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Review

Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2

by
Adel S. Girgis
1,*,
Siva S. Panda
2,3,*,
Benson M. Kariuki
4,
Mohamed S. Bekheit
1,
Reham F. Barghash
1 and
Dalia R. Aboshouk
1
1
Department of Pesticide Chemistry, National Research Centre, Dokki, Giza 12622, Egypt
2
Department of Chemistry and Biochemistry, Augusta University, Augusta, GA 30912, USA
3
Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA
4
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(18), 6603; https://doi.org/10.3390/molecules28186603
Submission received: 5 August 2023 / Revised: 7 September 2023 / Accepted: 9 September 2023 / Published: 13 September 2023
(This article belongs to the Special Issue Design, Synthesis and Structure-Activity Relationship of Biologically Active Inhibitors)
Browse Figures
Versions Notes

Abstract

:
The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. The disease quickly spreads due to the highly infectious SARS-CoV-2 virus, which has undergone numerous mutations. Despite intense research efforts by the scientific community since its emergence in 2019, no effective therapeutics have been discovered yet. While some repurposed drugs have been used to control the global outbreak and save lives, none have proven universally effective, particularly for severely infected patients. Although the spread of the disease is generally under control, anti-SARS-CoV-2 agents are still needed to combat current and future infections. This study reviews some of the most promising repurposed drugs containing indolyl heterocycle, which is an essential scaffold of many alkaloids with diverse bio-properties in various biological fields. The study also discusses natural and synthetic indole-containing compounds with anti-SARS-CoV-2 properties and computer-aided drug design (in silico studies) for optimizing anti-SARS-CoV-2 hits/leads.

1. Introduction

The indole moiety is one of the most privileged scaffolds in the alkaloid category. Indole-containing compounds are widely distributed in plants, animals, and microorganisms and represent important pharmacophores that can bind with receptors controlling bio-properties [1]. Diverse biological properties have been exhibited by natural and synthetic indole-containing analogs, including anti-microorganism activities such as antibacterial [2,3,4,5], antifungal [6,7,8], antiviral [9,10,11,12,13,14], and mycobacterial [15] action. Cipargamin (Figure 1), which has an indolyl scaffold, has been identified as a potent protein synthesis inhibitor in Plasmodium falciparum and has subsequently progressed to pre-clinical trials as a potential antimalarial drug [16]. Other potential antimalarial candidates with the indolyl scaffold have also been reported [17,18,19,20]. Anti-diabetic [21,22] and anti-inflammatory [23,24,25,26,27] properties have also been observed for indole derivatives. Figure 2 presents some of the indole-containing drugs approved for the treatment of a range of conditions [1,2,28,29,30,31,32,33,34,35,36,37,38]. Indole-based anticancer drugs and potent agents [28,39,40,41,42,43,44,45,46,47,48,49,50] are illustrated in Figure 3 and many indolyl analogs identified as antitumor-active candidates have also been reported [51,52,53,54,55,56,57].
The coronavirus disease 2019 (COVID-19) has proved to be one of the most serious crises facing human health in recorded history. The disease is caused by the fast-spreading infectious virus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), transmitted between humans and threatening human life worldwide. Until 2019, the virus strain had not been reported as invasive among humans [58]. The first infection was initially linked to a fish and wild animal market in Wuhan City, China, at the end of 2019 before the disease dramatically spread, within a few weeks, to almost all countries of the world, affecting millions of people [59]. The World Health Organization (WHO) declared a global severe emergency and pandemic in March 2020 [60]. To date (5 July 2023), WHO statistics have officially counted/confirmed 767.7 million infected patients with 6.949 million deaths worldwide [61].
The symptoms of COVID-19 are similar to those observed for many other conditions and seasonal diseases (flu is an example) and include cough, runny nose, mild fever, and headache. Breathing difficulties, chest pain, and hypertension occur in severe infections that require hospitalization in intensive care and oxygen supply [62,63]. The pandemic placed many countries under unprecedented economic pressure due to the curtailment of normal social activities that affected a significant amount of the global population. The scientific community, including research institutes, universities, and pharmaceutical companies, devoted considerable resources to studying the cell biology of SARS-CoV-2, identifying diagnostic agents, and optimizing effective therapeutics [64].
SARS-CoV-2 is a zoonotic single-strand RNA (ssRNA(+)) virus covered by glycoprotein spikes and belongs to the Coronaviridae family. It is mainly found in bats, but, for unknown reasons, was transmitted to the human species, leading to the global pandemic. The viral RNA genetic material can directly act as viral messenger RNA, producing the viral protein inside the host cell [65,66,67,68]. Numerous waves of viral mutations were detected, potentially affecting transmissibility and severity in humans. Delta (B.1.617) and Delta plus (B.1.617.2) are deadlier and more infectious than the other mutations (for example, Alpha, B.1.1.7; Beta, B.1.351; or Gamma, P.1) [62]. Omicron is more extensively mutated and was detected in November 2021 with the viral wave spreading worldwide. Although it has a higher risk of infection/reinfection, it has milder symptoms and lower fatality in vaccinated people. This may be a factor in the pandemic transitioning to an epidemic [69].
Vaccination is one of the most important means for controlling the development of a pandemic and saving human lives. The neutralizing antibodies from vaccination can protect against viral infection or at least result in milder/weaker symptoms upon infection. In the case of COVID-19, BNT162b2 (Pfizer “USA”/BioNTech “Germany”), mRNA-1273 (Moderna, MA, USA), and AZD1222 (University of Oxford “UK” and AstraZeneca “British-Swedish”) have been the most prominent vaccines discovered and used worldwide [60,69]. Herd immunity is the aim of large-scale vaccination, and it may limit the extent of infection and terminate a global pandemic. In the case of COVID-19, evidence for the acquired immunity in recovered patients was limited, raising questions about the herd immunity hypothesis. Consequently, the acquired immunity due to vaccination antibodies is not certain against infection/re-infection [59,70].
Biochemical studies have identified some proteins involved in SARS-CoV-2 infections (Figure 4 summarizes some) [71], and thus, are potential targets for controlling the infection and optimizing potential therapeutics.
The emerging healthcare crisis due to the global outbreak caused by the pathogenic SARS-CoV-2 virus united the scientific community and the pharmaceutical industry in a race against time in the search and optimization of any medicinal entity/device/therapeutic capable of controlling the spread of COVID-19 and bringing back normality [72]. De-novo drug development usually follows several successive steps. The first is the discovery of potent and safe agents from among many candidates. Preclinical studies support the biochemical mode of action and applicability of the agents as potentially therapeutic. Clinical trials are essential for assessing success and identifying side effects. The post-marketing safety monitoring step is necessary to continue the new therapeutics as one of the available medications. Drug development is, therefore, time-consuming and costly, requiring about 10–15 years and millions of dollars to progress from the pre-identification of the potent/lead compound through to the medical store. Only about 10% of the potential agents are successful [73,74,75].
In silico studies utilizing various techniques/software can assist in assigning anti-SARS-CoV-2 agents. This may shorten the time needed for identifying potential entities to be submitted for in vitro/in vivo testing followed by the clinical trial(s) phases. In other words, in silico studies are a shortcut to attaining the final targeted therapeutics, saving the time and money required [76,77]. Additionally, drug repurposing/re-profiling, a strategy that considers the use of approved or investigated drugs outside the original therapeutic application, can shorten the period needed due to the well-established safety profile and understood side effects/drawbacks. This approach has many advantages over developing entirely novel therapeutics, including cost reduction and lower risk [78,79,80]. Several antiviral (Remdesivir, GS-441524, Sofosbuvir, Lopinavir, Ritonavir, Oseltamivir, Triazavirin, Favipiravir, Galidesivir, Danoprevir, Molnupiravir, Nirmatrelvir), anticancer (Ruxolitinib, Toremifene, Carmofur, Selinexor, Zotatifin, Duvelisib, Zanubrutinib, Opaganib, Imatinib), antimalarial (Chloroquine, Hydroxychloroquine, Dihydroartemisinin, Piperaquine), anti-inflammatory (Ibuprofen, Naproxen, Indomethacin, Celecoxib), and immunomodulatory (Corticosteroids, Fingolimod, (R)-(+)-Thalidomide, (S)-(–)-Thalidomide) active agents/drugs have been repurposed for anti-SARS-CoV-2 application (Figure 5, Figure 6 and Figure 7) [63,81,82,83,84,85].
Remdesivir (Figure 5) is a broad-spectrum antiviral agent. It was the first therapeutic granted approval under emergency-use authorization by the Food and Drug Administration (FDA) [9,59,73]. Gilead Sciences originally developed it as an anti-Ebola virus agent. It was approved as a COVID-19 therapeutic with RNA-dependent RNA polymerase (RdRp) inhibitory properties due to its ability to be metabolized in the infected/host cell analogs to a nucleoside triphosphate. It can terminate viral replication through RdRp action via integration in the RNA viral chain [9,86]. Molnupiravir (Lagevrio) (Figure 5) was awarded FDA approval in December 2021 [87,88]. It also exerts its anti-SARS-CoV-2 activity via RdRp inhibition [9]. Paxlovid, a combination of Nirmatrelvir and Ritonavir (Figure 5), was awarded FDA approval in December 2021 [89]. Ritonavir/Pf-07321332 acts against SARS-CoV-2 through main protease (Mpro) inhibition [83].
Our current discussion builds upon our previous work, which aimed to explore materials with anti-SARS-CoV-2 properties that could potentially aid in identifying agents against COVID-19 [9,66,90,91,92,93]. Specifically, we examine indole-containing compounds, whether they are naturally occurring or artificially created, that may possess anti-SARS-CoV-2 properties (Supplementary Materials Table S1).

