ((3-(2-((S)-1-carboxy-2- (1H-indol-3-yl) ethylamino)-2-oxoacetyl)-2, 7a-dihydro- 1H-indol-1-yl) methyl) benzyl)-1H -indol-3-yl)-2-oxoacetamido) -3-(3a, 7a-dihydro-1H -indol-3-yl) propanoic acid exhibit best activity 145.
FIG. 8: ANTI-FUNGAL ACTIVITY OF INDOLE DERIVATIVES
Zhang et al., 2013, report class of new indole-based 1, 3, 4-oxadiazolesand the bioassays of majority of these particular analogue showed higher antifungal profile than pimprinine. Analogue (69) 2-(1H-indol-3-yl)-5- (trifluoromethyl)-2, b-dihydro-1, 3, 4-oxadiazole the most active on the pharmacologic assays Fig. 8 146.
A comprehensive mechanistic view of antimicrobial action metallic nanoparticles as drug delivery has been summarized and reviewed by few authors wherein they covered several microbial pathogens including fungal strains.147
Future perspective: Indole compounds are possessing various pharmacological and chemotherapeutic effects. There are several novel compounds to be reported for several activities. However, the challenging task for a scientist is to provide safety concern for any drug. Despite having potential antimicrobial and physiological action, clinical efficacy and regulatory importance are limited. Secondly, new developed indole compound are commonly hydrophobic which is a challenge for a formulation scientist working in formulation based project. Considering in vivo performance, it is prerequisite to collect enough preclinical pharmacokinetic data in a suitable animal model. These data become a basis for clinical trial of newly developed molecule. In current scenario, covid-19 pandemic attack challenged global healthcare system which provided a new window of understanding for mechanistic pathogenesis of virus in human body. Therefore, there is need to translate laboratory data to clinical bed using sound preclinical data and clinical history of indole drugs. Moreover, recent advances in nanotechnology played a versatile role to improve clinical efficacy and patient compliance. Herbal drugs are new option for the formulation scientist owing to safety aspects and wonderful benefits such as taxol, doxorubicin, amphotericin B, etc.
CONCLUSION: Several drugs are available possessing the indole nucleus and are involved in the treatment of various diseased conditions varying from acute to the chronic state. This analog can be traced in many commercially available marketed drugs approved by the US FDA for therapeutic purposes. A number of drugs bearing indole nucleus obtained from natural origin and synthetic processes are also under clinical trial. Moreover, researchers and chemists are still working together on indole containing novel compounds intended for several ailments diseased conditions, including infection and cancer.
However, minimum side effects and improving the biological activity still remained the major challenge. Data obtained from the extensive literature survey concluded that indole is a versatile nucleus touching almost all the disease conditions. A lot of intensive research needs to be carried out, looking at the potential of indole with other chemical entities. It is important to know that various potential indole derivatives need to be confirmed for its pharmacodynamics profile using suitable animal models in preclinical data. There is a scarcity of preclinical and clinical data of newly synthesized indole derivative with anticipated diverse therapeutic activity and potent antimicrobial efficacy.
ACKNOWLEDGEMENT: Authors would like to thank the Head, School of Pharmacy, Glocal University, India, for valuable scientific suggestions in writing the manuscript.
CONFLICTS OF INTEREST: The authors confirm that this article content has no conflicts of interest.
- Knepper K, Vanderheiden S and Brase S: Synthesis of diverse indole libraries on polystyrene resin-Scope and limitations of an organometallic reaction on solid supports. J Org Chem 2012; 8: 1191.
- Thanikachalam PV, Maurya RK, Garg V and Monga V: An insight into the medicinal perspective of synthetic analogs of indole: A review. Eur Jour Med Chem 2019; 180: 562-12.
- Von-Sundberg RJ: The Chemistry of Indoles. Organic Chemistry, a Series of Monographs, Vol. 18. Academic Press, New York–London 1970; 1(10): 489.
- Houlihan WJ: The chemistry of heterocyclic compounds. Wiley: New York, Part I- III, 25: 1972-79.
- Joule JA, Mills K and Smith GF: Heterocyclic Chemistry. 3rd edit; Chapman and Hall 1995.
- Baeyer A: Ueber die Reduction aromatischer Verbindungen mittelst Zinkstaub. Annalen Der Chemie Und Pharmacie, 1866; 140(3): 295-96.
- Won C, Shen X, Mashiguchi K, Zheng Z, Dai X, Cheng Y, Kasahara H, Kamiya Y, Chory J and Zhao Y: Conversion of tryptophan to indole-3-acetic acid by Tryptophan Aminotransferases of Arabidopsis and YUCCAs in Arabidopsis. Proc Natl Acad Sci USA 2011; 108: 18518-23.
- Zhang MZ, Mulholland N, Beattie D, Irwin D, Gu YC, Chen Q, Yang GF and Clough J: Synthesis and antifungal activity of 3-(1,3,4-oxadiazol-5-yl)-indoles and 3-(1,3,4-oxadiazol-5-yl) methyl-indoles. Eur J Med Chem 2013; 63: 22-32.
