Table 4 In vitro and in vivo studies of FIASMAs

Alverine

-

Show functional inhibition of ASMase with residual ASM activity of 21.7

-

[27]

Astemizole

Astemizole formed one hydrogen bond with ACE2 while three hydrogen bonds with H1R. Nitrogen on the hexahydropyridine ring of astemizole forms hydrogen bonds with ARG393 of ACE2 with distances of 2.14 Å. Asmidazole forms hydrogen bonds with LYS1016, ANS1055, and ASN1053 of H1R with distances of 1.92 Å, 2.39 Å, and 1.91 Å, respectively

The results showed that astemizole can bind to the ACE2 receptor and inhibit the invasion of SARS-COV-2 Spike pseudoviruses

–

[170]

Aprindine

-

Show functional inhibition of ASMase with residual ASM activity of 27.5

–

[27]

Amlodipine

Amlodipine showed binding affinity to S glycoprotein and 3-chymotrypsin-like protease was − 5.5, − 6.0, and − 5.2, respectively

Amlodipine Besylate showed antiviral activity against OC43 cells through binding and acting as a carbonic anhydrase inhibitor, calcium channel inhibitor, and PDE inhibitor

Chronic treatment with amlodipine could be significantly associated with low mortality of COVID-19 in patients

[171] [172]

Ambroxol

––-

––––

The system of sphingomyelinase/ceramide is very significant in transmitting SARS-CoV-2. They used Ambroxol, which has trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol structure as an inhibitor of ASMase. The Ambroxol is applied by inhalation, suggesting that the drug might inhibit the acid sphingomyelinase and, thereby, infection with SARS-CoV-2. They used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. They found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, all of which were prevented by pretreatment with ambroxol. They also obtained nasal epithelial cells from human volunteers before and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spike-induced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo [123]

[123]

Amiodarone

–

Amiodarone reduced SARS-CoV-2 and IAV titres ≥ 90% without any cytotoxic effects. It also inhibited SARS2 replication, reducing supernatant viral RNA load with a promising activity level

Amiodarone administration in an early disease phase might block SARS-CoV-2 replication

[156]-[173]

Amitriptyline

Amitriptyline showed binding to the allosteric site of SARS-CoV-2 Main Protease with − 5.9 kcal/mol

The results showed that the increased ASMase activity and ceramide release were inhibited by pretreatment with Amitriptyline at 0.625, 1.25, 2.5, and 5 μM. Thus, amitriptyline was regarded as an active inhibitor of ASMase

In healthy volunteers, oral administration of amitriptyline blocked infection of freshly isolated nasal epithelial cells with SARS‐CoV‐2

[174,175,176]

Benztropin

-

Benztropin inhibited ASMase activity by at least 50% at 10 µM

In healthy volunteers, oral administration of amitriptyline blocked infection of freshly isolated nasal epithelial cells with SARS‐CoV‐2

[174, 177]

Bepridil

Amitriptyline showed binding to the allosteric site of SARS-CoV-2 Main Protease with − 5.1 kcal/mol

Bepridil possesses significant anti − SARS-CoV-2 activity in both Vero E6 and A459/ACE2 cells in a dose-dependent manner with low micromolar effective concentration 50% (EC₅₀) values

-

[178]

Biperidene

-

Showed inhibitory impact on ASMase

-

[174]

Camylofine

-

Camylofin showed an inhibitory impact with a pKa of 10.02

-

[127]

Carvedilol

-

-

Carvedilol usage was not significantly associated with a reduced likelihood of a positive laboratory test result for SARS-CoV-2 among the 5 subgroups after adjusting for age, sex, race, smoking, and various disease comorbidities

[130]

Cepharanthine

Cepharanthine can block both the NSP12‐NSP7 interface and the NSP12‐NSP8 interface of SARS‐CoV‐2 and the NSP12‐NSP8 interface of SARS‐CoV.2

Cepharanthine showed potential antiviral activities against SARS-CoV-2, with IC₅₀ values between 0.1 and 10 μM

[179]

Clofazimine

Clofazimine inhibit 3CL^PRO

Clofazimine showed IC₅₀ value of 0.01 µM

Our data provide evidence that clofazimine may have a role in controlling the current COVID-19 pandemic and, more importantly, in dealing with coronavirus diseases that may emerge

[164, 180, 181]

Clemastine

Clemastin inhibits SARS-CoV-2 replication by non-specific (off-target) effects. Clemastine was docked into the agonist-bound state structure of the receptor (6DK1) with solvation-corrected docking of − 43 kcal/mol

Clemastine inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity with EC50 = 0.95 ± 0.83 µM

-

[136, 137, 182]

Cloperastine

Cloperastine inhibited SARS-CoV-2 replication by non-specific (off-target) effects

-

-

[182]

Chlorprothixene

-

Chlorprothixene inhibits the SARS-CoV replication with EC50s around 10 µM

-

[183]