2. Repurposed Indole-Containing Drugs

2.1. Umifenovir (Arbidol)

Umifenovir (Arbidol) (Figure 8) is a broad-spectrum antiviral drug with inhibitory properties against both RNA and DNA viruses such as Zika, influenza, hepatitis (HBV, HCV), ebola, West Nile, and herpes viruses [94,95]. It is one of the drugs that has been repurposed against COVID-19 and has IC50 = 4.11 μM against SARS-CoV-2 [96]. It acts through the inhibition of the lipid envelope thereby limiting contact, and hence, the fusion of the viral cell (membrane fusion inhibitor) with the host/human cell (targeting S-protein/ACE2 “angiotensin-converting enzyme 2”) [97,98,99,100]. Computational studies including molecular docking (PDB ID: 6LZG) [101] and molecular dynamics [102,103] support the mode of action. The antioxidant properties of Arbidol have also been attributed to its ability to react with free radicals. This may indicate that the anti-SARS-CoV-2 bio-properties of Arbidol arise from several biochemical pathways [94]. Clinical studies have confirmed the suitability of Arbidol as a monotherapy or in combination with other therapeutics for COVID-19 patients [104,105,106,107,108,109,110,111,112,113,114]. Some countries (e.g., Russia, China, and Iran [95]) have awarded licenses to Arbidol for the prevention or treatment of COVID-19 [115].
A series of Arbidol analogs 1–8 have been synthesized starting from 5-hydroxy-2-methylindole-3-carboxylate (Scheme 1). Potential binding of the compounds with the spike glycoprotein (S-protein, ACE2 binding) was determined (Figure 9) revealing no inhibition rates greater than 20%. Some inhibitory properties at low concentrations were higher than others but this can be explained in terms of the low solubility of the compounds in aqueous medium [96].
Arbidol analogs (A1–A36) have also been designed, through in silico studies using Schrodinger software, as inhibitors of ACE2, which is the key receptor that facilitates the entrance of the SARS-CoV-2 virus into the host cell (PDB ID: 6LZG) in addition to the proteases such as furin (PDB ID: 5MIM), TMPRSS2 (transmembrane protease serine 2), TMPS2 human, and 3CLpro (3 chymotrypsin-like protease, PDB ID: 6LU7), which are essential for the viral replication. This approach may enable the optimization of multi-targeted inhibitor agents with potential efficacy against COVID-19, but the lack of experimental bio-properties data limits progress [116] (Figure 10).