- Leon F, Habib E, Adkins JE, Furr EB, McCurdy CR and Cutler SJ: Phytochemical characterization of the leaves of Mitragynaspeciosa grown in U.S.A. Nat Prod Commun 2009; 4: 907-10.
- Chen FE and Huang J: Reserpine: A Challenge for total synthesis of natural products. Chem Rev 2005; 105: 4671-06.
- Young SN: How to increase serotonin in the human brain without drugs. J. Psychiatry Neurosci 2007; 32: 394-99.
- Diss LB, Robinson SD, Wu Y, Fidalgo S, Yeoman MS and Patel BA: Age related changes in melatonin release in the murine distal colon. ACS Chem Neurosci 2013; 4: 879-87.
- Patil SA, Patil R and Miller D: Indole molecules as inhibitors of tubulin polymerization: Potential new anticancer agents. Future Med Chem 2012; 4: 2085-15.
- Higdon JV, Delage B, Williams DE and Dashwood RH: Cruciferous vegetables and human cancer risk: Epidemiologic evidence and mechanistic basis. Pharmacol Res 2007; 55: 224-36.
- Rogan EG: The natural chemopreventive compound indole-3-carbinol: State of the science in-vivo. 2006; 20: 221-28.
- Kim YS and Milner JA: Targets for indole-3-carbinol in cancer prevention. J Nutr Biochem 2005; 16: 65-73.
- Atterhog JH, Duner H and Pernow B: Experience with pindolol, a beta receptor blocker, in the treatment of hypertension. Am J Med 1976; 60: 872-76.
- London GM, Asmar RG, O'Rourke MF and Safar ME: Project Investigators, Mechanism of selective systolic blood pressure reduction after a low dose combination of perindopril / indapamide in hypertensive subjects: comparison with atenolol. J Am Coll Cardiol 2004; 43: 92-99.
- Chen X, Zhan P, Li D and Liu X: Recent advances in DAPYs and related analogues as HIV-1 NNRTIs. Curr Med Chem 2011; 18: 359-76.
- Jacobi H and Dell HD: On the pharmacodynamics of acemetacin (author's transl), Arzneimittelforschung 1980; 30: 1348-62.
- Srivastava G, Somasundaram RT, Walfish PG and Ralhan R: Anticancer Activity of Apaziquone in Oral Cancer Cells and Xenograft Model: Implications for Oral Cancer Therapy. PLOS 2015; 10(7): 133735.
- Boriskin YS, Leneva IA, Pecheur EI and Polyak SJ: Arbidol: a broad-spectrum antiviral compound that blocks viral fusion. Curr Med Chem 2008; 15: 997-05.
- Battaglia S: Indole amide derivatives: synthesis, structure-activity relationships and molecular modelling studies of a new series of histamine H1-receptor antagonists. Eur Jour Med Chem 1999; 20(34): 93-05.
- Sharma V, Kumar P and Pathaka D: Biological Importance of the Indole Nucleus in Recent Years: A Comprehensive Review. J Heterocyclic Chem 2010; 47: 491.
- El-Gendy AA, Said MM, Ghareb N, Mostafa YM and El-Ashry ESH: Synthesis and biological activity of functionalized indole-2-carboxylates triazino- and pyridazino indoles. Arch Pharm (Weinheim) 2008; 341: 294-00.
- Dousson C, Alexandre FR, Amador A, Bonaric SB, Caillet C, Convard T, Costa D, Lioure A, Roland E, Rosinovsky S, Maldonado C, Parsy C, Trochet R, Storer A, Stewart J, Wang BA, Mayes C, Musiu B, Poddesu L, Vargiu M, Liuzzi A, Moussa J, Jakubik L, Hubbard M, Seifer D and Standring: Discovery of the Aryl-phospho-indole IDX899, a highly potent anti-HIV non1087 nucleoside reverse transcriptase inhibitor. Journal of Medicinal Chemistry 2016; 59: 1891-98.
- Gomha SM, Riyadh SM: Synthesis under microwave irradiation of [1, 2, 4] triazolo[3,4-b] [1,3,4]thiadiazoles and other diazoles bearing indole moieties and their antimicrobial evaluation. Molecules. 2011; 16: 8244-56.
- Yadav RR, Khan SI, Singh S, Khan IA, Vishwakarma RA and Bharate SB: Synthesis, anti-malarial and anti-tubercular activities of meridianin derivatives. European Journal of Medicinal Chemistry 2015; 98: 160-69.
- Giampieri M, Balbia A, Mazzeia A, Collab PL, Ibbab B and Loddob R: Antiviral activity of indole derivatives. Antiviral Research 2009; 83: 179-85.
- Zhang MZ, Jia CY, Gu YC, Mulholland N, Turner S, Beattie D, Zhang WH, Yang GF and Clough J: Synthesis and antifungal activity of novel indole-replaced streptochlorin analogues. European Journal of Medicinal Chemistry 2017; 126: 669-74.
- Mishra BB, Singh RK, Srivastava A, Tripathi VJ and Tiwari VK: Fighting against leishmaniasis: search of alkaloids as future true potential anti-leishmanial agents. Mini-Re. Med Chem 2009; 9 (1): 107-23.
