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

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.

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 The coronavirus disease 2019  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 Molecules 2023, 28, 6603 4 of 50 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.
Molecules 2023, 28, x FOR PEER REVIEW 4 of 57 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- 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 postmarketing 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].

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 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 (M pro ) inhibition [83].
Molecules 2023, 28, x FOR PEER REVIEW 9 of 57 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-2methylindole-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]. A series of Arbidol analogs 1-8 have been synthesized starting from 5-hydroxy-2methylindole-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 3CL pro (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). 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),   Figure 10. Glide scores predicted for Arbidol analogs against ACE2, Furin, and 3CL pro .

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].

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].

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

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

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 antiinflammation 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].

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.

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.

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.

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 3CL pro 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.

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/H 2 O) 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 3CL pro 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.

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. Spiroindolecontaining 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
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.
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. Scheme 9. Synthesis of spiroindoles 20 through azomethine ylide cycloaddition [149].

Indole with Dual Acting Proteases Inhibitor
Di Sarno [151] reported the synthesis of an indole-containing compound (22) with potential SARS-CoV-2 protease (M pro "main protease" and PL pro "papain-like protease") inhibitory properties (Scheme 11). 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.

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 screen-Scheme 11. Synthesis of indole-containing compound (22) of dual acting protease (M pro , PL pro ) inhibitors [151].

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].

SARS-CoV-2 (Main Protease, M pro ) Inhibitor
SARS-CoV-2 main protease (M pro or 3CL pro ) 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].
Many mushroom metabolites have potential biological activities. Psilacetin, psilo and psilocybine, which are psilocybin-mushroom components, have been subjecte M pro SARS-CoV-2 docking studies (PDB: 6LU7) utilizing AutoDock and AutoDock software. They reveal considerable binding affinity in the protein active site (interac docking scores = −6.0, −5.4, −5.8 kcal/mol for psilacetin, psilocin, and psilocybine, res tively) [159] (Figures 25 and 26).      A set of isatin-based protease inhibitors was collected from previous publications followed by in silico high throughput screening in the active pocket of M pro 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 M pro SARS-CoV-2 [72] (Figure 31).    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 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 M pro 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). to docking observations in M pro 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).

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].

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].
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].

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.