2.2. Indomethacin

Indomethacin (Figure 7) is a non-steroidal anti-inflammatory (NSAID) and analgesic drug used worldwide [29,117,118]. It works through the non-selective inhibition of cyclooxygenase (COX), which is the key enzyme to produce prostaglandin from arachidonic acid. Prostaglandin is responsible for inflammation and pain [119]. Inflammation is a natural response of the human body due to harmful effects. It is associated with many diseases, including microorganism (bacterial/viral) infections, cancers, and asthma [90].
Although indomethacin does not inhibit the replication of SARS-CoV-2 (infected Vero E6 bio-assay), studies have reported its potential as a co-treatment for COVID-19 patients due to its potent efficacy against symptoms associated with the disease [120,121,122,123,124]. Some Indomethacin-Remdesivir conjugates-based proteolysis-targeting chimeras (PROTAC) (B1–B4) have been reported with enhanced properties against SARS-CoV-2/NL/2020 and SARS-CoV-2/Padova/2021 strains relative to the parent indomethacin (EC50 = 94.9; CC50 > 500 µM against SARS-CoV-2/NL/2020) [121] (Figure 11). Conjugation between these drugs, or similar agents, can be a useful approach for optimizing promising hits/leads against SARS-CoV-2.

2.3. Lufotrelvir (PF-07304814)

Lufotrelvir (PF-07304814) (Figure 12) is a SARS-CoV-2 main protease (Mpro) inhibitor developed by Pfizer for intravenous application. The phosphate group is cleaved in vivo liberating PF-00835231, the effective agent against various viral strains [125].

2.4. Obatoclax (GX15-070)

Obatoclax (GX15-070) (Figure 13) is an antitumor agent (leukemia, lymphoma, and lung) via BCL-2 protein inhibition inducing mitochondrial apoptosis and has been subjected to Phase II clinical trials. It was repurposed for COVID-19 due to its promising properties against ACE2, thereby blocking cellular entry by the infectious virus [126].

3. Natural Indole-Containing Compounds

3.1. Melatonin

Melatonin is a natural hormone primarily biosynthesized from tryptophan by the pinealocytes of the pineal gland in the brain in the dark (hormone of darkness) and transferred by blood to the body organs from the cerebrospinal fluid. It exerts several biological properties [127,128,129,130,131] (Figure 14). The correlation between the COVID-19 fatalities in the elderly and the decrease in melatonin secretion rate drew attention to a possible application of the hormone for treatment [132]. The ability of melatonin as an antioxidant and anti-inflammation also suggested a potential role as an anti-SARS-CoV-2 [133]. Due to its safety profile and diverse bio-properties, numerous reports have considered the role of melatonin in preventing and treating COVID-19 [134,135,136,137,138,139]. Clinical studies/observations have supported its ability to reduce the severity of the disease, shorten the hospitalization period, or lead to complete recovery upon administration, either as a mono-therapeutic [137,138,139] or with other therapeutics, for COVID-19 infected patients [134,135,136].

3.2. Neoechinulin A, Echinulin, and Eurocristatine

The natural compounds neoechinulin A, echinulin, and eurocristatine (Figure 15) can be obtained from organisms such as Aspergillus fumigatus MR2012. Neoechinulin A and echinulin have Mpro-SARS-CoV-2 inhibitory properties (IC50 = 0.47, 3.90 μM, respectively) [140]. For comparison, the value is (IC50 = 0.36 μM) for GC376, a potent Mpro-SARS-CoV-2 inhibitor [141].
Neoechinulin B 11 can be extracted from Eurotium rubrum Hiji025. It has been synthesized in a two-step reaction involving the 2-indole aldehyde 9 and the appropriate 2,5-piperazinedione 10 in basic conditions followed by tetra-n-butylammonium fluoride. Alternatively, 11 could be obtained from the aldehyde 9 and 2,5-piperazinedione 12 in the presence of piperidine at 110 °C (Scheme 2). Neoechinulin B 11 has anti-SARS-CoV-2 properties (Vero E6, assay, IC50 = 32.9, CC50 > 70 μM) [142].

4. Synthetic Indole-Containing Compounds

4.1. Isatins

Erdmann and Laurent first isolated isatin (1H-indole-2,3-dione) as an oxidation product of indigo using nitric and chromic acids. Isatin is found in humans as a metabolic derivative of the adrenaline hormone and a component of secretion from the parotid gland of Bufo frogs. Various isatin derivatives also naturally occur in plants, such as methoxy phenylpentyl isatins (the melosatin alkaloids) isolated from Melochia tomentosa, a Caribbean tumorigenic plant. Isatin and its derivatives are an important group of heterocyclic compounds that can serve as precursors for drug synthesis. Since its discovery, a significant amount of research has been conducted on the synthesis and biological and industrial applications of isatin.
A series of isatin derivatives 13 have been synthesized through the reaction of aromatic amines with hydroxylamine hydrochloride (NH2OH.HCl) and chloral hydrate [Cl3CCH(OH)2] followed by cyclization with concentrated sulfuric acid (H2SO4) at 90 °C and alkylation (Scheme 3). Some of the synthesized isatin analogs 13 (C1–C29) revealed 3C-like protease (3CLpro) [or main protease (Mpro)] SARS-CoV-2 inhibitory properties relative to Tideglusib (positive control) [143] (Figure 16).

