Skip to main content
NCBI home page
Molecules logoLink to Molecules
. 2023 Sep 13;28(18):6603. doi: 10.3390/molecules28186603

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

Adel S Girgis 1,*, Siva S Panda 2,3,*, Benson M Kariuki 4, Mohamed S Bekheit 1, Reham F Barghash 1, Dalia R Aboshouk 1
Editors: Santo Previti, Roberta Ettari
PMCID: PMC10537473  PMID: 37764378

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.

Keywords: indole, COVID-19, SARS-CoV-2, alkaloids, natural, synthetic, in silico

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].

Figure 1.

Figure 1

Open in a new tab

Cipargamin (NITD609) is in pre-clinical studies as a potential antimalarial drug [16].

Figure 2.

Figure 2

Open in a new tab

Indole-containing drugs against different diseases [29,30,31,32,33,34,35,36,37,38].

Figure 3.

Figure 3

Open in a new tab

Indole-containing anticancer agents [40,41,42,43,44,45,46,47,48,49,50].

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.

Figure 4.

Figure 4

Open in a new tab

Proteins involved in the SARS-CoV-2 infection, which make them potential targets for optimizing therapeutics [71].

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].

Figure 5.

Figure 5

Open in a new tab

Repurposed antiviral agents with anti-SARS-CoV-2 properties [63,81,82,83,84,85].

Figure 6.

Figure 6

Open in a new tab

Repurposed anticancer agents with anti-SARS-CoV-2 properties [63,81,82,83,84,85].

Figure 7.

Figure 7

Open in a new tab

Repurposed antimalarial, anti-inflammatory, and immunomodulatory drugs with anti-SARS-CoV-2 properties [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].

Figure 8.

Figure 8

Open in a new tab

Umifenovir/Arbidol, repurposed drug for COVID-19.

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].

Scheme 1.

Scheme 1

Open in a new tab

Synthesis of Arbidol analogs 1–8 of potential binding of the spike glycoprotein (S-protein, ACE2).

Figure 9.

Figure 9

Open in a new tab

Inhibitory properties of Arbidol analogs 1–8.

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).

Figure 10.

Figure 10

Figure 10

Figure 10

Open in a new tab

Glide scores predicted for Arbidol analogs against ACE2, Furin, and 3CLpro.

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.

Figure 11.

Figure 11

Open in a new tab

Indomethacin-Remdesivir conjugates (B1–B4) against SARS-CoV-2/NL/2020 and SARS-CoV-2/Padova/2021 strains [121].

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].

Figure 12.

Figure 12

Open in a new tab

Lufotrelvir (PF-07304814) and its effective agent PF-00835231, Mpro-SARS-CoV-2 inhibitor [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].

Figure 13.

Figure 13

Open in a new tab

Obatoclax (GX15-070); EC50: 23.2 µM, repurposed drug for COVID-19 [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].

Figure 14.

Figure 14

Open in a new tab

Main functions/properties of melatonin [127,128,129,130,131].

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].

Figure 15.

Figure 15

Open in a new tab

Natural neoechinulin A, echinulin, and eurocristatine from Aspergillus fumigatus MR2012 and GC376 (potent Mpro-SARS-CoV-2 inhibitor) [140,141].

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].

Scheme 2.

Scheme 2

Open in a new tab

Synthesis of Neoechinulin B (11) of anti-SARS-CoV-2 properties [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).

Scheme 3.

Scheme 3

Open in a new tab

Synthesis of isatin derivatives 13 of potential 3CLpro inhibitory properties [143].

Figure 16.

Figure 16

Figure 16

Open in a new tab

The 3C-like protease (3CLpro) inhibitory properties of isatin analogs 13 (C1–C29) [143].

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.

Scheme 4.

Scheme 4

Open in a new tab

Synthesis of 2-[(indol-3-yl)thio)]acetamides 14 of potential RdRp inhibitory properties [144].

Figure 17.

Figure 17

Figure 17

Open in a new tab

The inhibitory properties of anti-SARSCoV-2 RdRp (IC50, µM) of the synthesized 2-[(indol-3-yl)thio)]acetamides 14 (D1–D27) [144].

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).

Figure 18.

Figure 18

Open in a new tab

Inhibitory properties of SARS-CoV-2 RdRp (HEK293T cells transfected with nsp12) of acetamide-containing indoles (E1–E5) [145].

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).

Scheme 5.

Scheme 5

Open in a new tab

Synthesis of indole-chloropyridine conjugates 15 of potential anti-SARS-CoV-2 properties [59].

Figure 19.

Figure 19

Figure 19

Open in a new tab

Anti-SARS-CoV-2 and 3CLpro inhibitory properties of the indole-chloropyridine conjugates 15 (F1–F15) [59].

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].

Figure 20.

Figure 20

Open in a new tab

Indomethacin-chloropyridine conjugate 16 of potential anti-SARS-CoV-2 properties [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].

Scheme 6.

Scheme 6

Open in a new tab

Diindole-substituted benzimidazole 17 [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].

Scheme 7.

Scheme 7

Open in a new tab

Synthesis of 3-alkenyl-2-oxindoles 18 [148].

Scheme 8.

Scheme 8

Open in a new tab

Synthesis of 3-alkenyl-2-oxindoles 19 [148].

Figure 21.

Figure 21

Open in a new tab

Anti-SARS-CoV-2 properties of tested 3-alkenyl-2-oxindoles 18 (G1–G3) and 19 (H1–H3) [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).

Scheme 9.

Scheme 9

Open in a new tab

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

Figure 22.

Figure 22

Open in a new tab

Anti-SARS-CoV-2 properties of spiroindoles 20 (I1–I15) [149].

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).

Scheme 10.

Scheme 10

Open in a new tab

Synthesis of spiroindole-containing compounds 21 (J1–J3) bearing a phosphonate group [150].

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).

Scheme 11.

Scheme 11

Open in a new tab

Synthesis of indole-containing compound (22) of dual acting protease (Mpro, PLpro) inhibitors [151].

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).

Scheme 12.

Scheme 12

Open in a new tab

Synthesis of 3-substitued indoles 23 [62].

Figure 23.

Figure 23

Open in a new tab

In silico predicted 3-substituted indoles 23 (K1–K6) of potential inhibitory properties against main protease 6LU7 and spike glycoprotein 7NX7 [62].

Figure 24.

Figure 24

Figure 24

Open in a new tab

(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].

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).

Figure 25.

Figure 25

Open in a new tab

Psilacetin, psilocin, and psilocybine of potential anti-Mpro SARS-CoV-2 [159].

Figure 26.

Figure 26

Open in a new tab

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].

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).

Figure 27.

Figure 27

Figure 27

Open in a new tab

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].

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).

Scheme 13.

Scheme 13

Open in a new tab

Synthesis of bis-Schiff base 24 [161].

Figure 28.

Figure 28

Open in a new tab

2D-docking interaction of Schiff bases and N3 in the active site of Mpro SARS-CoV-2 (PDB: 6LU7) [161].

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).

Figure 29.

Figure 29

Figure 29

Figure 29

Open in a new tab

Oxindoles (M1–M31) with in silico Mpro SARS-CoV-2 properties [162].

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).

Figure 30.

Figure 30

Open in a new tab

Isatin analogs (N1–N5) with potenial in silico Mpro SARS-CoV-2 inhibitory properties [72].

Figure 31.

Figure 31

Open in a new tab

Indole analogs (O1–O3) through Zinc drug-like library with potential properties against Mpro SARS-CoV-2.

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).

Figure 32.