Chlorpromazine

Chlorpromazine inhibited SARS-CoV-2 replication by non-specific (off-target) effects

Chlorpromazine didn’t inhibit the virus replication

Inhibited viral replication in the lungs but protected against SARS-CoV-2

[184, 185]

Clomiphene

-

Clomiphene showed an inhibitory impact with IC50 of 3.32 µM

-

[142]

Clomipramine

-

Clomipramine showed an IC50 average of 5.63

-

[184]

Conessine

-

Show functional inhibition of ASMase with residual ASM activity of 20.8

-

[27]

Cyclobenzaprine

-

-

-

Cyproheptadine

-

-

-

Desipramine

-

Desipramine with concentrations of 5 μM and 35 μM inhibited acid sphingomyelinase activity

-

[186]

Desloratadine

-

Desloratadine, a commonly used antiallergic, well-tolerated with no major side effects, potently reduced the production of SARS-CoV-2 RNA in Vero-E6 cells

Finally, the ex vivo kinetic of the antiviral effect of desloratadine was evaluated on primary Human Nasal Epithelial Cells (HNEC), showing a significant delay of viral RNA production with a maximal reduction reached after 72 h of treatment

[187]

Dicycloverine

-

Dicycloverine, showed antiviral efficacy against SARS-CoV-2, reducing viral infection by at least 50%,

-

[188]

Dilazep

-

-

-

Dimebon

-

Inhibited ASMase with residual activity 44.1%

-

[27]

Doxepine

-

Doxepin could inhibit SARS-CoV-2 spike pseudovirus from entering the ACE2-expressing cell, reducing the infection rate to 25.82%

-

[189]

Drofenine

-

Drofenine showed an inhibitory impact through pKa alteration of 9.21

-

[127]

Emetine

Emetine (P5) showed binding energy to RNA-dependent RNA polymerase (RdRp) enzyme with − 7.81 kcal/mol

Antiviral effect of emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 0.46 μM

-

[148, 190],

Fendeline

-

-

-

Flupenthixol

Flupenthixol showed docking PLANTS score with RdRp and MPro with − 91.70 and − 91.82, respectively

Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that flupenthixol significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising activity level

Flupenthixol inhibited viral entry in our lung organoid model

[136, 191]

Fluoxetine

Fluoxetine demonstrates non-serotonergic, anti-inflammatory effects. Our results show a critical role for IL6 signal transduction protein (IL6ST) and NF-kappaB Subunit 1 (NFKB1) in fluoxetine’s ability to act as a potential therapy for hyperinflammatory states such as asthma, sepsis, and COVID-19

Fluoxetine with concentrations between 5 μM and 35 μM inhibited acid sphingomyelinase activity

In this multicenter retrospective observational study involving a large sample of patients hospitalized for COVID-19, we found that antidepressant use, at a mean dosage of 21.6 (SD = 14.1) fluoxetine-equivalent milligrams, was significantly and substantially associated with reduced risk of intubation or death, independently of patient characteristics, clinical and biological markers of disease severity, and other psychotropic medications

[144, 186]

Fluvoxamine

Fluvoxamine reduced the viral infection, as measured by luciferase reporter activity

Treatment of COVID-19 patients with fluvoxamine for 2 weeks also effectively decreased the development of clinical deterioration

[143, 152]

Fluphenazine

Fluphenazine revealed the best binding pattern and the highest docking score against the main protease binding site (–11.75 kcal/mol)

Fluphenazine dihydrochloride showed IC₅₀ (Avg) of 6.36 against against SARS-CoV-2

-

[153, 184]

Flupentixol

-

-

-

Flunarizine

Flunarizine by a spike protein docking screen

Flunarizine showed an impact against SARS-CoV-2, which was confirmed through cytopathic effect (CPE) assay in Vero E6 cells with EC50 (uM) of 10.0

-

[185, 192]

Hydroxyzin

The drugs that passed all applied lysosomotropism criteria are azithromycin, promethazine, cyclizine, chloroquine, clemastine, hydroxyzine, rifabutin and vicriviroc, and drugs that do not have data for one of the criteria but passed all the others are chlorcyclizine, homochlorcyclizine and quinacrine

The diphenhydramine, hydroxyzine, and azelastine to exhibit direct antiviral activity against SARS-CoV-2 in vitro

Usage of hydroxyzine was associated with reduced incidence of SARS-CoV-2 positivity in subjects greater than age 61

[154, 193]

Imipramine

Inhibitor candidate for SARS-CoV-2 Main Protease

Concentrations between 5 μM and 35 μM inhibited acid sphingomyelinase activity

-

[176, 186]

Loperamide

-

Loperamide hydrochloride showed antiviral effect against In vitro live virus

-

[179]

Loratadine

In vitro, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike pseudotyped viral infection experiments indicated that histamine H1 antagonists loratadine (LOR) and desloratadine (DES) could prevent the entry of the pseudotyped virus into ACE2-overexpressing HEK293T cells and showed that DES was more effective