4.2. 2-[(Indol-3-yl)thio]acetamides

2-[(Indol-3-yl)thio]acetamides 14 (D1–D27) were synthesized through the reaction of indole derivatives with Bunte salt ethyl acetate-2-sodium thiosulfate in iodine/DMSO at 60 °C followed by hydrolysis (NaOH, EtOH/H2O) and coupling with the appropriate amine (Scheme 4). Some of the synthesized agents exhibited RdRp inhibitory properties relative to Remdesivir [144] (Figure 17). Considering these observations (Figure 17) and those mentioned in Figure 16, it can be concluded that the substituent attached to the indolyl heterocycle plays a crucial role in the mode of action. Compounds in Figure 16 exhibited 3CLpro inhibitory properties whereas, those of Figure 17 revealed RdRp inhibitory properties. So, the mutual mode of action may be optimized by manipulating the substitution of the indolyl heterocycle for assigning potent anti-SARS-CoV-2 agents.
A set of acetamide-containing indoles (E1–E5) with possible RdRp SARS-CoV-2 inhibitory properties have been explored. The efficacy of the most promising agents was comparable to that of Remdesivir (EC50 = 1.05 μM) [145] (Figure 18).

4.3. Indole-Chloropyridine Conjugates

A variety of indole-chloropyridine conjugates 15 (F1–F15) were synthesized via reaction of the appropriate indolecarboxylic acid with 3-chloropyridin-5-ols or 5-amino-3-chloropyridines using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and dimethylaminopyridine (DMAP) in methylene chloride (CH2Cl2) (Scheme 5). Anti-SARS-CoV-2 activities (Vero E6 assay) with 3CLpro inhibitory properties were observed for some of the synthesized agents [59] (Figure 19).
Indomethacin-chloropyridine conjugate 16 (Figure 20) is also possible by utilizing the same reaction conditions (EDC and DMAP in CH2Cl2, 53% yield). Anti-SARS-CoV-2 activity was observed for the compound (EC50 against SARS-CoV-2 = 30.2 μM, IC50 against 3CLpro SARS-CoV-2 = 5.32 μM) [146].

4.4. Diindole-Substituted Benzimidazole

The condensation of 3-indolealdehyde with o-phenylenediamine under green conditions (in water at 75 °C) in a 2:1 molar ratio afforded the corresponding diindole-substituted benzimidazole 17 (Scheme 6). The synthesized agent revealed 92.4% cell viability (Vero E6) at 9.0 μM concentration in comparison to 99.23% for Remdesivir at 10 μM. The antiviral properties of 17 were supported by the immunofluorescence assay [147].

4.5. 3-Alkenyl-2-Oxindoles

Anti-SARS-CoV-2 3-alkenyl-2-oxindoles 18 and 19 were obtained through acidic dehydration (HCl/EtOH) from the corresponding 3-hydroxy analogs (Scheme 7 and Scheme 8). Some of the synthesized agents showed potent anti-SARS-CoV-2 properties (Figure 21) relative to the standards (IC50 = 29.25, 19.78, 1382, CC50 = 356.4, 377.7, 2633 μM for Hydroxychloroquine, Chloroquine, and Favipiravir, respectively) in the Vero E6 assay [148].

4.6. Spiroindoles

Spirocyclic compounds are organic compounds with a rigid, 3D-geometrical structure. In 1911, A. Pictet and T. Spengler reported the first spiro-analog intermediate. Spiroindole-containing compounds are important due to the versatile biological properties established by diverse natural and synthetic analogs originating from the C-3 indolyl ring with many heterocycles affording various motifs.
Spiroindoles 20 were synthesized through the cycloaddition of azomethine ylide (obtained from sarcosine and isatins) with 3,5-diylidene-4-piperidones (Scheme 9). Promising anti-SARS-CoV-2 properties were shown by some of the synthesized agents (I1–I15) in the Vero E6 assay relative to the standards Hydroxychloroquine, Chloroquine, and Favipiravir [149] (Figure 22).
Anti-SARS-CoV-2 spiroindole-containing compounds bearing a phosphonate group 21 (J1–J3) were recently reported with potential Mpro inhibitory properties, synthesized through azomethine (generated from the reaction of isatin and sarcosine) reaction with the appropriate 3,5-bis((E)-ylidene)-1-phosphonate-4-piperidone [150] (Scheme 10).
It is notable that the spiroindoles with a sulfonyl group (Figure 22) are more promising anti-SARS-CoV-2 agents relative to those with a phosphonate group.

4.7. Indole with Dual Acting Proteases Inhibitor

Di Sarno [151] reported the synthesis of an indole-containing compound (22) with potential SARS-CoV-2 protease (Mpro “main protease” and PLpro “papain-like protease”) inhibitory properties (Scheme 11).

5. In Silico Predicted Anti-SARS-CoV-2 Indoles

The use of computational techniques is an accessible approach to identifying effective hits/leads and accelerating the drug discovery program directed towards the development of anti-SARS-CoV-2, either through repurposing or de novo drug design. Virtual screening can reduce the time and cost needed for establishing possible bioactive agents. However, the agents identified by in silico studies still require supporting experimental bio-properties investigations to realize the benefits of these studies [152,153].