Figure 32

Open in a new tab

Indole-containing compounds (P1, P2) of potential in vitro anti-SARS-CoV-2 and in silico Mpro properties [163].

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).

Scheme 14.

Scheme 14

Open in a new tab

Synthesis of indole-containing compounds 25 [164].

Figure 33.

Figure 33

Open in a new tab

2D-docking interaction of indole-containing compounds 25 in the active site of SARS-CoV-2 spike glycoprotein (PDB: 6WPT) [164].

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).

Figure 34.

Figure 34

Open in a new tab

2D-docking interaction of Compounds ID: ZINC4217536 and ZINC95567760 in PDB ID 6LU7 [165].

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].

Figure 35.

Figure 35

Open in a new tab

Binding energy of potential RdRp isatin analogs (Q1–Q10) in PDB ID: 7BTF active pocket [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.

Acknowledgments

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

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.

Click here for additional data file. (556KB, zip)

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.

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.

Funding Statement

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

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

References

  • 1.George N., Akhtar J., Al Balushi K.A., Alam Khan S. Rational drug design strategies for the development of promising multi-target directed indole hybrids as Anti-Alzheimer agents. Bioorganic Chem. 2022;127:105941. doi: 10.1016/j.bioorg.2022.105941. [DOI] [PubMed] [Google Scholar]
  • 2.Qin H.-L., Liu J., Fang W.-Y., Ravindar L., Rakesh K. Indole-based derivatives as potential antibacterial activity against methicillin-resistance Staphylococcus aureus (MRSA) Eur. J. Med. Chem. 2020;194:112245. doi: 10.1016/j.ejmech.2020.112245. [DOI] [PubMed] [Google Scholar]
  • 3.Ramkissoon A., Seepersaud M., Maxwell A., Jayaraman J., Ramsubhag A. Isolation and Antibacterial Activity of Indole Alkaloids from Pseudomonas aeruginosa UWI-1. Molecules. 2020;25:3744. doi: 10.3390/molecules25163744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Liu Y., Cui Y., Lu L., Gong Y., Han W., Piao G. Natural indole-containing alkaloids and their antibacterial activities. Arch. Pharm. 2020;353:e2000120. doi: 10.1002/ardp.202000120. [DOI] [PubMed] [Google Scholar]
  • 5.Meng T., Hou Y., Shang C., Zhang J., Zhang B. Recent advances in indole dimers and hybrids with antibacterial activity against methicillin-resistant Staphylococcus aureus. Arch. Pharm. 2021;354:e2000266. doi: 10.1002/ardp.202000266. [DOI] [PubMed] [Google Scholar]
  • 6.Ma J., Jiang Y., Zhuang X., Chen H., Shen Y., Mao Z., Rao G., Wang R. Discovery of novel indole and indoline derivatives against Candida albicans as potent antifungal agents. Bioorganic Med. Chem. Lett. 2022;71:128826. doi: 10.1016/j.bmcl.2022.128826. [DOI] [PubMed] [Google Scholar]
  • 7.Bolous M., Arumugam N., Almansour A.I., Kumar R.S., Maruoka K., Antharam V.C., Thangamani S. Broad-spectrum antifungal activity of spirooxindolo-pyrrolidine tethered indole/imidazole hybrid heterocycles against fungal pathogens. Bioorganic Med. Chem. Lett. 2019;29:2059–2063. doi: 10.1016/j.bmcl.2019.07.022. [DOI] [PubMed] [Google Scholar]
  • 8.Yang M.-L., Chen J., Sun M., Zhang D.-B., Gao K. Antifungal Indole Alkaloids from Winchia calophylla. Planta Medica. 2016;82:712–716. doi: 10.1055/s-0042-102459. [DOI] [PubMed] [Google Scholar]
  • 9.Bekheit M.S., Panda S.S., Girgis A.S. Potential RNA-dependent RNA polymerase (RdRp) inhibitors as prospective drug candidates for SARS-CoV-2. Eur. J. Med. Chem. 2023;252:115292. doi: 10.1016/j.ejmech.2023.115292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Nie S., Zhao J., Wu X., Yao Y., Wu F., Lin Y.-L., Li X., Kneubehl A.R., Vogt M.B., Rico-Hesse R., et al. Synthesis, structure-activity relationship and antiviral activity of indole-containing inhibitors of Flavivirus NS2B-NS3 protease. Eur. J. Med. Chem. 2021;225:113767. doi: 10.1016/j.ejmech.2021.113767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Wei C., Zhao L., Sun Z., Hu D., Song B. Discovery of novel indole derivatives containing dithioacetal as potential antiviral agents for plants. Pestic. Biochem. Physiol. 2020;166:104568. doi: 10.1016/j.pestbp.2020.104568. [DOI] [PubMed] [Google Scholar]
  • 12.Zhang M.-Z., Chen Q., Yang G.-F. A review on recent developments of indole-containing antiviral agents. Eur. J. Med. Chem. 2015;89:421–441. doi: 10.1016/j.ejmech.2014.10.065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Blaising J., Polyak S.J., Pécheur E.-I. Arbidol as a broad-spectrum antiviral: An update. Antivir. Res. 2014;107:84–94. doi: 10.1016/j.antiviral.2014.04.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Giampieri M., Balbi A., Mazzei M., La Colla P., Ibba C., Loddo R. Antiviral activity of indole derivatives. Antivir. Res. 2009;83:179–185. doi: 10.1016/j.antiviral.2009.05.001. [DOI] [PubMed] [Google Scholar]
  • 15.Mashayekhi V., Tehrani K.H.M.E., Azerang P., Sardari S., Kobarfard F. Synthesis, antimycobacterial and anticancer activity of novel indole-based thiosemicarbazones. Arch. Pharmacal. Res. 2013;44:1–13. doi: 10.1007/s12272-013-0242-z. [DOI] [PubMed] [Google Scholar]
  • 16.Yu B., Yu D.-Q., Liu H.-M. Spirooxindoles: Promising scaffolds for anticancer agents. Eur. J. Med. Chem. 2015;97:673–698. doi: 10.1016/j.ejmech.2014.06.056. [DOI] [PubMed] [Google Scholar]
  • 17.Chauhan M., Saxena A., Saha B. An insight in anti-malarial potential of indole scaffold: A review. Eur. J. Med. Chem. 2021;218:113400. doi: 10.1016/j.ejmech.2021.113400. [DOI] [PubMed] [Google Scholar]
  • 18.Surur A.S., Huluka S.A., Mitku M.L., Asres K. Indole: The After Next Scaffold of Antiplasmodial Agents? Drug Des. Dev. Ther. 2020;14:4855–4867. doi: 10.2147/DDDT.S278588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Li J., Sun X., Li J., Yu F., Zhang Y., Huang X., Jiang F. The antimalarial activity of indole alkaloids and hybrids. Arch. Pharm. 2020;353:e2000131. doi: 10.1002/ardp.202000131. [DOI] [PubMed] [Google Scholar]
  • 20.Vasconcelos S.N., Meissner A.K., Ferraz W.R., Trossini G.H., Wrenger C., Stefani A.H. Indole-3-glyoxyl tyrosine: Synthesis and antimalarial activity against Plasmodium falciparum. Futur. Med. Chem. 2019;11:525–538. doi: 10.4155/fmc-2018-0246. [DOI] [PubMed] [Google Scholar]
  • 21.Tamura Y., Morita I., Hinata Y., Kojima E., Ozasa H., Ikemoto H., Asano M., Wada T., Hayasaki-Kajiwara Y., Iwasaki T., et al. Identification of novel indole derivatives as highly potent AMPK activators with anti-diabetic profiles. Bioorganic Med. Chem. Lett. 2022;68:128769. doi: 10.1016/j.bmcl.2022.128769. [DOI] [PubMed] [Google Scholar]