- Estevão MS, Carvalho LC, Ribeiro D, Couto D, Freitas M, Gomes A, Ferreira LM, Fernandes E and Marques MMB: Antioxidant activity of unexplored indole derivatives: Synthesis and screening. European Journal of Medicinal Chemistry 2010; 45: 4869-78.
- Stec J, Onajole Lun OK, Guo H, Merenbloom B, Vistoli G, Bishai WR and Kozikowski AP: Indole-2-carboxamide-based MmpL3 inhibitors show exceptional anti-tubercular activity in an animal model of tuberculosis infection. Journal of Medicinal Chemistry 2016; 10: 6232-47.
- Ishikawa H, Colby DA and Boger DL: Direct coupling of catharanthine and vindoline to provide vinblastine: Total synthesis of (þ)- and ent-(-)-vinblastine. J Am Chem Soc 2008; 130: 420-21.
- Desa-Alves FR, Barreiro EJ and Fraga C: From nature to drug discovery: the indole scaffold as a ‘privileged structure. Mini-Reviews in Medicinal Chemistry 2009; 9: 782-93.
- Evans BE, Rittle KE, Bock MG, DiPardo RM, Freidinger RM, Whitter WL, Lundell G. F, Veber DF, Anderson PS, Chang RS, Lotti VJ, Cerino DJ, Chen TB, Kling PJ, Kunkel KA, Springer JP and Hirshfield J: Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. Journal of Medicinal Chemistry 1988; 31: 2235-46.
- Welsch ME, Snyder SA and Stockwell BR: Privileged scaffolds for library design and drug discovery. Current Opinion in Chemical Biology 2010; 14: 347-61.
- Kaushik NK, Kaushik N, Attri P, Kumar N, Kim CH, Verma AK and Choi EH: Biomedical importance of indoles. Molecules 2013; 18: 6620-62.
- Dolle RE and Nelson Jr KH: Comprehensive survey of combinatorial library synthesis. J Comb Chem 1999; 1: 235-282.
- Franzen RG: Recent advances in the preparation of heterocycles on solid support: A review of the literature. J Comb Chem 2000; 2: 195-14.
- Dolle RE: Comprehensive survey of combinatorial library synthesis. J Comb Chem 2001; 3: 477-17.
- Cao C, Shi Y and Odom AL: Intermolecular alkyne hydroamination by 1, 1-Disubstituted hydrazines. Org Lett 2002; 4: 2853-56.
- Buchwald CJ and Buchwald SL: Palladium-catalyzed regioselective hydrodebromination of dibromoindoles: application to the enantioselective synthesis of indolodioxane U86192A. J Org Chem 2004; 69: 3336-39.
- Sundberg RJ, Laurino JP and Laurino JP: Cyclization of 2-[N-(methylsulfonyl)anilino]acetaldehyde diethyl acetals to indoles. Evidence for stereoelectronic effects in intramolecular electrophilic aromatic substitution Journal of Organic Chemistry. The Journal of Organic Chemistry 1984; 49: 249-54.
- Hemetsberger H, Knittel D and Weidmann H: "Enazide, 3. Mitt.: Thermolyse von α-Azidozimtestern; Synthese von Indolderivaten." Monatshefte für Chemie/Chemical Monthly 1970; 101(1): 161-65.
- Hayakawa K, Yasukouchi T and Kanematsu K: A new approach to the efficient indole synthesis by allene intramolecular cycloaddition. Tetrahedron Lett 1986; 27: 1837-40.
- Moskal J and Van Leusen AM: A new synthesis of indoles by electrocyclic ring closure of dialkenylpyrroles. Synthesis of alkenylpyrroles from 1-tosylalkenyl isocyanides and Michael acceptors. Journal of Organic Chemistry 1986; 51: 4131-39.
- Ketcha, Daniel M, Wilson LJ and Portlock DE: "The solid-phase Nenitzescu indole synthesis." Tetrahedron Letters 2000; 41(33): 6253-57.
- Houlihan WJ, Parrino VA and Uike Y: Lithiation of N-(2-Alkylphenyl)alkanamides and Related Compounds. A Modified Madelung Indole Synthesis. Journal of Medicinal Chemistry 1981; 46: 4511-15.
- Baudin JB, Julia SA: Synthesis of indoles from N-aryl-1-alkenylsulphinamides. Tetrahedron Lett 1986; 27: 837-40.
- Tabbi A, Kaplancikli ZA, Tebbani D, Yurttas L, Canturk Z, Atli O, Baysal M and Zitounl GL: Synthesis of novel thiazolylpyrazoline derivatives and evaluation of their antimicrobial activities and cytotoxicities. Turk J Chem 2016; 40: 641-54.
- World Health Organization (WHO), http://www.who. int/ mediacentre/ news/ releases/ 2018/antibiotic-resistance-found/en/ Retrieved on 30-08-2018.
- Sanna G, Madeddu S, Giliberti G, Piras S, Struga M, Wrzosek M, Tomaszewska K, Koziol AE, Savchenko O, Lis T, Stefanska J, Tomaszewski P, Skrzycki MD and Szulczyk: Synthesis and biological evaluation of novel indole-derived thioureas. Molecules 2018; 23(10): 2554.