5.1. SARS-CoV-2 (Main Protease, Mpro) Inhibitor

SARS-CoV-2 main protease (Mpro or 3CLpro) controls many essential viral processes including maturation, replication, and transcription. This makes it a potential target for optimizing therapeutics against COVID-19 [154,155]. Paxlovid is a prominent protease inhibitor approved by the FDA at the end of 2021 for mild and moderately effected patients. It is a combination of two therapeutics, Nirmatrelvir (3CL protease inhibitor) and Ritonavir (protease inhibitor, therapeutic against HIV/AIDS). Paxlovid is effective at reducing the hospitalization period when administrated at the beginning of COVID-19 symptoms [156,157,158].
In this section, representative examples of computationally predicted Mpro SARS-CoV-2 inhibitors will be highlighted. Jayabal et al. reported the synthesis of 3-substituted indoles 23 through a multi-component green synthetic approach via the reaction of nitroketene S,S-acetal, diamine-containing compound, 3-formylchromone, and indole in the presence of In(OTf)3 as a catalyst in refluxing ethanol [62] (Scheme 12). Computationally, some of the synthesized agents (K1–K6) showed inhibitory properties for SARS-COV-2 Mpro (PDB: 6LU7) and spike glycoprotein (PDB: 7NX7) utilizing Auto Dock-Vina software (v. 1.1.2). For comparison, Remdesivir binding energy = −7.7, −6.5 kcal/mol is against main protease 6LU7 and spike glycoprotein 7NX7, respectively [62] (Figure 23 and Figure 24).
Many mushroom metabolites have potential biological activities. Psilacetin, psilocin, and psilocybine, which are psilocybin-mushroom components, have been subjected to Mpro SARS-CoV-2 docking studies (PDB: 6LU7) utilizing AutoDock and AutoDock vina software. They reveal considerable binding affinity in the protein active site (interaction docking scores = −6.0, −5.4, −5.8 kcal/mol for psilacetin, psilocin, and psilocybine, respectively) [159] (Figure 25 and Figure 26).
A series of indolyl chalcones (L1–L25) have also been explored against Mpro (PDB: 6YB7), spike protein (PDB: 6LZG), and RNA-dependent RNA polymerase (PDB: 6M71) in silico by the blind docking technique utilizing AutoDock Vina v.1.1.2. Some of the results suggested promising inhibitory properties that may help narrow the search for anti-SARS-CoV-2 candidates [160] (Figure 27).
The Schiff bases formed from the condensation of isatin and 2-(1-aminobenzyl)benzimidazole revealed in silico possible Mpro SARS-CoV-2 inhibitory properties (3CL protease, PDB: 6LU7, AutoDock 4.2 software). The 5-bromo-substituted analog of bis-Schiff base 24 formed from the condensation of 2-(1-aminobenzyl)benzimidazole and the corresponding bis-isatin in ethanol containing a few drops of AcOH at room temperature (Scheme 13) is the most promising [161] (Figure 28).
A set of 2-oxindole derivatives (M1–M31) with in silico Mpro SARS-CoV-2 inhibitory properties were mentioned (PDB ID: 6LU7, Molegro Virtual Docker version 7.0.0 Software, MVD) [162] (Figure 29).
A set of isatin-based protease inhibitors was collected from previous publications followed by in silico high throughput screening in the active pocket of Mpro SARS-CoV-2 (chain-A, PDB: 6M03). The most promising agents (N1–N5) were identified based on the observed binding affinities (Figure 30). Searching the Zinc drug-like library for similar analogs followed by virtual screening (AutoDock Vina) identified indole analogs (O1–O3) with potential inhibitory properties against Mpro SARS-CoV-2 [72] (Figure 31).
Hattori et al. have also reported the in silico Mpro SARS-CoV-2 properties (PDB: 6Y2F, Maestro Version 10.7.015) in addition to the in vitro activity (Vero E6 assay) of indole-containing compounds (P1 and P2) [163] (Figure 32).
2-Indole-containing compounds 25 were obtained through the reaction of indole, furan-2-ylmethylenehydrazine, and appropriate aldehyde in ethanol (Scheme 14). Considerable activity against SARS-CoV-2 spike glycoprotein (PDB: 6WPT, Schrodinger 12.4 software) was observed for some of the synthesized agents [164] (Figure 33).
A computational study considered food chemicals and components named as dark chemical matters could predict some effective anti-SARS-CoV-2 hits. Compound ID: ZINC4217536 (ZINC database) was mentioned as a promising antiviral active agent due to docking observations in Mpro of SARS-CoV-2 (PDB ID 6LU7) utilizing MOE (Molecular Operating Environment v.2019 software). It reveals hydrogen bonding interaction with CYS145 and GLU166 in addition to a π-interaction with HIS41 (all these amino acids are the key components of the protein active site). Compound ID: ZINC95567760, which contains a fused indolyl heterocycle, also reveals a promising docking interaction in the PDB: 6LU7. Hydrogen bonding interaction with CYS145, in addition to π-interactions with GLU166 and GLY143, support these assumptions [165] (Figure 34).

5.2. RdRp (RNA-Dependent RNA Polymerase) Inhibitor

The RdRp enzyme is one of the most reliable targets for optimizing potent antiviral therapeutics. This is attributed to its ability to terminate the viral RNA replication in addition to the lack of any similar RdRp in the host cell, thus minimizing off-target effects [9,166].
A computational study has also explored isatin analogs (Q1–Q10) for the identification of promising RdRp SARS-CoV-2 inhibitor agents (PDB ID: 7BTF, AutoDock); the most promising compounds discovered are exhibited in Figure 35 [167].
López-López et al. [168] have pointed out that an analysis of ChEMBL (chemical database of bioactive agents created by the European Bioinformatics Institute) indicates that 10 μM is a convenient benchmark by which to differentiate active from inactive compounds. Assigning such parameters can help distinguish between active and inactive compounds as well as help improve effectiveness. Structure activity/property relationship (SAR/APR) software can assist with this aspect. Manipulating the chemical structure based on the physic-chemical parameters (descriptors) can turn the inactive or mildly active agents into potent effective ones. This explains the interest of medicinal chemistry researchers in QSAR/QSPR studies [119,169,170].

6. Conclusions

COVID-19 has proven to be one of the most serious crises facing human health in recorded history. The scientific community has been tirelessly working to optimize effective therapeutics. While vaccination has been successful in controlling the pandemic, research into the effective treatment of current and future mutants remains crucial. One area of focus has been on the indole scaffold, which includes many alkaloid categories and has shown promise in the fight against COVID-19. Repurposed indole-containing drugs, as well as various natural and synthetic indole analogs, have been investigated for anti-SARS-CoV-2 efficacy. In silico studies were utilized to generate new hits and optimize leads against SARS-CoV-2. 3-Alkenyl-2-oxindoles and spiroindoles are potentially valuable anti-SARS-CoV-2 agents that can be synthesized in a regio-selective approach. From the cited reports, it can be concluded that indole-containing compounds are important lead molecules and can be further optimized for the development of potential agents against SARS-CoV-2.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28186603/s1, Table S1: List of potential Indole-based compounds and their activities (IC50/EC50) against SARS-CoV-2.

Author Contributions

Conceptualization, A.S.G. and S.S.P.; Methodology, A.S.G. and S.S.P.; Software, A.S.G. and S.S.P.; Resources, A.S.G. and S.S.P.; Writing—Original Draft Preparation, A.S.G., S.S.P., B.M.K., M.S.B., R.F.B. and D.R.A.; Writing—Review & Editing, A.S.G., S.S.P., B.M.K., M.S.B., R.F.B. and D.R.A. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported financially by National Research Centre, Egypt, project ID: 13060103.

Acknowledgments

We thank the Department of Chemistry and Biochemistry at Augusta University for its support.

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Sample Availability

Not application.

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Molecules 28 06603 g001
Figure 1. Cipargamin (NITD609) is in pre-clinical studies as a potential antimalarial drug [16].
Figure 1. Cipargamin (NITD609) is in pre-clinical studies as a potential antimalarial drug [16].
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Molecules 28 06603 g002
Figure 2. Indole-containing drugs against different diseases [29,30,31,32,33,34,35,36,37,38].
Figure 2. Indole-containing drugs against different diseases [29,30,31,32,33,34,35,36,37,38].
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Molecules 28 06603 g003
Figure 3. Indole-containing anticancer agents [40,41,42,43,44,45,46,47,48,49,50].
Figure 3. Indole-containing anticancer agents [40,41,42,43,44,45,46,47,48,49,50].
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Molecules 28 06603 g004
Figure 4. Proteins involved in the SARS-CoV-2 infection, which make them potential targets for optimizing therapeutics [71].
Figure 4. Proteins involved in the SARS-CoV-2 infection, which make them potential targets for optimizing therapeutics [71].
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Molecules 28 06603 g005
Figure 5. Repurposed antiviral agents with anti-SARS-CoV-2 properties [63,81,82,83,84,85].
Figure 5. Repurposed antiviral agents with anti-SARS-CoV-2 properties [63,81,82,83,84,85].
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Molecules 28 06603 g006
Figure 6. Repurposed anticancer agents with anti-SARS-CoV-2 properties [63,81,82,83,84,85].
Figure 6. Repurposed anticancer agents with anti-SARS-CoV-2 properties [63,81,82,83,84,85].
Molecules 28 06603 g006
Molecules 28 06603 g007
Figure 7. Repurposed antimalarial, anti-inflammatory, and immunomodulatory drugs with anti-SARS-CoV-2 properties [63,81,82,83,84,85].
Figure 7. Repurposed antimalarial, anti-inflammatory, and immunomodulatory drugs with anti-SARS-CoV-2 properties [63,81,82,83,84,85].
Molecules 28 06603 g007
Molecules 28 06603 g008
Figure 8. Umifenovir/Arbidol, repurposed drug for COVID-19.
Figure 8. Umifenovir/Arbidol, repurposed drug for COVID-19.
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Molecules 28 06603 sch001
Scheme 1. Synthesis of Arbidol analogs 1–8 of potential binding of the spike glycoprotein (S-protein, ACE2).
Scheme 1. Synthesis of Arbidol analogs 1–8 of potential binding of the spike glycoprotein (S-protein, ACE2).
Molecules 28 06603 sch001
Molecules 28 06603 g009
Figure 9. Inhibitory properties of Arbidol analogs 1–8.
Figure 9. Inhibitory properties of Arbidol analogs 1–8.
Molecules 28 06603 g009
Molecules 28 06603 g010aMolecules 28 06603 g010bMolecules 28 06603 g010c
Figure 10. Glide scores predicted for Arbidol analogs against ACE2, Furin, and 3CLpro.
Figure 10. Glide scores predicted for Arbidol analogs against ACE2, Furin, and 3CLpro.
Molecules 28 06603 g010aMolecules 28 06603 g010bMolecules 28 06603 g010c
Molecules 28 06603 g011
Figure 11. Indomethacin-Remdesivir conjugates (B1–B4) against SARS-CoV-2/NL/2020 and SARS-CoV-2/Padova/2021 strains [121].
Figure 11. Indomethacin-Remdesivir conjugates (B1–B4) against SARS-CoV-2/NL/2020 and SARS-CoV-2/Padova/2021 strains [121].
Molecules 28 06603 g011
Molecules 28 06603 g012
Figure 12. Lufotrelvir (PF-07304814) and its effective agent PF-00835231, Mpro-SARS-CoV-2 inhibitor [125].
Figure 12. Lufotrelvir (PF-07304814) and its effective agent PF-00835231, Mpro-SARS-CoV-2 inhibitor [125].
Molecules 28 06603 g012
Molecules 28 06603 g013
Figure 13. Obatoclax (GX15-070); EC50: 23.2 µM, repurposed drug for COVID-19 [126].
Figure 13. Obatoclax (GX15-070); EC50: 23.2 µM, repurposed drug for COVID-19 [126].
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Molecules 28 06603 g014
Figure 14. Main functions/properties of melatonin [127,128,129,130,131].
Figure 14. Main functions/properties of melatonin [127,128,129,130,131].
Molecules 28 06603 g014
Molecules 28 06603 g015
Figure 15. Natural neoechinulin A, echinulin, and eurocristatine from Aspergillus fumigatus MR2012 and GC376 (potent Mpro-SARS-CoV-2 inhibitor) [140,141].
Figure 15. Natural neoechinulin A, echinulin, and eurocristatine from Aspergillus fumigatus MR2012 and GC376 (potent Mpro-SARS-CoV-2 inhibitor) [140,141].
Molecules 28 06603 g015
Molecules 28 06603 sch002
Scheme 2. Synthesis of Neoechinulin B (11) of anti-SARS-CoV-2 properties [142].