  • 22.Nazir M., Abbasi M.A., Rehman A.U., Siddiqui S.Z., Khan K.M., Kanwal, Salar U., Shahid M., Ashraf M., Lodhi M.A., et al. New indole based hybrid oxadiazole scaffolds with N-substituted acetamides: As potent anti-diabetic agents. Bioorganic Chem. 2018;81:253–263. doi: 10.1016/j.bioorg.2018.08.010. [DOI] [PubMed] [Google Scholar]
  • 23.Kumari A., Singh R.K. Synthesis, Molecular Docking and Biological Evaluation of N -Substituted Indole Derivatives as Potential Anti-Inflammatory and Antioxidant Agents. Chem. Biodivers. 2022;19:e202200290. doi: 10.1002/cbdv.202200290. [DOI] [PubMed] [Google Scholar]
  • 24.Jacob T.T., Gomes F.O.S., de Miranda M.D.S., de Almeida S.M.V., da Cruz-Filho I.J., Peixoto C.A., da Silva T.G., Moreira D.R.M., de Melo C.M.L., de Oliveira J.F., et al. Anti-inflammatory activity of novel thiosemicarbazone compounds indole-based as COX inhibitors. Pharmacol. Rep. 2021;73:907–925. doi: 10.1007/s43440-021-00221-7. [DOI] [PubMed] [Google Scholar]
  • 25.Song L.-L., Mu Y.-L., Zhang H.-C., Wu G.-Y., Sun J.-Y. A new indole alkaloid with anti-inflammatory from the branches of Nauclea officinalis. Nat. Prod. Res. 2020;34:2283–2288. doi: 10.1080/14786419.2018.1536130. [DOI] [PubMed] [Google Scholar]
  • 26.Sharma S., Kumar D., Singh G., Monga V., Kumar B. Recent advancements in the development of heterocyclic anti-inflammatory agents. Eur. J. Med. Chem. 2020;200:112438. doi: 10.1016/j.ejmech.2020.112438. [DOI] [PubMed] [Google Scholar]
  • 27.Jiang L., Pu H., Qin X., Liu J., Wen Z., Huang Y., Xiang J., Xiang Y., Ju J., Duan Y., et al. Syn-2, 3-diols and anti-inflammatory indole derivatives from Streptomyces sp. CB09001. Nat. Prod. Res. 2021;35:144–151. doi: 10.1080/14786419.2019.1611812. [DOI] [PubMed] [Google Scholar]
  • 28.Hong Y., Zhu Y.-Y., He Q., Gu S.-X. Indole derivatives as tubulin polymerization inhibitors for the development of promising anticancer agents. Bioorganic Med. Chem. 2022;55:116597. doi: 10.1016/j.bmc.2021.116597. [DOI] [PubMed] [Google Scholar]
  • 29.Tivorbex FDA Approval History. [(accessed on 6 July 2023)]. Available online: https://www.drugs.com/history/tivorbex.html.
  • 30.Li G., Wang Y., De Clercq E. Approved HIV reverse transcriptase inhibitors in the past decade. Acta Pharm. Sin. B. 2022;12:1567–1590. doi: 10.1016/j.apsb.2021.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Delavirdine Gets FDA Approval. [(accessed on 6 July 2023)]; Available online: https://pubmed.ncbi.nlm.nih.gov/11364363/
  • 32.Umifenovir. [(accessed on 6 July 2023)]. Available online: https://go.drugbank.com/drugs/DB13609.
  • 33.Visken. [(accessed on 6 July 2023)]; Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018285s034lbl.pdf.
  • 34.Cronenwett W.J. Schizophrenia Pharmacology: Past, Present, and Future Targets for Intervention. Focus. 2016;14:308–314. doi: 10.1176/appi.focus.20160009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Mailman R.B., Murthy V. Third Generation Antipsychotic Drugs: Partial Agonism or Receptor Functional Selectivity? Curr. Pharm. Des. 2010;16:488–501. doi: 10.2174/138161210790361461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Zuplenz FDA Approval History. [(accessed on 6 July 2023)]. Available online: https://www.drugs.com/history/zuplenz.html.
  • 37.Serdolect FDA Approval Status. [(accessed on 6 July 2023)]. Available online: https://www.drugs.com/history/serdolect.html.
  • 38.Merck’s Maxalt Approved in USA. [(accessed on 6 July 2023)]. Available online: https://www.thepharmaletter.com/article/merck-s-maxalt-approved-in-usa.
  • 39.Han Y., Dong W., Guo Q., Li X., Huang L. The importance of indole and azaindole scaffold in the development of antitumor agents. Eur. J. Med. Chem. 2020;203:112506. doi: 10.1016/j.ejmech.2020.112506. [DOI] [PubMed] [Google Scholar]
  • 40.Sutent FDA Approval History. [(accessed on 6 July 2023)]. Available online: https://www.drugs.com/history/sutent.html.
  • 41.Sunitinib Malate. [(accessed on 6 July 2023)]; Available online: https://www.cancer.gov/about-cancer/treatment/drugs/sunitinibmalate.
  • 42.Tagrisso FDA Approval History. [(accessed on 6 July 2023)]. Available online: https://www.drugs.com/history/tagrisso.html.
  • 43.Osimertinib Mesylate. [(accessed on 6 July 2023)]; Available online: https://www.cancer.gov/about-cancer/treatment/drugs/osimertinib.
  • 44.Rucaparib Camsylate. [(accessed on 6 July 2023)]; Available online: https://www.cancer.gov/about-cancer/treatment/drugs/rucaparibcamsylate.
  • 45.Li S. Anlotinib: A Novel Targeted Drug for Bone and Soft Tissue Sarcoma. Front. Oncol. 2021;11:664853. doi: 10.3389/fonc.2021.664853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Syed Y.Y. Anlotinib: First Global Approval. Drugs. 2018;78:1057–1062. doi: 10.1007/s40265-018-0939-x. [DOI] [PubMed] [Google Scholar]
  • 47.Farydak FDA Approval History. [(accessed on 6 July 2023)]. Available online: https://www.drugs.com/history/farydak.html.
  • 48.Rydapt FDA Approval History. [(accessed on 6 July 2023)]. Available online: https://www.drugs.com/history/rydapt.html.
  • 49.Alecensa (Alectinib) FDA Approval History-Drugs.com. [(accessed on 20 September 2020)]. Available online: https://www.drugs.com/history/alecensa.html.
  • 50.Alectinib. [(accessed on 6 July 2023)]; Available online: https://www.cancer.gov/about-cancer/treatment/drugs/alectinib.
  • 51.Dadashpour S., Emami S. Indole in the target-based design of anticancer agents: A versatile scaffold with diverse mechanisms. Eur. J. Med. Chem. 2018;150:9–29. doi: 10.1016/j.ejmech.2018.02.065. [DOI] [PubMed] [Google Scholar]
  • 52.Patil R., Patil A.S., Beaman K.D., Patil A.S. Indole molecules as inhibitors of tubulin polymerization: Potential new anticancer agents, an update (2013–2015) Futur. Med. Chem. 2016;8:1291–1316. doi: 10.4155/fmc-2016-0047. [DOI] [PubMed] [Google Scholar]
  • 53.Patil S.A., Patil R., Miller D.D. Indole molecules as inhibitors of tubulin polymerization: Potential new anticancer agents. Futur. Med. Chem. 2012;4:2085–2115. doi: 10.4155/fmc.12.141. [DOI] [PubMed] [Google Scholar]
  • 54.Ahmad A., Sakr A.W., Rahman K.W. Anticancer Properties of Indole Compounds: Mechanism of Apoptosis Induction and Role in Chemotherapy. Curr. Drug Targets. 2010;11:652–666. doi: 10.2174/138945010791170923. [DOI] [PubMed] [Google Scholar]
  • 55.Panda S.S., Girgis A.S., Aziz M.N., Bekheit M.S. Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold. Molecules. 2023;28:618. doi: 10.3390/molecules28020618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Seliem I.A., Panda S.S., Girgis A.S., Tran Q.L., Said M.F., Bekheit M.S., Abdelnaser A., Nasr S., Fayad W., Soliman A.A.F., et al. Development of Isatin-Based Schiff Bases Targeting VEGFR-2 Inhibition: Synthesis, Characterization, Antiproliferative Properties, and QSAR Studies. ChemMedChem. 2022;17:e202200164. doi: 10.1002/cmdc.202200164. [DOI] [PubMed] [Google Scholar]