Prior usage of loratadine was associated with a reduced incidence of positive SARS-CoV-2 test results in individuals 61 years and above in a statistically significant manner

[154, 158]

Maproteline

-

-

-

Melatonine

The establish that a combinatorial drug treatment using melatonin and toremifene will provide an effective therapeutic strategy to mitigate the severity of COVID-19

In summary, combining mercaptopurine and melatonin may offer a potential combination therapy for 2019-nCoV/SARS-CoV-2 by synergistically targeting papain-like protease, ACE2, c-Jun signalling, and anti-inflammatory pathways

The risk was reduced in those who had pneumococcal polysaccharide or influenza vaccine or were on melatonin, paroxetine, or carvedilol

[160, 194, 195]

Mebhydroline

-

Mebhydroline causes in vitro inhibition of acid sphingomyelinase

-

[174]

Mebeverine

-

-

-

Mibefradile

-

Mibefradile causes in vitro inhibition of acid sphingomyelinase

-

[174]

Norfluoxetine

-

-

-

Nortriptyline

The potential to reverse transcriptomic signature upon SARS-CoV-2 through acting as an antagonist for Adrenergic uptake inhibitor

-

-

[196]

Paroxetine

-

-

Most potentially impactful is the reduced risk of testing positive in patients who were on melatonin, carvedilol, and paroxetine, which are drugs identified in drug-repurposing studies to have a potential benefit against COVID-19

[160]

Perphenazine

-

-

-

Pimozide

Pimozide, tested by computational docking analysis and in vitro assays, has been suggested to inhibit the main protease of SARS-CoV-2 (MPro)

Pimozide, ebastine, and bepridil were the three most potent FDA/EMA-approved medicines, with IC50 values of 42 ± 2, 57 ± 12, and 72 ± 12 µM, respectively

Pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability

-

[143, 178]

Pimethexene

-

-

-

Profenamine

Profenamine showed binding affinity to ASMase of − 8.7 kcal/mol

-

-

[197]

Promethazine

-Promethazine showed effectiveness against either SARS-CoV, SARS-CoV-2 or MERS viruses or two or all of them, supporting the potential value of this antiviral strategy

-Promethazine is a candidate for targeting COVID-19 Related Genes

Promethazine hydrochloride showed IC50 (avg) of 9.21 μM

-

[184, 193, 198]

Promazine

-

Promazine was identified as a high-confidence inhibitor of SARS-CoV-2 replication

-

[199]

Protriptyline

-

-

-

Quinacrine

The remaining top candidate drugs identified by our analysis include kinase inhibitors erlotinib, alvocidib, dasatinib, antimalarial quinacrine, and phenothiazine thioridazine, a more commonly used antipsychotic. These drugs also have antiviral properties and are yet to be explored for the treatment of COVID-19

-

-

[200]

Sertindole

-

Sertindole showed in vitro inhibition of acid sphingomyelinase

-

[174]

Solasodine

Solasodine showed a binding affinity of − 8.7 against ASMase

-

-

Sertraline

-

Mechanistically, sertraline HCl was found to block SARS-CoV-2 S protein-mediated cell fusion

-

[164]

Suloctidil

-

-

-

Tamoxifene

Overall, we recommend that tamoxifen may protect against cytokine storms, alleviate ARDS in COVID-19 patients, and reduce the incidence of critical illness and mortality

Tamoxifen citrateshowed IC50 (avg) of 34.12 μM

-

[184, 198]

Thioridazine

Thioridazine and its identified photoproducts (mesoridazine and sulforidazine) have high biological activity on the virus Mpro. This shows that thioridazine and its two photoproducts might represent new potent medicines to be used for treatment in this outbreak

-

Thioridazine has anti-SARS-CoV-2 activity in vitro

-

[164, 201]

Tomatidine

Profenamine showed binding affinity to ASMase of − 8.7 kcal/mol

-

-

Terfenadine

-

Terfenadine can reverse the transcriptional landscape induced by SARS-CoV-2 infection when tested on Vero-E6 cells infected with SARS-CoV-2 and on human pluripotent stem-cell-derived pancreatic endocrine organoid cultures

-

[202]

Trifluoperazine

Trifluoperazine was predicted to bind to Mpro and RdRp (PLANTS scores < − 80.00), thus corroborating putative multimodal actions

Trifluoperazine 2HCl showed antiviral activity against SARS-CoV-2 with CC50 and IC50(μM) of 29.29 and 11.75, respectively

-

[164, 191]

Triflupromazine

-

The triflupromazine demonstrated antiviral activity in a screen against MERS-CoV replication in Huh-7 cells

-

[24]

Trimipramine

Amitriptyline showed binding to the allosteric site of SARS-CoV-2 Main Protease with − 5.5 kcal/mol

-

-

[176]

Zolantidine

-

-

-