- Hafez NAA, Elsayed MA, El-Shahawi MM, Awad GEA and Alia KA: Synthesis and antimicrobial activity of new thiazolidine-based heterocycles as rhodanine. J Heterocyclic Chem 2018; 55: 685-91.
- Abo-Ashour MF, Eldehna WM, George RF, Abdel-Aziz MM, Elaasser MM, Abdel Gawad NM, Gupta A, Bhakta S and Abou-Seri SM: Novel indole-thiazolidinone conjugates: Design, synthesis and whole-cell phenotypic evaluation as a novel class of antimicrobial agents. Eur J Med Chem 2018; 160: 49-60.
- Sayed M. Kamal El-Dean AM, Ahmed M and Hassanien R: Synthesis of some heterocyclic compounds derived from indole as antimicrobial agents. Synt Comm 2018; 48:413-421.
- Gani RS, Karabasanagouda T, Kumari S, Chalannavar RK, Malabadi RB, Chougale RB, Masti S and Kasai D: Chemo selective synthesis and evaluation of antimicrobial activity of novel 5-hydroxyindole derivatives. Der Pharmacia Sinica 2017; 8: 1-9.
- Mane YD, Sarnikar YP, Surwase S. Biradar DO. Gorepatil PB, Shinde VS and Khade BC: Design, synthesis, and antimicrobial activity of novel 5-substituted indole-2-carboxamide derivatives. Res Chem Intermediates 2017; 43: 1253-75.
- Badgujar JR, More DH and Meshram JS: Synthesis, antimicrobial and antioxidant activity ofpyrazole-based sulfonamide derivatives. Ind J Microbiol 2018; 58: 93-99.
- Faria JV, Vegi PF, Miguita AGC, Dos Santos MS, Boechat N and Barnardino AMR: Recently reported biological activities of pyrazole compounds. Bioorg Med Chem 2017; 25: 5891-03.
- Skocibusic M, Odžak R, Ramić A, Smolić T, Hrenar T and Primožič I: Novel imidazolaldoximes with broad-spectrum antimicrobial potency against multidrug-resistant gramnegative bacteria. Molecules 2018; 23: 1212.
- Quazi I, Sastry VG and Ansari JA: Synthesis and antimicrobial activity of indole derivative bearing the pyrazole moiety. IJPSR 2017; 8: 1145-15.
- Rajaraman DM, Sundararajan G, Loganath NK and Krishnasamy K: Synthesis, molecular structure, DFT studies and antimicrobial activities of some novel 3-(1-(3,4-dimethoxyphenethyl)-4,5-diphenyl-1H-imidazol-2-yl)-1H-indole derivatives and its molecular docking studies. J Mol Str 2017; 1127: 597-10.
- Yadav BP, Ahmad I and Thakur M: Synthesis of some novel indole derivatives as potential antibacterial, antifungal and antimalarial agents. IOSR. J Pharm 2016; 6: 27-33.
- Choppara P, Bethu MS, Prasad YV, Rao JV, UdayRanjan TJ, Siva Prasad GV, Doradla R and Murthy YLN: Synthesis, characterization and cytotoxic investigations of novelbis(indole) analogues besides antimicrobial study. Arab J Chem 2015; https://doi.org/10.1016/j.arabjc.2015. 05.015.
- Gali R, Banothu J, Gondru R, Bavantula R, Velivela Y and Crooks PA: One pot multicomponent synthesis of indole incorporated thiazolylcoumarins and their antibacterial, anticancer and DNA cleavage studies. Bioorg Med Chem Lett 2015; 25: 106-12.
- Popiołek: Hydrazide-hydrazones as potential antimicrobial agents: overview of the literature since 2010. Med Chem Res 2017: 26; 287-01.
- Neeraj K, Chauhan LS: Antimicrobial potential of hydrazide-hydrazone derivatives: review. Int J Pharm Clinical Res 2015; 7: 154-61.
- Shirinzadeh H, Altanlar H, Altanlar N, Yucel N, Ozden S and Suzen S: Antimicrobial evaluation of indole-containing hydrazone derivatives, Z. Naturforsch C. 2011; 66: 340-44.
- Nassar E: Synthesis, (in-vitro) Antitumor and Antimicrobial Activity of some Pyrazoline, Pyridine, and Pyrimidine Derivatives Linked to Indole Moiety. Jour Am Sc 2010; 6: 338-347.
- El-Sayed MT, Suzen S, Altanlar N, Ohlsen K and Hilgeroth A: Discovery of bisindolyl-substituted cycloalkane-anellated indoles as novel class of anti-bacterial agents against S. aureus and MRSA. Bioorg Med Chem Lett 2015; 26(1): 218-21.
- Praveen C, Bethu MS, Prasad YV, Rao JV, Ranjan TJU, Siva Prasad GV, Doradla R and Murthy YL: Synthesis, characterization and cytotoxic investigations of novel bis(indole) analogues besides antimicrobial study. Arabian J Chem 2019; 12(8): 2721-31.
- Shi Z, Zhao Z, Huang M and Fu X: Ultrasound-assisted, one-pot, three-component synthesis and antibacterial activities of novel indole derivatives containing 1, 3, 4-oxadiazole and 1, 2, 4-triazole moieties.CR Chimie 2015; 18 (12): 1320-27.
- Kaplancikli TA, Turan-Zitouni G and Chevallet P: Synthesis and antituberculosis activity of new 3-alkylsulfanyl-1, 2, 4- triazole derivatives. J Enzyme Inhib Med Chem 2005; 20: 179-82.
- Global Tuberculosis Report. World Health Organization (WHO), 2019; Available from: www.who.int/tb [last accessed on January 28, 2020].
- World Health Organization (WHO), http:// www. who. int/ tb/ publications / global_ report/en/. World Health Organization. Retrieved on 20-04-2018.
- CDC: Reported tuberculosis in the United States, 2016. Atlanta, GA: US Department of Health and Human Services. CDC 2017.
- Abo-Ashour MF, Eldehna WM, George RF, Abdel-Aziz MM, Elaasser MM, Abdel Gawad NM, Gupta A, Bhakta S and Abou-Seri SM: Novel indole-thiazolidinone conjugates: Design, synthesis and whole-cell phenotypic evaluation as a novel class of antimicrobial agents. European Journal of Medicinal Chemistry 2018; 160: 49-60.
- Trott O, Olson AJ: AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455-61.
- Khan GA, Warb JA, Kumar IA, Sheikh A, Saxenaa R and Das A: facile synthesis of novel indole derivatives as potential antitubercular agents. Journal of Taibah University Medical Sciences 2017; 11: 921.
- Rohde KH, Michaels HA and Nefzi A: Synthesis and antitubercular activity of 1, 2, 4- trisubstituedpiperazines, Bioorg Med Chem Lett 2016; 26; 2206-09.
- Patel KN, Telvekar VN: Design, synthesis and antitubercular evaluation of novel series of N-[4-(piperazin-1-yl) phenyl] cinnamamide derivatives. European Journal of Medicinal Chemistry 2014; 75: 43-56.
- Naidu KM, Srinivasarao S, Agnieszka N, Ewa AK, Kumar MM and Chandra KV: Seeking potent anti-tubercular agents: Design, synthesis, anti-tubercular activity and docking study of various (triazoles/indole)-piperazin-1-yl/1, 4-diazepan-1-yl) benzo [d] isoxazole derivatives. Bioorg Med Chem Lett 2016; 26: 2245-50.
- Stec J, Onajole OK, Lun S, Guo H, Merenbloom B, Vistoli G, Bishai WR and Kozikowski AP: Indole-2-carboxamide-based mmpl3 inhibitors show exceptional antitubercular activity in an animal model of tuberculosis infection. Journal of Medicinal Chemistry 2016; 59: 6232-47.
- Schrödinger Release 2019-4: Bio Luminate, Schrödinger, LLC, New York, NY 2019
- Desai NC, Somani H, Trivedi A, Bhatt K, Nawale L, Khedkar VM, Jha PC and Sarkar D: Synthesis, biological evaluation and molecular docking study of some novel indole and pyridinebased 1.3.4-oxadiazole derivatives as potential antitubercular agents. Bioorganic & Medicinal Chemistry Letters 2016; 26: 1776-83.
- Khan GA, War JA, Naikoo GA, Pandit UJ and Das R: Porous CuO catalyzed green synthesis of some novel 3-alkylated indoles as potent antitubercular agents. J Saudi Chem Soc 2018; 22: 6-15.
- Mandewale MC, Thorat B, Shelke D and Yamgar R: Synthesis and biological evaluation of new hydrazone derivatives of quinoline and their Cu(II) and Zn(II) complexes against Mycobacterium tuberculosis. Bioinorg Chem Appl 2015; 201: 153015.
- Thomas B, Anju LS and Harindran J: Novel mannich bases of 4-thiazolidinone derivatives as antitubercular agents. IJRPC 2014; 4: 351-359.
- Mustapha C, Mandewale MC, Udaysinha C, Patil UC, Shedge SV, Dappadwad UR and Yamgar RS: A review on quinolinehydrazone derivatives as a new class of potent antitubercular and anticancer agents. Beni-Suef Univ. J Basic Appl Sci 2017; 6: 354-61.
- Üstündağ GC, Şatana D, Özhan G and Çapan G: Indole-based hydrazide-hydrazones and 4-thiazolidinones: synthesis and evaluation as antitubercular and anticancer agents. J Enzyme Inhib Med Chem 2016; 1: 369-80.
- Kondreddi RR, Jiricek J, Rao SP, Lakshminarayana SB, Camacho LR, Rao R, Herve M, Bifani P, Ma NL, Kuhen K and Goh A: Chatterjee AK, Dick T, Diagana TT, Manjunatha UH and Smith PW: Design, synthesis, and biological evaluation of indole-2-carboxamides: a promising class of antituberculosis agents. J Med Chem 2013; 56: 8849-59.
- Tehrani KHME, Mashayekhi V, Azerang P, Sardari S, Kobarfard F and Ostamizadeh KR: Synthesis and antimycobacterial activity of novel thiadiazolylhydrazones of 1-substituted indole- 3-carboxaldehydes. Chem Biol Drug Des 2014; 83: 224-36.
- Selvaretnam AAP, Sahu PS, Sahu M and Ambu S: A review of concurrent infections of malaria and dengue in Asia. Asian Pacific J Trop Biomedicine 2016; 6: 633-38.
- World Health Organization (WHO), http:// apps. who. int/ iris/ bitstream/ handle/ 10665/259492/9789241565523-e jsessionid=D585F2C066C6B97CEA476DF1B59DC6A D?sequence=1 Retrieved on 30-08-2018.
- Yadav BP, Ahmad I and Thakur M: Synthesis of some novel indole derivatives as potential antibacterial, antifungal and antimalarial agents. IOSR. J Pharm 2016; 6: 27-33.
- Schuck DC, Jordão AK, Nakabashi M, Cunha AC, Ferreira VF and Garcia CR: Synthetic indole and melatonin derivatives exhibit antimalarial activity on the cell cycle of the human malaria parasite Plasmodium falciparum. Eur J Med Chem 2014; 78: 375-82.
- Singh SK, Singh S: A brief history of quinoline as antimalarial agents. Int J Pharm Sci Rev Res 2014; 25: 295-02.
- Golden EB, Cho H, Y, Hofman FM, Louie SG, Schönthal AH and Chen TC: Quinoline based antimalarial drugs: a novel class of autophagy inhibitors, Neurosurg Focus 2015; 38: doi.org/10.3171/2014.12. FOCUS14748.
- Teguh SC, Klonis N, Duffy S, Lucantoni L, Avery VM, Hutton CA, Baell JB and Tilley L: Novel conjugated quinoline-indoles compromise plasmodium falciparum mitochondrial function and show promising antimalarial activity. J Med Chem 2013; 56: 6200-15.
- Bharate SB, Yadav RR, Khan SI, Tekwani BL, Jacob MR, Khan IA and Vishwakarma RA: Meridianin and its analogs as antimalarial agents. Med Chem Comm 2013; 4: 1042-48.
- Santos SA, Lukens AK, Coelho L, Nogueira F, Dyann F, Wirth Mazitschek R, Moreira R, Paulo A: Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype. Eur J Med Chem 2015; 102: 320-33.
- Schuck DC, Jordao AK, Nakabashi M, Cunha AC, Ferreira VF and Garcia CRS: Synthetic indole and melatonin derivatives exhibit antimalarial activity on the cell cycle of the human malaria parasite Plasmodium Falciparum. Eur J Med Chem 2014; 78: 375-82.
- https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics. Retrieved on 22-04-2018.
- Zhang MZ, Chen Q and Yang GF: A review on recent developments of indole-containing antiviral agents. Eur J Med Chem 2015; 89: 421-41.
- Scuotto M, Abdelnabi R, Collarile S, Schiraldi C, Delang L, Massa A, Ferla S, Brancale A, Leyssen P, Neyts J and Filosa R: Discovery of novel multi-target indole-based derivatives as potent and selective inhibitors of chikungunya virus replication. Bioorg Med Chem 2016; 25: 327-37.
- Jiang T, Kuhen KL, Wolff K, Yin H, Bieza K, Caldwell J, Bursulaya B, T zhang K, Karanewsky D, He Y: Design, synthesis and biological evaluations of novel oxindoles as HIV-1 non-nucleoside reverse transcriptase inhibitors. Part I, Bioorg Med Chem Lett 2006; 2109-12.
- Chen L, Liu Y, Song H, Liu Y, Wang L, Wang Q: Expanding indole diversity: direct 1-step synthesis of 1,2-fused indoles and spiroindolines from 2-halo anilines for fast SAR antiviral elucidation against tobacco mosaic virus (TMV). Mol Divers 2017; 21: 61-68.
- Musella S, di Sarno V, Ciaglia T, Sala M, Spensiero A, Scala MC, Ostacolo C, Andrei, GJ Balzarini, Snoeck R, Novellino E, Campiglia P, Bertamino A and Gomez-Monterrey IM: Identification of an indole-based derivative as potent and selective Varicella-zostervirus (VZV) inhibitor. Eur J Med Chem 2016; 124: 773-81.
- Hamad NS, Al-Haidery NH, Al-Masoudi IA, Sabri L, Sabri NA and Al-Masoudi N: Amino acid derivatives, part 4: synthesis and anti-HIV activity of new naphthalene derivatives. Arch Pharm (Weinheim) 2010; 343: 397-03.
- Giapieri M, Balbi A, Mazzei M, La Colla P, Ibba C and Loddo R: Antiviral activity of indole derivatives. Antiviral Res 2009; 83: 179-85.
- Soumya-Bindu AH: Opportunistic diseases as a consequence of HIV/AIDS. J AIDS Clinic Res 2 (2011) 133. http://dx.doi.org/10.4172/2155- 6113.1000133
- https://data.unicef.org/topic/hivaids/global-regional-trends/. Retrieved on 24-04-2018.
- Sanna G, Madeddu S, Giliberti G, Piras S, Struga M, Wrzosek MG, Kubiak- Tomaszewska AE, Koziol O, Savchenko T, Lis J, Stefanska P, Tomaszewski M and Skrzycki D: Synthesis and biological evaluation of novel indole-derived thioureas. Molecule 2018; 10: 2554.
- Dousson C, Alexandre FR, Amador A, Bonaric S, Bot S, Caillet C, Convard T, Costa D, Lioure MP, Roland A, Rosinovsky S, Maldonado C, Parsy C, Trochet R, Storer A, Stewart J, Wang B A, Mayes C, Musiu B, Poddesu, Vargiu M, Liuzzi A, Moussa J, Jakubik L, Hubbard M and Seifer D: Discovery of the Aryl-phosphoindole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor. J Med Chem 2016; 59: 1891-98.
- Ravichandran VS, Shalini K, Venkateskuma S and Dhanaraj A: Exploring the structuralinsights of Indole-7-carboxamides as anti-HIV agents. FARMACIA 2016; 64: 745-56.
- Lu P, Ashok CL, Chander YT and Zheng S: Murugesan. Design, synthesis, and biologicalevaluation of 1-(thiophen-2-yl)-9H-pyrido [3,4-b] indole derivatives as anti-HIV agents. Chem Biol Drug Des 2015; 85: 722-28.
- Jiang HX, Zhuang DM, Huang XX, Cao JY, Zhang CB and Jiang B: Design, synthesis,and biological evaluation of novel trifluoromethyl indoles as potent HIV-1 NNRTIs with animproved drug resistance profile. Org Biomol Chem 2014; 12: 3446-58.
- Ferro S, Morreale LS, Christ F, Debyser Z, Gitto R and Chimirri A: Synthesis and biologicalevaluation of novel antiviral agents as protein-protein interaction inhibitors. J Enzyme Inhib Med Chem 2014; 29: 237-42.
- Hassam M, Basson AE, Liotta DC, Morris L, Van Otterlo WA and Pelly SC: Novel Cyclopropyl-Indole Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors. ACS Med Chem Lett 2012; 3: 470-75.
- Balupuri A, Gadhe CG, Balasubramanian PK, Cho G and Kothandan SJ: In-silico study onindole derivatives as anti HIV-1 agents: a combined docking, molecular dynamics and 3DQSARstudy. Arch Pharm Res 2014; 37: 1001-15.
- Yeung KS, Qiu ZQ, Fang H, Yang Z, Zadjura L, Eggers CD, Riccardi B, Gong KPY, Browning YF, Gao Q, Hansel S, Lin PF, Santone, NA, Meanwell J and Kadow NF: Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents. Bioorg Med Chem Lett 2013; 23: 198-02.
- La G, Regina A, Brancale A, Piscitelli F, Amiglini V, Cosconati SG, Samuele A, Gonzalez E, Clotet B, Schols D, Este Novellino JA and Silvestri ER: New nitrogen containing substituent at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors. J Med Chem 2012; 55: 6634-38.
- La Regina G, Coluccia A, Brancale A, Piscitelli F, Gatti V, Maga G., Samuele A, Pannecouque C, Schols D, Balzarini J, Novellino E and Silvestri R: Indolylarylsulfones as HIV-1nonnucleoside reverse transcriptase inhibitors: new cyclic substituents at indole-2-carboxamide. J Med Chem 2011; 54: 1587-98.
- Tichy M, Pohl R, Xu HY, Chen Y, Yokokawa F and Shi P: Synthesis and antiviral activity of 4,6-disubstituted pyrimido[4,5-b] indole ribonucleosides. Bioorg Med Chem 2012; 20: 6123-33.
- Xue S, Ma L, Gao R and Li Y: Synthesis and antiviral activity of some novel indole-2-carboxylate derivatives. Acta Pharmaceutica Sinica B 2014; 4: 313-21.
- Zhang N, Turpoff A, Zhang X, Huang S, Liu Y, Almstead N, Njoroge FG, Gu Z, Graci J, Jung SP, Pichardo J, Colacino J, Lahser F, Ingravallo P, Weetall M, Nomeir A and Karp GM: Discovery of 2-(4-sulfonamidophenyl)-indole 3-carboxamides as potent and selective inhibitors with broad hepatitis C virus genotype activity targeting HCV NS4B. Bioorg Med Chem Letts 2015.
- Mitropoulos P, Konidas P and Durkin-Konidas M: New World cutaneous leishmaniasis: updated review of current and future diagnosis and treatment. J Am Acad Dermatol 2010; 63: 309-22.
- Oryan A, Akbari M: Worldwide risk factors in leishmaniasis. Asian Pac J Trop Med 2016; 9: 925-32.
- Porwal S, Gupta S and Chauhan PMS: gem-Dithioacetylated indole derivatives as novel antileishmanial agents. Bioorg Med Chem Lett 2017; 27: 4643-46.
- Félix MB, de Souza ER, de Lima MDCA, Frade DKG, Serafim KADF, Rodrigues P L DN, Néris FF, Ribeiro L, Scotti MT, Scotti TM, Mendonça junior FJB and de Oliveira MR: Antileishmanial activity of new thipheneindole hybrids: Junior, Design, synthesis, biological and cytotoxic evaluation and chemometric-studies. Bioorg Med Chem 2016; 24: 3972-77.