  • 57.Girgis A.S., Panda S.S., Aziz M.N., Steel P.J., Hall C.D., Katritzky A.R. Rational design, synthesis, and 2D-QSAR study of anti-oncological alkaloids against hepatoma and cervical carcinoma. RSC Adv. 2015;5:28554–28569. doi: 10.1039/C4RA16663A. [DOI] [Google Scholar]
  • 58.Lee Y.Y., Park H.H., Park W., Kim H., Jang J.G., Hong K.S., Lee J.-Y., Seo H.S., Na D.H., Kim T.-H., et al. Long-acting nanoparticulate DNase-1 for effective suppression of SARS-CoV-2-mediated neutrophil activities and cytokine storm. Biomaterials. 2021;267:120389. doi: 10.1016/j.biomaterials.2020.120389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Ghosh A.K., Raghavaiah J., Shahabi D., Yadav M., Anson B.J., Lendy E.K., Hattori S.-I., Higashi-Kuwata N., Mitsuya H., Mesecar A.D. Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure–Activity Relationship, and X-ray Structural Studies. J. Med. Chem. 2021;64:14702–14714. doi: 10.1021/acs.jmedchem.1c01214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Mishra S.K., Tripathi T. One year update on the COVID-19 pandemic: Where are we now? Acta Trop. 2021;214:105778. doi: 10.1016/j.actatropica.2020.105778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.WHO Coronavirus (COVID-19) Dashboard. [(accessed on 25 February 2023)]. Available online: https://covid19.who.int/
  • 62.Jayabal K., Elumalai D., Leelakrishnan S., Bhattacharya S., Rengarajan V., Kannan T., Chuang S.-C. Green and Regioselective Approach for the Synthesis of 3-Substituted Indole Based 1,2-Dihydropyridine and Azaxanthone Derivatives as a Potential Lead for SARS-CoV-2 and Delta Plus Mutant Virus: DFT and Docking Studies. ACS Omega. 2022;7:43856–43876. doi: 10.1021/acsomega.2c04990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Ahmad S. The race to treat COVID-19: Potential therapeutic agents for the prevention and treatment of SARS-CoV-2. Eur. J. Med. Chem. 2021;213:113157. doi: 10.1016/j.ejmech.2021.113157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Sanders J.M., Monogue M.L., Jodlowski T.Z., Cutrell J.B. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19), A Review. JAMA. 2020;323:1824–1836. doi: 10.1001/jama.2020.6019. [DOI] [PubMed] [Google Scholar]
  • 65.Zheng L., Zhang L., Huang J., Nandakumar K.S., Liu S., Cheng K. Potential treatment methods targeting 2019-nCoV infection. Eur. J. Med. Chem. 2020;205:112687. doi: 10.1016/j.ejmech.2020.112687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Seliem I.A., Panda S.S., Girgis A.S., Moatasim Y., Kandeil A., Mostafa A., Ali M.A., Nossier E.S., Rasslan F., Srour A.M., et al. New quinoline-triazole conjugates: Synthesis, and antiviral properties against SARS-CoV-2. Bioorganic Chem. 2021;114:105117. doi: 10.1016/j.bioorg.2021.105117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Zhou P., Yang X.-L., Wang X.-G., Hu B., Zhang L., Zhang W., Si H.-R., Zhu Y., Li B., Huang C.-L., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273. doi: 10.1038/s41586-020-2012-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Banerjee R., Perera L., Tillekeratne L.V. Potential SARS-CoV-2 main protease inhibitors. Drug Discov. Today. 2021;26:804–816. doi: 10.1016/j.drudis.2020.12.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Araf Y., Akter F., Tang Y., Fatemi R., Alam Parvez S., Zheng C., Hossain G. Omicron variant of SARS-CoV-2: Genomics, transmissibility, and responses to current COVID-19 vaccines. J. Med. Virol. 2022;94:1825–1832. doi: 10.1002/jmv.27588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.He M., Huang Y., Wang Y., Liu J., Han M., Xiao Y., Zhang N., Gui H., Qiu H., Cao L., et al. Metabolomics-based investigation of SARS-CoV-2 vaccination (Sinovac) reveals an immune-dependent metabolite biomarker. Front. Immunol. 2022;13:954801. doi: 10.3389/fimmu.2022.954801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Yapasert R., Khaw-On P., Banjerdpongchai R. Coronavirus Infection-Associated Cell Death Signaling and Potential Therapeutic Targets. Molecules. 2021;26:7459. doi: 10.3390/molecules26247459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Varadharajan V., Arumugam G.S., Shanmugam S. Isatin-based virtual high throughput screening, molecular docking, DFT, QM/MM, MD and MM-PBSA study of novel inhibitors of SARS-CoV-2 main protease. J. Biomol. Struct. Dyn. 2022;40:7852–7867. doi: 10.1080/07391102.2021.1904003. [DOI] [PubMed] [Google Scholar]
  • 73.Hua Y., Dai X., Xu Y., Xing G., Liu H., Lu T., Chen Y., Zhang Y. Drug repositioning: Progress and challenges in drug discovery for various diseases. Eur. J. Med. Chem. 2022;234:114239. doi: 10.1016/j.ejmech.2022.114239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Pillaiyar T., Meenakshisundaram S., Manickam M., Sankaranarayanan M. A medicinal chemistry perspective of drug repositioning: Recent advances and challenges in drug discovery. Eur. J. Med. Chem. 2020;195:112275. doi: 10.1016/j.ejmech.2020.112275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Kumar S., Kovalenko S., Bhardwaj S., Sethi A., Gorobets N.Y., Desenko S.M., Poonam, Rathi B. Drug repurposing against SARS-CoV-2 using computational approaches. Drug Discov. Today. 2022;27:2015–2027. doi: 10.1016/j.drudis.2022.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Mohamed K., Yazdanpanah N., Saghazadeh A., Rezaei N. Computational drug discovery and repurposing for the treatment of COVID-19: A systematic review. Bioorganic Chem. 2021;106:104490. doi: 10.1016/j.bioorg.2020.104490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Chiou W.-C., Hsu M.-S., Chen Y.-T., Yang J.-M., Tsay Y.-G., Huang H.-C., Huang C. Repurposing existing drugs: Identification of SARS-CoV-2 3C-like protease inhibitors. J. Enzym. Inhib. Med. Chem. 2021;36:147–153. doi: 10.1080/14756366.2020.1850710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Thaysen J., Boisen A., Hansen O., Bouwstra S. Atomic Force Microscopy Probe with Piezoresistive Read-out and a Highly Symmetrical Wheatstone Bridge Arrangement. Sens. Actuators A Phys. 2001;83:47–53. doi: 10.1016/S0924-4247(00)00299-5. [DOI] [Google Scholar]