Scheme 2. Synthesis of Neoechinulin B (11) of anti-SARS-CoV-2 properties [142].
Molecules 28 06603 sch002
Molecules 28 06603 sch003
Scheme 3. Synthesis of isatin derivatives 13 of potential 3CLpro inhibitory properties [143].
Scheme 3. Synthesis of isatin derivatives 13 of potential 3CLpro inhibitory properties [143].
Molecules 28 06603 sch003
Molecules 28 06603 g016aMolecules 28 06603 g016b
Figure 16. The 3C-like protease (3CLpro) inhibitory properties of isatin analogs 13 (C1–C29) [143].
Figure 16. The 3C-like protease (3CLpro) inhibitory properties of isatin analogs 13 (C1–C29) [143].
Molecules 28 06603 g016aMolecules 28 06603 g016b
Molecules 28 06603 sch004
Scheme 4. Synthesis of 2-[(indol-3-yl)thio)]acetamides 14 of potential RdRp inhibitory properties [144].
Scheme 4. Synthesis of 2-[(indol-3-yl)thio)]acetamides 14 of potential RdRp inhibitory properties [144].
Molecules 28 06603 sch004
Molecules 28 06603 g017aMolecules 28 06603 g017b
Figure 17. The inhibitory properties of anti-SARSCoV-2 RdRp (IC50, µM) of the synthesized 2-[(indol-3-yl)thio)]acetamides 14 (D1–D27) [144].
Figure 17. The inhibitory properties of anti-SARSCoV-2 RdRp (IC50, µM) of the synthesized 2-[(indol-3-yl)thio)]acetamides 14 (D1–D27) [144].
Molecules 28 06603 g017aMolecules 28 06603 g017b
Molecules 28 06603 g018
Figure 18. Inhibitory properties of SARS-CoV-2 RdRp (HEK293T cells transfected with nsp12) of acetamide-containing indoles (E1–E5) [145].
Figure 18. Inhibitory properties of SARS-CoV-2 RdRp (HEK293T cells transfected with nsp12) of acetamide-containing indoles (E1–E5) [145].
Molecules 28 06603 g018
Molecules 28 06603 sch005
Scheme 5. Synthesis of indole-chloropyridine conjugates 15 of potential anti-SARS-CoV-2 properties [59].
Scheme 5. Synthesis of indole-chloropyridine conjugates 15 of potential anti-SARS-CoV-2 properties [59].
Molecules 28 06603 sch005
Molecules 28 06603 g019aMolecules 28 06603 g019b
Figure 19. Anti-SARS-CoV-2 and 3CLpro inhibitory properties of the indole-chloropyridine conjugates 15 (F1–F15) [59].
Figure 19. Anti-SARS-CoV-2 and 3CLpro inhibitory properties of the indole-chloropyridine conjugates 15 (F1–F15) [59].
Molecules 28 06603 g019aMolecules 28 06603 g019b
Molecules 28 06603 g020
Figure 20. Indomethacin-chloropyridine conjugate 16 of potential anti-SARS-CoV-2 properties [146].
Figure 20. Indomethacin-chloropyridine conjugate 16 of potential anti-SARS-CoV-2 properties [146].
Molecules 28 06603 g020
Molecules 28 06603 sch006
Scheme 6. Diindole-substituted benzimidazole 17 [147].
Scheme 6. Diindole-substituted benzimidazole 17 [147].
Molecules 28 06603 sch006
Molecules 28 06603 sch007
Scheme 7. Synthesis of 3-alkenyl-2-oxindoles 18 [148].
Scheme 7. Synthesis of 3-alkenyl-2-oxindoles 18 [148].
Molecules 28 06603 sch007
Molecules 28 06603 sch008
Scheme 8. Synthesis of 3-alkenyl-2-oxindoles 19 [148].
Scheme 8. Synthesis of 3-alkenyl-2-oxindoles 19 [148].
Molecules 28 06603 sch008
Molecules 28 06603 g021
Figure 21. Anti-SARS-CoV-2 properties of tested 3-alkenyl-2-oxindoles 18 (G1–G3) and 19 (H1–H3) [148].
Figure 21. Anti-SARS-CoV-2 properties of tested 3-alkenyl-2-oxindoles 18 (G1–G3) and 19 (H1–H3) [148].
Molecules 28 06603 g021
Molecules 28 06603 sch009
Scheme 9. Synthesis of spiroindoles 20 through azomethine ylide cycloaddition [149].
Scheme 9. Synthesis of spiroindoles 20 through azomethine ylide cycloaddition [149].
Molecules 28 06603 sch009
Molecules 28 06603 g022
Figure 22. Anti-SARS-CoV-2 properties of spiroindoles 20 (I1–I15) [149].
Figure 22. Anti-SARS-CoV-2 properties of spiroindoles 20 (I1–I15) [149].
Molecules 28 06603 g022
Molecules 28 06603 sch010
Scheme 10. Synthesis of spiroindole-containing compounds 21 (J1–J3) bearing a phosphonate group [150].
Scheme 10. Synthesis of spiroindole-containing compounds 21 (J1–J3) bearing a phosphonate group [150].
Molecules 28 06603 sch010
Molecules 28 06603 sch011
Scheme 11. Synthesis of indole-containing compound (22) of dual acting protease (Mpro, PLpro) inhibitors [151].
Scheme 11. Synthesis of indole-containing compound (22) of dual acting protease (Mpro, PLpro) inhibitors [151].
Molecules 28 06603 sch011
Molecules 28 06603 sch012
Scheme 12. Synthesis of 3-substitued indoles 23 [62].
Scheme 12. Synthesis of 3-substitued indoles 23 [62].
Molecules 28 06603 sch012
Molecules 28 06603 g023
Figure 23. In silico predicted 3-substituted indoles 23 (K1–K6) of potential inhibitory properties against main protease 6LU7 and spike glycoprotein 7NX7 [62].
Figure 23. In silico predicted 3-substituted indoles 23 (K1–K6) of potential inhibitory properties against main protease 6LU7 and spike glycoprotein 7NX7 [62].
Molecules 28 06603 g023
Molecules 28 06603 g024aMolecules 28 06603 g024b
Figure 24. (upper) Representation of Remdesivir and predicted 3-substituted indoles 23 revealing potential properties against 6LU7 [62]. (lower) Representation of Remdesivir and predicted 3-substituted indoles 23 revealing potential properties against 7NX7 [62].
Figure 24. (upper) Representation of Remdesivir and predicted 3-substituted indoles 23 revealing potential properties against 6LU7 [62]. (lower) Representation of Remdesivir and predicted 3-substituted indoles 23 revealing potential properties against 7NX7 [62].
Molecules 28 06603 g024aMolecules 28 06603 g024b
Molecules 28 06603 g025
Figure 25. Psilacetin, psilocin, and psilocybine of potential anti-Mpro SARS-CoV-2 [159].
Figure 25. Psilacetin, psilocin, and psilocybine of potential anti-Mpro SARS-CoV-2 [159].
Molecules 28 06603 g025
Molecules 28 06603 g026
Figure 26. 2D- and 3D-docking interactions of (A,B), N3 inhibitor; (C,D), psilacetin; (E,F), psilocin; and (G,H), psilocybine in the active pocket of Mpro SARS-CoV-2 (PDB: 6LU7) [159].
Figure 26. 2D- and 3D-docking interactions of (A,B), N3 inhibitor; (C,D), psilacetin; (E,F), psilocin; and (G,H), psilocybine in the active pocket of Mpro SARS-CoV-2 (PDB: 6LU7) [159].
Molecules 28 06603 g026
Molecules 28 06603 g027aMolecules 28 06603 g027b
Figure 27. In silico predicted indolyl chalcones (L1–L25) and their binding energies in Mpro (PDB: 6YB7), spike protein (PDB: 6LZG), and RNA-dependent RNA polymerase (PDB: 6M71) [160].
Figure 27. In silico predicted indolyl chalcones (L1–L25) and their binding energies in Mpro (PDB: 6YB7), spike protein (PDB: 6LZG), and RNA-dependent RNA polymerase (PDB: 6M71) [160].
Molecules 28 06603 g027aMolecules 28 06603 g027b
Molecules 28 06603 sch013
Scheme 13. Synthesis of bis-Schiff base 24 [161].
Scheme 13. Synthesis of bis-Schiff base 24 [161].
Molecules 28 06603 sch013
Molecules 28 06603 g028
Figure 28. 2D-docking interaction of Schiff bases and N3 in the active site of Mpro SARS-CoV-2 (PDB: 6LU7) [161].
Figure 28. 2D-docking interaction of Schiff bases and N3 in the active site of Mpro SARS-CoV-2 (PDB: 6LU7) [161].
Molecules 28 06603 g028
Molecules 28 06603 g029aMolecules 28 06603 g029bMolecules 28 06603 g029c
Figure 29. Oxindoles (M1–M31) with in silico Mpro SARS-CoV-2 properties [162].
Figure 29. Oxindoles (M1–M31) with in silico Mpro SARS-CoV-2 properties [162].
Molecules 28 06603 g029aMolecules 28 06603 g029bMolecules 28 06603 g029c
Molecules 28 06603 g030
Figure 30. Isatin analogs (N1–N5) with potenial in silico Mpro SARS-CoV-2 inhibitory properties [72].
Figure 30. Isatin analogs (N1–N5) with potenial in silico Mpro SARS-CoV-2 inhibitory properties [72].
Molecules 28 06603 g030
Molecules 28 06603 g031
Figure 31. Indole analogs (O1–O3) through Zinc drug-like library with potential properties against Mpro SARS-CoV-2.
Figure 31. Indole analogs (O1–O3) through Zinc drug-like library with potential properties against Mpro SARS-CoV-2.
Molecules 28 06603 g031
Molecules 28 06603 g032
Figure 32. Indole-containing compounds (P1, P2) of potential in vitro anti-SARS-CoV-2 and in silico Mpro properties [163].
Figure 32. Indole-containing compounds (P1, P2) of potential in vitro anti-SARS-CoV-2 and in silico Mpro properties [163].
Molecules 28 06603 g032
Molecules 28 06603 sch014
Scheme 14. Synthesis of indole-containing compounds 25 [164].
Scheme 14. Synthesis of indole-containing compounds 25 [164].
Molecules 28 06603 sch014
Molecules 28 06603 g033
Figure 33. 2D-docking interaction of indole-containing compounds 25 in the active site of SARS-CoV-2 spike glycoprotein (PDB: 6WPT) [164].
Figure 33. 2D-docking interaction of indole-containing compounds 25 in the active site of SARS-CoV-2 spike glycoprotein (PDB: 6WPT) [164].
Molecules 28 06603 g033
Molecules 28 06603 g034
Figure 34. 2D-docking interaction of Compounds ID: ZINC4217536 and ZINC95567760 in PDB ID 6LU7 [165].
Figure 34. 2D-docking interaction of Compounds ID: ZINC4217536 and ZINC95567760 in PDB ID 6LU7 [165].
Molecules 28 06603 g034
Molecules 28 06603 g035
Figure 35. Binding energy of potential RdRp isatin analogs (Q1–Q10) in PDB ID: 7BTF active pocket [167].
Figure 35. Binding energy of potential RdRp isatin analogs (Q1–Q10) in PDB ID: 7BTF active pocket [167].
Molecules 28 06603 g035
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MDPI and ACS Style

Girgis, A.S.; Panda, S.S.; Kariuki, B.M.; Bekheit, M.S.; Barghash, R.F.; Aboshouk, D.R. Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2. Molecules 2023, 28, 6603. https://doi.org/10.3390/molecules28186603

AMA Style

Girgis AS, Panda SS, Kariuki BM, Bekheit MS, Barghash RF, Aboshouk DR. Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2. Molecules. 2023; 28(18):6603. https://doi.org/10.3390/molecules28186603

Chicago/Turabian Style

Girgis, Adel S., Siva S. Panda, Benson M. Kariuki, Mohamed S. Bekheit, Reham F. Barghash, and Dalia R. Aboshouk. 2023. "Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2" Molecules 28, no. 18: 6603. https://doi.org/10.3390/molecules28186603

APA Style

Girgis, A. S., Panda, S. S., Kariuki, B. M., Bekheit, M. S., Barghash, R. F., & Aboshouk, D. R. (2023). Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2. Molecules, 28(18), 6603. https://doi.org/10.3390/molecules28186603

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