- Sharma R, Pandey AK, Shivahare R, Srivastava K, Gupta S and Chauhan PM: Triazino indole-quinoline hybrid: a novel approach to antileishmanial agents. Bioorg Med Chem Lett 2014; 24: 298-01.
- Bharate SB, Bharate JB, Khan SI, Tekwani BL, Jacob MR, Mudududdla R, Yadav R. R, Singh B, Sharma PR, Maity S, Singh B, Khan IA and Vishwakarma RA: Discovery of 3,3'-diindolylmethanes as potent antileishmanial agents. Eur J Med Chem 2013; 63: 435-43.
- Singh GS, Al-Kahraman YM, Mpadi D and Yasinzai M: Synthesis of N-(1-methyl-1H-indol- 3-yl) methylene-amines and 3, 3-diaryl-4- (1-methyl-1H-indol-3-yl) azetidin-2-ones as potential antileishmanial agents. Bioorg Med Chem Lett 2012; 22: 5704-06.
- Zhang MZ, Chen Q, Mulholland N, Beattie D, Irwin D, Gu YC, Yang GF and Clough J: Synthesis and fungicidal activity of novel pimprinine analogues. Eur J Med Chem 2012; 53: 283-91.
- Zhang MZ, Mulholland N, Beattie D, Irwin D, Gu YC, Chen Q, Yang GF and Clough J: Synthesis and antifungal activity of 3-(1,3,4-oxadiazol-5-yl)-indoles and 3-(1,3,4-oxadiazol-5- yl)methyl-indoles. Eur J Med Chem 2013; 63: 22-32.
- Zhang MZ, Chen Q, Xie CH, Mulholland N, Turner S, Irwin D, Gu YC, Yang GF and Clough J: Synthesis and antifungal activity of novel streptochlorin analogues 2015; 92: 776-783.
- Jia CY, Xu LY, Yu X, Ding YB, Jin B, Zhang MZ, Zhang WH and Yang GF: An efficient synthesis and antifungal evaluation of natural product streptochlorin and its analogues. Fitoterapia 2018; 125: 106-10.
- Chung-KyuRyu, Jung Yoon Lee, Rae-Eun Park, Mi-Young Ma and Ji-HeeNho: Synthesis and antifungal activity of 1H-indole-4,7-diones. Bioorg Medi Chem Lett 2007; 17: 127-31.
- Mishra S, Kaur M and Singh P: Rational modification of a lead molecule: Improving the antifungal activity of indole triazole–amino acid conjugates. 10.1016/j.ejmech.2018.06. 039 EJMECH 10509.
- Xu H and Fan L: Synthesis and antifungal activities of novel indole [1,2-c]-1,2,4-benzotriazine derivatives against phytopathogenic fungi in-vitro. Eur Jour Med Chem 2011; 46: 364-69.
- Ming-Zhi Z and Mulholland N: Synthesis and antifungal activity of 3-(1, 3, 4-oxadiazol-5-yl)-indoles and 3-(1,3,4-oxadiazol-5-yl) methyl-indoles. Eur Jour Med Chem 2013; 63: 22-32.
- Song Y, Wua F and Zhang C: Ionic liquid catalyzed synthesis of 2-(indole-3-yl)-thiochroman-4- ones and their novel antifungal activities. Bioorg Med Chem Lett 2015; 25: 259-61.
- Song Y, Wu F, Zhang C, Liang G, Zhou G and Yu J: Ionic liquid catalyzed synthesis of 2-(indole-3-yl)-thiochroman-4-ones and their novel antifungal activities. Bioorg Med Chem Letts 2015; 25: 259-61.
- Pooja P, Singh P, Pawar K, Vikramdeo KS, Mondal N and Komath SS: Synthesis of amino acid appended indoles: Appreciable anti-fungal activity and inhibition of ergosterol biosynthesis as their probable mode of action. European Journal of Medicinal Chemistry 2014; 80: 325-39.
- Zhang M, Mulholland N, Beattie D, Irwin D, Gu Y, Chen Q, Yang G and Clough J: Synthesis and antifungal activity of 3-(1, 3, 4-oxadiazol-5-yl)-indoles and 3-(1, 3, 4-oxadiazol-5-yl) methyl-indoles. Eur J Med Chem 2013; 63: 22-32.
- Dakal TC, Kumar A, Majumdar RS, Yadav V. Mechanistic basis of antimicrobial actions of silver nanoparticles. Frontiers in microbiology 2016; 7: 1-17.
How to cite this article:
Hussain K, Alam MJ, Hussain A and Siddique NA: Therapeutic significance of indole scaffold in medicinal chemistry. Int J Pharm Sci & Res 2020; 11(11): 5441-60. doi: 10.13040/IJPSR.0975-8232.11(11).5441-60.
All © 2013 are reserved by the International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
K. Hussain, M. J. Alam, A. Hussain and N. A. Siddique *
Bioactive Natural Compound, Laboratory (BNCL), Department of Pharmacognosy and Phytochemistry, Glocal School of Pharmacy, Glocal University, Saharanpur, Uttar Pradesh, India.
11 February 2020
27 April 2020
08 May 2020
01 November 2020