  • 79.Sarkar A., Mandal K. Repurposing an Antiviral Drug against SARS-CoV-2 Main Protease. Angew. Chem. Int. Ed. 2021;60:23492–23494. doi: 10.1002/anie.202107481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Batalha P.N., Forezi L.S., Lima C.G., Pauli F.P., Boechat F.C., de Souza M.C.B., Cunha A.C., Ferreira V.F., Silva F.d.C.d. Drug repurposing for the treatment of COVID-19: Pharmacological aspects and synthetic approaches. Bioorganic Chem. 2021;106:104488. doi: 10.1016/j.bioorg.2020.104488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Dowarah J., Marak B.N., Yadav U.C.S., Singh V.P. Potential drug development and therapeutic approaches for clinical intervention in COVID-19. Bioorganic Chem. 2021;114:105016. doi: 10.1016/j.bioorg.2021.105016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Trivedi A., Verna D. Kumar, Possible treatment and strategies for COVID-19: Review and assessment. Eur. Rev. Med. Pharmacol. Sci. 2020;24:12593–12608. doi: 10.26355/eurrev_202012_24057. [DOI] [PubMed] [Google Scholar]
  • 83.Ashour A.N., Elmaaty A.A., Sarhan A.A., Elkaeed E.B., Moussa A.M., Erfan I.A., Al-Karmalawy A.A. A Systematic Review of the Global Intervention for SARS-CoV-2 Combating: From Drugs Repurposing to Molnupiravir Approval. Drug Des. Dev. Ther. 2022;16:685–715. doi: 10.2147/DDDT.S354841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Santos J., Brierley S., Gandhi M.J., Cohen M.A., Moschella P.C., Declan A.B.L. Repurposing Therapeutics for Potential Treatment of SARS-CoV-2: A Review. Viruses. 2020;12:705. doi: 10.3390/v12070705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Zhang X., Yang Y., Grimstein M., Liu G., Kitabi E., Fan J., Wang Y., Earp J., Weaver J.L., Zhu H., et al. Anti–SARS-CoV-2 Repurposing Drug Database: Clinical Pharmacology Considerations. CPT Pharmacomet. Syst. Pharmacol. 2021;10:973–982. doi: 10.1002/psp4.12681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Simonis A., Theobald S.J., Fätkenheuer G., Rybniker J., Malin J.J. A comparative analysis of remdesivir and other repurposed antivirals against SARS-CoV-2. EMBO Mol. Med. 2021;13:e13105. doi: 10.15252/emmm.202013105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Molnupiravir [(accessed on 6 July 2023)]. Available online: https://go.drugbank.com/drugs/DB15661.
  • 88.Lagevrio FDA Approval Status. [(accessed on 6 July 2023)]. Available online: https://www.drugs.com/history/molnupiravir.html.
  • 89.Paxlovid FDA Approval History. [(accessed on 6 July 2023)]. Available online: https://www.drugs.com/history/paxlovid.html.
  • 90.Srour A.M., Panda S.S., Mostafa A., Fayad W., El-Manawaty M.A., Soliman A.A.F., Moatasim Y., El Taweel A., Abdelhameed M.F., Bekheit M.S., et al. Synthesis of aspirin-curcumin mimic conjugates of potential antitumor and anti-SARS-CoV-2 properties. Bioorganic Chem. 2021;117:105466. doi: 10.1016/j.bioorg.2021.105466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Seliem I.A., Girgis A.S., Moatasim Y., Kandeil A., Mostafa A., Ali M.A., Bekheit M.S., Panda S.S. New Pyrazine Conjugates: Synthesis, Computational Studies, and Antiviral Properties against SARS-CoV-2. ChemMedChem. 2021;16:3418–3427. doi: 10.1002/cmdc.202100476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Youssef M.A., Panda S.S., Aboshouk D.R., Said M.F., El Taweel A., GabAllah M., Fayad W., Soliman A.F., Mostafa A., Fawzy N.G., et al. Novel Curcumin Mimics: Design, Synthesis, Biological Properties and Computational Studies of Piperidone-Piperazine Conjugates. ChemistrySelect. 2022;7:e202201406. doi: 10.1002/slct.202201406. [DOI] [Google Scholar]
  • 93.Wyman K.A., Girgis A.S., Surapaneni P.S., Moore J.M., Shama N.M.A., Mahmoud S.H., Mostafa A., Barghash R.F., Juan Z., Dobaria R.D., et al. Synthesis of Potential Antiviral Agents for SARS-CoV-2 Using Molecular Hybridization Approach. Molecules. 2022;27:5923. doi: 10.3390/molecules27185923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Li C., Wang L., Ren L. Antiviral mechanisms of candidate chemical medicines and traditional Chinese medicines for SARS-CoV-2 infection. Virus Res. 2020;286:198073. doi: 10.1016/j.virusres.2020.198073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Leneva I., Kartashova N., Poromov A., Gracheva A., Korchevaya E., Glubokova E., Borisova O., Shtro A., Loginova S., Shchukina V., et al. Antiviral Activity of Umifenovir In Vitro against a Broad Spectrum of Coronaviruses, Including the Novel SARS-CoV-2 Virus. Viruses. 2021;13:1665. doi: 10.3390/v13081665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Tanaka H., Miyagi S., Yoshida Y., Lamb J.S., Chick C.N., Luhata L.P., Shibata M., Tanaka E., Suzuki Y., Usuki T. Synthesis and Biological Evaluation of Umifenovir Analogues as Anti-SARS-CoV-2 Agents. ChemistrySelect. 2022;7:e202202097. doi: 10.1002/slct.202202097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Shuster A., Pechalrieu D., Jackson C.B., Abegg D., Choe H., Adibekian A. Clinical Antiviral Drug Arbidol Inhibits Infection by SARS-CoV-2 and Variants through Direct Binding to the Spike Protein. ACS Chem. Biol. 2021;16:2845–2851. doi: 10.1021/acschembio.1c00756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Yadav A.K., Wen S., Xu X., Yu L. Antiviral treatment in COVID-19: Which is the most promising?—A narrative review. Ann. Palliat. Med. 2021;10:707–720. doi: 10.21037/apm-20-1755. [DOI] [PubMed] [Google Scholar]
  • 99.Pan X., Dong L., Yang L., Chen D., Peng C. Potential drugs for the treatment of the novel coronavirus pneumonia (COVID-19) in China. Virus Res. 2020;286:198057. doi: 10.1016/j.virusres.2020.198057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Wang D., Li Z., Liu Y. An overview of the safety, clinical application and antiviral research of the COVID-19 therapeutics. J. Infect. Public Health. 2020;13:1405–1414. doi: 10.1016/j.jiph.2020.07.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Padhi A.K., Seal A., Khan J.M., Ahamed M., Tripathi T. Unraveling the mechanism of arbidol binding and inhibition of SARS-CoV-2: Insights from atomistic simulations. Eur. J. Pharmacol. 2021;894:173836. doi: 10.1016/j.ejphar.2020.173836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Borisevich S.S., Khamitov E.M., Gureev M.A., Yarovaya O.I., Rudometova N.B., Zybkina A.V., Mordvinova E.D., Shcherbakov D.N., Maksyutov R.A., Salakhutdinov N.F. Simulation of Molecular Dynamics of SARS-CoV-2 S-Protein in the Presence of Multiple Arbidol Molecules: Interactions and Binding Mode Insights. Viruses. 2022;14:119. doi: 10.3390/v14010119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Vankadari N. Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein. Int. J. Antimicrob. Agents. 2020;56:105998. doi: 10.1016/j.ijantimicag.2020.105998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Zhu Z., Lu Z., Xu T., Chen C., Yang G., Zha T., Lu J., Xue Y. Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. J. Infect. 2020;81:e21–e23. doi: 10.1016/j.jinf.2020.03.060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Nojomi M., Yassin Z., Keyvani H., Makiani M.J., Roham M., Laali A., Dehghan N., Navaei M., Ranjbar M. Effect of Arbidol (Umifenovir) on COVID-19: A randomized controlled trial. BMC Infect. Dis. 2020;20:954. doi: 10.1186/s12879-020-05698-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Li Y., Xie Z., Lin W., Cai W., Wen C., Guan Y., Mo X., Wang J., Wang Y., Peng P., et al. Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients with Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial. Med. 2020;1:105–113.e4. doi: 10.1016/j.medj.2020.04.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Wang Z., Yang B., Li Q., Wen L., Zhang R. Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China. Clin. Infect. Dis. 2020;71:769–777. doi: 10.1093/cid/ciaa272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Amani B., Amani B., Zareei S., Zareei M. Efficacy and safety of arbidol (umifenovir) in patients with COVID-19: A systematic review and meta-analysis. Immun. Inflamm. Dis. 2021;9:1197–1208. doi: 10.1002/iid3.502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Wang Z., Chen X., Lu Y., Chen F., Zhang W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci. Trends. 2020;14:64–68. doi: 10.5582/bst.2020.01030. [DOI] [PubMed] [Google Scholar]
  • 110.Ramachandran R., Bhosale V., Reddy H., Atam V., Faridi M., Fatima J., Shukla V., Khan A.Z., Khan H., Singh V., et al. Phase III, Randomized, Double-blind, Placebo controlled trial of Efficacy, Safety and Tolerability of Antiviral drug Umifenovir vs Standard care of therapy in non-severe COVID-19 patients. Int. J. Infect. Dis. 2022;115:62–69. doi: 10.1016/j.ijid.2021.11.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.Yu M., Wang D., Li S., Lei Y., Wei J., Huang L. Meta-analysis of arbidol versus lopinavir/ritonavir in the treatment of coronavirus disease 2019. J. Med. Virol. 2022;94:1513–1522. doi: 10.1002/jmv.27481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Yang C., Ke C., Yue D., Li W., Hu Z., Liu W., Hu S., Wang S., Liu J. Effectiveness of Arbidol for COVID-19 Prevention in Health Professionals. Front. Public Health. 2020;8:249. doi: 10.3389/fpubh.2020.00249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Li M., Yu T., Zhu J., Wang Y., Yang Y., Zhao K., Yi Y., He J., Li C., He J. Comparison of the antiviral effect of Arbidol and Chloroquine in treating COVID-19. Ann. Palliat. Med. 2021;10:3307–3312. doi: 10.21037/apm-21-400. [DOI] [PubMed] [Google Scholar]
  • 114.He X.-L., Zhou Y.-Y., Fu W., Xue Y.-E., Liang M.-Y., Yang B.-H., Ma W.-L., Zhou Q., Chen L., Zhang J.-C., et al. Prolonged SARS-CoV-2 Viral Shedding in Patients with COVID-19 was Associated with Delayed Initiation of Arbidol Treatment and Consulting Doctor Later: A Retrospective Cohort Study. Curr. Med. Sci. 2021;41:1096–1104. doi: 10.1007/s11596-021-2434-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Ul’Yanovskii N.V., Kosyakov D.S., Sypalov S.A., Varsegov I.S., Shavrina I.S., Lebedev A.T. Antiviral drug Umifenovir (Arbidol) in municipal wastewater during the COVID-19 pandemic: Estimated levels and transformation. Sci. Total Environ. 2022;805:150380. doi: 10.1016/j.scitotenv.2021.150380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Choudhary S., Silakari O. Scaffold morphing of arbidol (umifenovir) in search of multi-targeting therapy halting the interaction of SARS-CoV-2 with ACE2 and other proteases involved in COVID-19. Virus Res. 2020;289:198146. doi: 10.1016/j.virusres.2020.198146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117.Hart F.D., Boardman P.L. Indomethacin: A New Non-steroid Anti-inflammatory Agent. BMJ. 1963;2:965–970. doi: 10.1136/bmj.2.5363.965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Ghanim A.M., Girgis A.S., Kariuki B.M., Samir N., Said M.F., Abdelnaser A., Nasr S., Bekheit M.S., Abdelhameed M.F., Almalki A.J., et al. Design and synthesis of ibuprofen-quinoline conjugates as potential anti-inflammatory and analgesic drug candidates. Bioorganic Chem. 2022;119:105557. doi: 10.1016/j.bioorg.2021.105557. [DOI] [PubMed] [Google Scholar]
  • 119.Bokhtia R.M., Panda S.S., Girgis A.S., Samir N., Said M.F., Abdelnaser A., Nasr S., Bekheit M.S., Dawood A.S., Sharma H., et al. New NSAID Conjugates as Potent and Selective COX-2 Inhibitors: Synthesis, Molecular Modeling and Biological Investigation. Molecules. 2023;28:1945. doi: 10.3390/molecules28041945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 120.Ravichandran R., Mohan S.K., Sukumaran S.K., Kamaraj D., Daivasuga S.S., Ravi S.O.A.S., Vijayaraghavalu S., Kumar R.K. An open label randomized clinical trial of Indomethacin for mild and moderate hospitalised COVID-19 patients. Sci. Rep. 2022;12:6413. doi: 10.1038/s41598-022-10370-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121.Desantis J., Mercorelli B., Celegato M., Croci F., Bazzacco A., Baroni M., Siragusa L., Cruciani G., Loregian A., Goracci L. Indomethacin-based PROTACs as pan-coronavirus antiviral agents. Eur. J. Med. Chem. 2021;226:113814. doi: 10.1016/j.ejmech.2021.113814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122.Gomeni R., Xu T., Gao X., Bressolle-Gomeni F. Model based approach for estimating the dosage regimen of indomethacin a potential antiviral treatment of patients infected with SARS CoV-2. J. Pharmacokinet. Pharmacodyn. 2020;47:189–198. doi: 10.1007/s10928-020-09690-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 123.Krymchantowski A.V., Silva-Néto R.P., Jevoux C., Krymchantowski A.G. Indomethacin for refractory COVID or post-COVID headache: A retrospective study. Acta Neurol. Belg. 2022;122:465–469. doi: 10.1007/s13760-021-01790-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 124.Shekhar N., Kaur H., Sarma P., Prakash A., Medhi B. Indomethacin: An exploratory study of antiviral mechanism and host-pathogen interaction in COVID-19. Expert Rev. Anti-Infect. Ther. 2022;20:383–390. doi: 10.1080/14787210.2022.1990756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 125.Li J., Lin C., Zhou X., Zhong F., Zeng P., McCormick P.J., Jiang H., Zhang J. Structural Basis of Main Proteases of Coronavirus Bound to Drug Candidate PF-07304814. J. Mol. Biol. 2022;434:167706. doi: 10.1016/j.jmb.2022.167706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Mao B., Le-Trilling V.T.K., Wang K., Mennerich D., Hu J., Zhao Z., Zheng J., Deng Y., Katschinski B., Xu S., et al. Obatoclax inhibits SARS-CoV-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro. Emerg. Microbes Infect. 2022;11:483–497. doi: 10.1080/22221751.2022.2026739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127.Begum R., Mamun-Or-Rashid A.N.M., Lucy T.T., Pramanik K., Sil B.K., Mukerjee N., Tagde P., Yagi M., Yonei Y. Potential Therapeutic Approach of Melatonin against Omicron and Some Other Variants of SARS-CoV-2. Molecules. 2022;27:6934. doi: 10.3390/molecules27206934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 128.Vlachou M., Siamidi A., Dedeloudi A., Konstantinidou S.K., Papanastasiou I.P. Pineal hormone melatonin as an adjuvant treatment for COVID-19 (Review) Int. J. Mol. Med. 2021;47:47. doi: 10.3892/ijmm.2021.4880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 129.Parlakpinar H., Polat S., Acet H.A. Pharmacological agents under investigation in the treatment of coronavirus disease 2019 and the importance of melatonin. Fundam. Clin. Pharmacol. 2021;35:62–75. doi: 10.1111/fcp.12589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 130.Feitosa E.L., Júnior F.T.D.S.S., Neto J.A.D.O.N., Matos L.F.L., Moura M.H.D.S., Rosales T.O., De Freitas G.B.L. COVID-19: Rational discovery of the therapeutic potential of Melatonin as a SARS-CoV-2 main Protease Inhibitor. Int. J. Med. Sci. 2020;17:2133–2146. doi: 10.7150/ijms.48053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 131.Zhang R., Wang X., Ni L., Di X., Ma B., Niu S., Liu C., Reiter R.J. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020;250:117583. doi: 10.1016/j.lfs.2020.117583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 132.Öztürk G., Akbulut K.G., Güney S. Melatonin, aging, and COVID-19: Could melatonin be beneficial for COVID-19 treatment in the elderly? Turk. J. Med. Sci. 2020;50:1504–1512. doi: 10.3906/sag-2005-356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 133.Wichniak A., Kania A., Siemiński M., Cubała W.J. Melatonin as a Potential Adjuvant Treatment for COVID-19 beyond Sleep Disorders. Int. J. Mol. Sci. 2021;22:8623. doi: 10.3390/ijms22168623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 134.Reiter R.J., Sharma R., Simko F., Dominguez-Rodriguez A., Tesarik J., Neel R.L., Slominski A.T., Kleszczynski K., Martin-Gimenez V.M., Manucha W., et al. Melatonin: Highlighting its use as a potential treatment for SARS-CoV-2 infection. Cell. Mol. Life Sci. 2022;79:143. doi: 10.1007/s00018-021-04102-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 135.García I.G., Rodriguez-Rubio M., Mariblanca A.R., de Soto L.M., García L.D., Villatoro J.M., Parada J.Q., Meseguer E.S., Rosales M.J., González J., et al. A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21:466. doi: 10.1186/s13063-020-04436-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 136.Hasan Z.T., Al Atrakji M.Q.Y.M.A., Mehuaiden A.K. The Effect of Melatonin on Thrombosis, Sepsis and Mortality Rate in COVID-19 Patients. Int. J. Infect. Dis. 2022;114:79–84. doi: 10.1016/j.ijid.2021.10.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 137.Lan S., Lee H., Chao C., Chang S., Lu L., Lai C. Efficacy of melatonin in the treatment of patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials. J. Med. Virol. 2022;94:2102–2107. doi: 10.1002/jmv.27595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 138.Farnoosh G., Akbariqomi M., Badri T., Bagheri M., Izadi M., Saeedi-Boroujeni A., Rezaie E., Ghaleh H.E.G., Aghamollaei H., Fasihi-Ramandi M., et al. Efficacy of a Low Dose of Melatonin as an Adjunctive Therapy in Hospitalized Patients with COVID-19: A Randomized, Double-blind Clinical Trial. Arch. Med. Res. 2022;53:79–85. doi: 10.1016/j.arcmed.2021.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 139.Ziaei A., Davoodian P., Dadvand H., Safa O., Hassanipour S., Omidi M., Masjedi M., Mahmoudikia F., Rafiee B., Fathalipour M. Evaluation of the efficacy and safety of Melatonin in moderately ill patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020;21:882. doi: 10.1186/s13063-020-04737-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 140.Alhadrami H.A., Burgio G., Thissera B., Orfali R., Jiffri S.E., Yaseen M., Sayed A.M., Rateb M.E. Neoechinulin A as a Promising SARS-CoV-2 Mpro Inhibitor: In Vitro and In Silico Study Showing the Ability of Simulations in Discerning Active from Inactive Enzyme Inhibitors. Mar. Drugs. 2022;20:163. doi: 10.3390/md20030163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 141.Vuong W., Khan M.B., Fischer C., Arutyunova E., Lamer T., Shields J., Saffran H.A., McKay R.T., van Belkum M.J., Joyce M.A., et al. Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication. Nat. Commun. 2020;11:4282. doi: 10.1038/s41467-020-18096-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 142.Nishiuchi K., Ohashi H., Nishioka K., Yamasaki M., Furuta M., Mashiko T., Tomoshige S., Ohgane K., Kamisuki S., Watashi K., et al. Synthesis and Antiviral Activities of Neoechinulin B and Its Derivatives. J. Nat. Prod. 2021;85:284–291. doi: 10.1021/acs.jnatprod.1c01120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 143.Liu P., Liu H., Sun Q., Liang H., Li C., Deng X., Liu Y., Lai L. Potent inhibitors of SARS-CoV-2 3C-like protease derived from N-substituted isatin compounds. Eur. J. Med. Chem. 2020;206:112702. doi: 10.1016/j.ejmech.2020.112702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 144.Zhang G.-N., Zhao J., Li Q., Wang M., Zhu M., Wang J., Cen S., Wang Y. Discovery and optimization of 2-((1H-indol-3-yl)thio)-N-benzyl-acetamides as novel SARS-CoV-2 RdRp inhibitors. Eur. J. Med. Chem. 2021;223:113622. doi: 10.1016/j.ejmech.2021.113622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 145.Zhao J., Zhang G., Zhang Y., Yi D., Li Q., Ma L., Guo S., Li X., Guo F., Lin R., et al. 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors. Antivir. Res. 2021;196:105209. doi: 10.1016/j.antiviral.2021.105209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 146.Ghosh A.K., Shahabi D., Yadav M., Kovela S., Anson B.J., Lendy E.K., Bonham C., Sirohi D., Brito-Sierra C.A., Hattori S.-I., et al. Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors. Molecules. 2021;26:5782. doi: 10.3390/molecules26195782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 147.Mudi P.K., Mahanty A.K., Kotakonda M., Prasad S., Bhattacharyya S., Biswas B. A benzimidazole scaffold as a promising inhibitor against SARS-CoV-2. J. Biomol. Struct. Dyn. 2023;41:1798–1810. doi: 10.1080/07391102.2021.2024448. [DOI] [PubMed] [Google Scholar]
  • 148.Girgis A.S., Panda S.S., Srour A.M., Abdelnaser A., Nasr S., Moatasim Y., Kutkat O., El Taweel A., Kandeil A., Mostafa A., et al. 3-Alkenyl-2-oxindoles: Synthesis, antiproliferative and antiviral properties against SARS-CoV-2. Bioorganic Chem. 2021;114:105131. doi: 10.1016/j.bioorg.2021.105131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 149.Fawazy N.G., Panda S.S., Mostafa A., Kariuki B.M., Bekheit M.S., Moatasim Y., Kutkat O., Fayad W., El-Manawaty M.A., Soliman A.A.F., et al. Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties. Sci. Rep. 2022;12:13880. doi: 10.1038/s41598-022-17883-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 150.Bekheit M.S., Panda S.S., Kariuki B.M., Mahmoud S.H., Mostafa A., Girgis A.S. Spiroindole-containing compounds bearing phosphonate group of potential Mpro-SARS-CoV-2 inhibitory properties. Eur. J. Med. Chem. 2023;258:115563. doi: 10.1016/j.ejmech.2023.115563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 151.Di Sarno V., Lauro G., Musella S., Ciaglia T., Vestuto V., Sala M., Scala M.C., Smaldone G., Di Matteo F., Novi S., et al. Identification of a dual acting SARS-CoV-2 proteases inhibitor through in silico design and step-by-step biological characterization. Eur. J. Med. Chem. 2021;226:113863. doi: 10.1016/j.ejmech.2021.113863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 152.Serra A., Fratello M., Federico A., Ojha R., Provenzani R., Tasnadi E., Cattelani L., del Giudice G., Kinaret P.A.S., A Saarimäki L., et al. Computationally prioritized drugs inhibit SARS-CoV-2 infection and syncytia formation. Brief. Bioinform. 2022;23:bbab507. doi: 10.1093/bib/bbab507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 153.Panda S.S., Girgis A.S., Thomas S.J., Capito J.E., George R.F., Salman A., El-Manawaty M.A., Samir A. Synthesis, pharmacological profile and 2D-QSAR studies of curcumin-amino acid conjugates as potential drug candidates. Eur. J. Med. Chem. 2020;196:112293. doi: 10.1016/j.ejmech.2020.112293. [DOI] [PubMed] [Google Scholar]
  • 154.Mohseni M., Bahrami H., Farajmand B., Hosseini F.S., Amanlou M., Salehabadi H. Indole alkaloids as potential candidates against COVID-19: An in silico study. J. Mol. Model. 2022;28:144. doi: 10.1007/s00894-022-05137-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 155.Raj V., Lee J.-H., Shim J.-J., Lee J. Antiviral activities of 4H-chromen-4-one scaffold-containing flavonoids against SARS–CoV–2 using computational and in vitro approaches. J. Mol. Liq. 2022;353:118775. doi: 10.1016/j.molliq.2022.118775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 156.WHO Recommends Highly Successful COVID-19 Therapy and Calls for Wide Geographical Distribution and Transparency from Originator. [(accessed on 11 September 2023)]. Available online: https://www.who.int/news/item/22-04-2022-who-recommends-highly-successful-covid-19-therapy-and-calls-for-wide-geographical-distribution-and-transparency-from-originator.
  • 157.Discover expert implementation tips for using DrugBank Conditions Data. [(accessed on 6 July 2023)]. Available online: https://go.drugbank.com/unearth/q?utf8=%E2%9C%93&searcher=drugs&query=Paxlovid.
  • 158.Reina J., Iglesias C. Nirmatrelvir plus ritonavir (Paxlovid) a potent SARS-CoV-2 3CLpro protease inhibitor combination. Rev. Esp. Quim. 2022;35:236–240. doi: 10.37201/req/002.2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 159.Khan F.I., Hassan F., Lai D. In Silico Studies on Psilocybin Drug Derivatives Against SARS-CoV-2 and Cytokine Storm of Human Interleukin-6 Receptor. Front. Immunol. 2022;12:794780. doi: 10.3389/fimmu.2021.794780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 160.Vijayakumar B.G., Ramesh D., Joji A., Prakasan J.J., Kannan T. In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2. Eur. J. Pharmacol. 2020;886:173448. doi: 10.1016/j.ejphar.2020.173448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 161.Singhal S., Khanna P., Khanna L. Synthesis, comparative in vitro antibacterial, antioxidant and UV fluorescence studies of bis indole Schiff bases and molecular docking with ct-DNA and SARS-CoV-2 Mpro. Luminescence. 2021;36:1531–1543. doi: 10.1002/bio.4098. [DOI] [PubMed] [Google Scholar]
  • 162.Shah V.R., Bhaliya J.D., Patel G.M. In silico approach: Docking study of oxindole derivatives against the main protease of COVID-19 and its comparison with existing therapeutic agents. J. Basic Clin. Physiol. Pharmacol. 2021;32:197–214. doi: 10.1515/jbcpp-2020-0262. [DOI] [PubMed] [Google Scholar]
  • 163.Hattori S.-I., Higashi-Kuwata N., Hayashi H., Allu S.R., Raghavaiah J., Bulut H., Das D., Anson B.J., Lendy E.K., Takamatsu Y., et al. A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication. Nat. Commun. 2021;12:668. doi: 10.1038/s41467-021-20900-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 164.Gobinath P., Packialakshmi P., Vijayakumar K., Abdellattif M.H., Shahbaaz M., Idhayadhulla A., Surendrakumar R. Synthesis and Cytotoxic Activity of Novel Indole Derivatives and Their in silico Screening on Spike Glycoprotein of SARS-CoV-2. Front. Mol. Biosci. 2021;8:637989. doi: 10.3389/fmolb.2021.637989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 165.Santibáñez-Morán M.G., López-López E., Prieto-Martínez F.D., Sánchez-Cruz N., Medina-Franco J.L. Consensus virtual screening of dark chemical matter and food chemicals uncover potential inhibitors of SARS-CoV-2 main protease. RSC Adv. 2020;10:25089–25099. doi: 10.1039/D0RA04922K. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 166.Xu X., Chen Y., Lu X., Zhang W., Fang W., Yuan L., Wang X. An update on inhibitors targeting RNA-dependent RNA polymerase for COVID-19 treatment: Promises and challenges. Biochem. Pharmacol. 2022;205:115279. doi: 10.1016/j.bcp.2022.115279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 167.Kumar M.R., Gideon D.A., Mariadasse R., Nirusimhan V., Rosita A.S., Edward J.C., Jeyaraman J., Dhayabaran V. In silico evaluation of isatin-based derivatives with RNA-dependent RNA polymerase of the novel coronavirus SARS-CoV-2. J. Biomol. Struct. Dyn. 2022;40:6710–6724. doi: 10.1080/07391102.2021.1890223. [DOI] [PubMed] [Google Scholar]
  • 168.López-López E., Gortari E.F.-D., Medina-Franco J.L. Yes SIR! On the structure–inactivity relationships in drug discovery. Drug Discov. Today. 2022;27:2353–2362. doi: 10.1016/j.drudis.2022.05.005. [DOI] [PubMed] [Google Scholar]
  • 169.Bokhtia R.M., Girgis A.S., Ibrahim T.S., Rasslan F., Nossier E.S., Barghash R.F., Sakhuja R., Abdel-Aal E.H., Panda S.S., Al-Mahmoudy A.M.M. Synthesis, Antibacterial Evaluation, and Computational Studies of a Diverse Set of Linezolid Conjugates. Pharmaceuticals. 2022;15:191. doi: 10.3390/ph15020191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 170.Bokhtia R.M., Panda S.S., Girgis A.S., Honkanadavar H.H., Ibrahim T.S., George R.F., Kashef M.T., Fayad W., Sakhuja R., Abdel-Aal E.H., et al. Fluoroquinolone-3-carboxamide amino acid conjugates: Synthesis, antibacterial properties and molecular modeling studies. Med. Chem. 2021;17:71–84. doi: 10.2174/1573406415666190904143852. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Click here for additional data file. (556KB, zip)

Articles from Molecules are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES