Table 1.
The overview of phenolic compounds with anti-HSV activity.
| Compound | Antiherpetic and Cytotoxicity Assays, Strains, Cells, and Reference Agents | Results | Additional Information | Source | |
|---|---|---|---|---|---|
| Flavonoids | Epicatechin (1) | MTT cell viability ACV SI = 4.5 |
HSV-1, SI = 6.0 (29-R) | Dietary phenolics | [26] |
| Epigallocatechin (2) | HSV-1, SI = 5.2 (KOS), 12.8 (29-R) | ||||
| Robinetinidol(4α-6)gallocatechin (3) | HSV-1 SI = 5.2 (KOS), 5.0 (29-R) | ||||
| Apigenin (4) | CPE, PRA, YRA ACV for HSV-1 EC50 = 50 μM, SI = 10; HSV-2, EC50 = 50 μM, SI = 10 |
HSV-1, EC50 = 5 μM, SI = 50; HSV-2, EC50 N/A, SI N/A | Dietary phenolics, green tea, propolis, some flavonoid rich medicinal plants. Flavanols and flavonols appear to be more active than flavones. Furthermore, treatment of Vero cells with ECG (8) and galangin (11) before virus adsorption led to a slight enhancement of inhibition, indicating that an intracellular effect may be involved. |
[27] | |
| Baicalin (5) | HSV-1 EC50 = 5 μM, SI= 200; HSV-2 EC50 N/A, SI N/A | ||||
| Catechin hydrate (6) | HSV-1, EC50 = 4 μM, SI = 250; HSV-2, EC50 N/A, SI N/A | ||||
| Chrysin (7) | HSV-1 EC50 = 2.5 μM, SI= 4; HSV-2 EC50 N/A, SI N/A | ||||
| Epicatechin (1) | HSV-1, EC50 = 2.5 μM, SI = 40; HSV-2, EC50 = 35 μM, SI = 2.9 | ||||
| Epicatechin gallate (8) | HSV-1, EC50 = 4 μM, SI = 125; HSV-2, EC50 = 63 μM, SI = 7.9 | ||||
| Epigallocatechin (2) | HSV-1, EC50 = 2.5 μM, SI = 100; HSV-2, EC50 N/A, SI N/A | ||||
| Epigallocatechin gallate (9) | HSV-1, EC50 = 2.5 μM, SI = 40; HSV-2, EC50 N/A, SI N/A | ||||
| Fisetin (10) | HSV-1 EC50 2.5 μM, SI = 40; HSV-2 EC50 N/A, SI N/A | ||||
| Galangin (11) | HSV-1 EC50 2.5 μM, SI = 400; HSV-2 EC50 N/A, SI N/A | ||||
| Genistein (12) | HSV-1 EC50 5 μM, SI = 50; HSV-2 EC50 50 μM, SI = 5 | ||||
| Kaempferol (13) | HSV-1 EC50 15 μM, SI = 3.3; HSV-2 EC50 N/A, SI N/A | ||||
| Luteolin (14) | HSV-1 EC50 5 μM, SI = 20; HSV-2 EC50 N/A, SI N/A | ||||
| Myricetin (15) | HSV-1 EC50 5 μM, SI = 20; HSV-2 EC50 N/A, SI N/A | ||||
| Naringenin (16) | HSV-1 EC50 4 μM, SI = 187.5; HSV-2 EC50 22.5 μM, SI 33.3 | ||||
| Naringin (17) | HSV-1 EC50 2.5 μM, SI = 400; HSV-2 EC50 N/A, SI N/A | ||||
| Rutin (18) | HSV-1 EC50 5 μM, SI = 2000; HSV-2 EC50 N/A, SI N/A | ||||
| Quercetin (19) | HSV-1 EC50 5 μM, SI = 20; HSV-2 EC50 35 μM, SI = 2.9 | ||||
| Quercetin (19) | Raw 264.7 and Vero cells, HSV-1 PRA, Western blot analysis, quantitative RT-PCR |
Reduction in plaque formation of 90% at 30 µg/mL | Inhibition of the expressions of HSV proteins (gD, ICP0) and genes (ICP0, UL13, UL52). Specific suppression of the expression of TLR-3, inhibition of transcriptional factors NF-κB and IRF3. | [28] | |
| Epigallocatechin gallate (9) | IP (%) | IP: 100% | Dietary phenolic, green tea component |
[29] | |
| % PFU | At 1 μM cca 40%, at 5 µM cca 5% | [30] | |||
| Houttuynoid M (20) | PFA ACV IC50 0.15 μM; SI>1333 |
IC50 17.72 μM; SI> 11.29 IC50 12.42 μM; SI> 16.10 |
Houttuynia cordata | [31] | |
| Houttuynoid A (21) | |||||
| 1. β-galactosidase assay - the activity of enzyme measured in cell lysates 2. PRA 3. Progeny HSV-1 yield assay - effect on HSV-1 multiplication |
1. HSV-1 (F) IC50 23.50 ± 1.82 μM, CC50 166.36 ± 9.27 μM 2. HSV-1 (F) IC50 of 21.08 μM 3. HSV-1 (F) multiplication reduced by 100% at 75 μM |
Possible mechanism—blocking viral membrane fusion | [32] | ||
| Genistein (12) | Vero cells, HSV-1 (KOS), HSV-1 (29 R), HSV-2 (333) PRA ACV: IC50 2.44 μM, SI >1818 (KOS), NA (29 R), IC50 3.30 μM, SI >303 (333) |
IC50 (μM); SI: HSV-1 (KOS)/HSV-1 (29 R)/HSV-2 (333) 14.02, 3.88/7.76, 7.01/14.12, 6.95 |
Isoflavonoid, soya beans, alfalfa | [33] | |
| Kuwanon C (22) | Vero cells, HSV-1 PRA ACV IC50 1.45 μg/mL; SI 144.8 |
HSV-1 IC50 0.91 ± 0.43 μg/mL; SI 230.8 | In silico analysis along with antibacterial and anti-inflammatory effects | [34] | |
| Kuwanon T (23) | HSV-1 IC50 0.64 ± 0.52 μg/mL; SI 328.1 | ||||
| Kuwanon U (24) | HSV-1 IC50 1.93 ± 1.13 μg/mL; SI 108.8 | ||||
| Kuwanon E (25) | Vero cells, HSV-2 TRA ACV IC50 1.65 μg/mL; SI 127.3 |
HSV-2 IC50 1.61 ± 0.31 μg/mL; SI 130.4 | |||
| Luteoforol (26) | Vero cells, HSV-1 (KOS, VR733) CPE as 50% tissue culture infective dose (TCID50/50 μL) ACV reduced the titer by 3.16 log10 against strain KOS and by 3 log10 against strain VR733 |
Reduced the titer by 2.9 log10 against strain KOS and by 3.18 log10 against strain VR733 | Hypericum connatum | [35] | |
| Luteolin (14) | Vero cells, HSV-2 PRA ACV EC50 2.6 μg/mL, SI= 42.53 |
HSV-2 EC50 22.4 μg/mL, SI = 12.43 | Dietary flavonoid | [36] | |
| Theaflavin-3,3′-digallate (27) | Vero cells, HSV-1 PRA Flow cytometry antiviral assay Fluorescence confocal microscopy |
EC50 20 μM; SI = 5.625 | Green tea | [37] | |
| Cycloartocarpin (28) | Vero cells, HSV-1 (KOS), HSV-2 (186) PRA ACV HSV-1 IC50 1.5 μM; HSV-2 IC50 2.9 μM |
HSV-1 IC50 28.2 μM; HSV-2 IC50 23.5 μM | Prenylated phenolics Morus spp., Artocarpus spp. |
[38] | |
| Isocyclomorusin (29) | HSV-1 IC50 30.4 μM; HSV-2 IC50 27.2 μM | ||||
| Norartocarpetin (30) | HSV-1 IC50 63 μM; HSV-2 IC50 52.2 μM | ||||
| Catechin-7-gallate (31) | Vero cells, HSV-1 CPE ACV CC50 >200 ± 0.4 μg/mL |
CC50 43.2 ± 2.3 μg/mL | Dietary phenols Low activity, questionable results. |
[39] | |
| Kaempferol-3-O-6′´-O-galloyl-β-D-glucopyranoside (32) | CC50 124.1 ± 1.2 μg/mL | ||||
| Kaempferol (13) | CC50 76.1 ± 0.2 μg/mL | ||||
| Quercetin-3-O-6´´-O-galloyl-β-D-glucopyranoside (33) | CC50 175.6 ± 0.9 μg/mL | ||||
| Quercetin (19) | CC50 78.1 ± 0.8 μg/mL | ||||
| 7-O-galloyltricetiflavan (34) | Vero cells, HSV-1 CPE ACV IC50 0.25 μg/mL |
IC50 30 μg/mL |
Pithecellobium clypearia Other viruses tested |
[40] | |
| 7,4′-di-O-galloyltricetiflavan (35) | IC50 20 μg/mL | ||||
| Strychnobiflavone (36) | Vero cells, HSV-1 (KOS), HSV-2 (333) PRA Post infection treatment ACV HSV-1 IC50 1.38 μg/mL, SI > 1.449; HSV-2 IC50 3.23 μg/mL, SI > 619 |
HSV-1 (KOS) IC50 11.82 μg/mL, SI = 22.61; HSV-2 (strain 333) IC50 6.31 μg/mL, SI = 42.33 | Strychnos pseudoquina | [41] | |
| Derivatives of phenolic acids | Ethyl 2,4-dihydroxybenzoate (37) | Vero cells, HSV-1 PRA ACV IC50 1.45 μg/mL; SI 144.8 |
HSV-1 IC50 1.32 ± 0.44 μg/mL; SI 159.1 | In silico analysis; antibacterial and anti-inflammatory effects | [34] |
| Gallic acid (38) | Vero cells, HSV-1 CPE ACV CC50 > 200 ± 0.4 μg/mL |
CC50 49.8 ± 0.4 μg/mL | Dietary phenols Low activity, questionable results. |
[39] | |
| IP (%) | IP: 100 % | Dietary phenolics | [29] | ||
|
Alkyl derivatives of gallic acid
Octyl gallate (39) |
HEp-2 and Vero cells, HSV-1 CPE |
Octyl gallate directly inactivates HSV-1 (virucidal activity). 39 suppresses both the intracellular multiplication and the release of the virus. 39 selectively accelerates the death of the virus-infected cells. The addition of the compound (39), even at 6 h post-infection, completely abolished the formation of progeny virus in the infected cells. |
Other viruses tested including HSV-1: Inhibition was enhanced by the compounds with a higher number of carbons in the alkyl moieties, maximum at 12 (lauryl gallate), however, cytotoxicity was increased. |
[42] | |
| Chebulagic acid (40) | IPF ACV IC50 29.04 ± 1.04 μg/mL |
HSV-2 IC50 1.41 ± 0.51 μg/mL | Dose-dependently potent in vitro direct anti-viral activity. Effective prevention of the attachment as well as penetration of the HSV-2 to Vero cells. | [43] | |
| Chebulinic acid (41) | HSV-2 IC50 0.06 ± 0.002 μg/mL | ||||
| Tellimagrandin I (42) | IPF At 0.75 μg/mL ACV completely protected Vero cells against infection |
EC50 of 2.6 μM for the direct mode, 5.0 μM for the absorption mode. | Ellagitannin—Cornus spp., Eucalyptus spp., Melaleuca styphelioides | [44] | |
| N-trans-ferulolyl tyramine (43) | IP (%) | IP: 100% | Dietary phenolics | [29] | |
| Protocatechuic acid (44) | Vero cells, HSV-2 ACV EC50 1.43 μg/mL, SI= 140 |
EC50 0.92 µg/mL, SI = 217 | Dietary phenolic, metabolite of gut degradation of phenolics | [45] | |
| Psoromic acid (45) | Vero cells, HSV-1, HSV-2 ACV for HSV-1 IC50 2.6 μM; SI 119.2; for HSV-2 EC50 2.8 μM; SI 110.7 |
HSV-1 IC50 1.9 μM; SI 163.2 HSV-2 EC50 2.7 μM; SI 114.8 |
Study of synergy with ACV and inhibition of HSV-1 DNA polymerase (in vitro and in silico assays). | [46] | |
| Rhinacanthinic acid C (46) | Vero cells, HSV-2 PRA ACV ED50 14.67 μg/mL |
ED50 58.98 μg/mL | Rhinacanthus nasutus | [47] | |
| Anthrones | Antrodin A (47) | Vero cells, HSV-1, HSV-2 PRA ACV HSV-1 IC50 2.1 μg/mL, SI = 61.9, HSV-2 IC50 2.9 μg/mL, SI = 44.8 |
HSV-1 IC50 5.8 μg/mL, SI= 18.97, HSV-2 IC50 5.5 μg/mL, SI= 20.0 |
Antrodia camphorate Additive effect of 47 with ACV |
[48] |
| Aspergilol H (48) | HSV-1 PRA ACV EC50 3.0 μM |
HSV-1 EC50 4.68 μM | Deep-sea fungus Aspergillus versicolor | [49] | |
| Aspergilol I (49) | HSV-1 EC50 6.25 μM | ||||
| Coccoquinone A (50) | HSV-1 EC50 3.12 μM | ||||
|
Stilbenoids and
2-arylbenzofurans |
Kuwanon X (51) | Vero cells, HSV-1 (15577 and clinical strains), HSV-2 (333) PRA ACV IC50 0.1 µg/mL for all strains |
HSV-1 IC50 2.2 and 1.5 μg/mL; HSV-2 IC50 2.5 µg/mL | Prenylated phenol, Morus spp. 51 did not inactivate cell-free HSV-1 particles but inhibited cellular adsorption and penetration of HSV-1 viral particles. Following viral penetration, 51 reduced the expression of HSV-1 IE and L genes and decreased the synthesis of HSV-1 DNA. Furthermore, 51 inhibited the HSV-1-induced nuclear factor (NF)-κB activation through blocking the nuclear translocation and DNA binding of NF-κB. |
[50] |
| Mulberrofuran B (52) | Vero cells, HSV-2 TRA ACV IC50 1.65 μg/mL; SI 127.3 |
HSV-2 IC50 0.93 ± 0.23 μg/mL; SI 225.8 | In silico analysis; antibacterial and anti-inflammatory effects | [34] | |
| Oxyresveratrol (53) | Vero cells, HSV-1 (KOS), HSV-2 (186) PRA ACV HSV-1 IC50 1.5 μM; HSV-2 IC50 2.9 μM |
HSV-1 IC50 42.8 μM; HSV-2 IC50 42.5 μM | Stilbenoid Morus spp., Artocarpus spp. |
[38] | |
| Other phenolics | Coniferyl aldehyde (54) | Vero cells, HSV-1, HSV-2 ACV HSV-1 EC50 0.8 μg/mL |
HSV-1 EC50 6.39 μg/mL, SI = 78.3 HSV-2 EC50 41.2 μg/mL, SI = 12.1 |
Phenolic, Quercus suber, Simira glaziovii, S. eleiezeriana | [51] |
| Coumestrol (55) | Vero cells, HSV-1 (KOS), HSV-1 (29 R), HSV-2 (333) PRA ACV: IC50 2.44 μM, SI >1818 (KOS), NA (29 R), IC50 3.30 μM, SI >303 (333) |
IC50 (μM), SI: HSV-1 (KOS)/HSV-1 (29 R)/HSV-2(333) 11.62, 9.6/3.34, 31.52/35.53, 28.14 |
Coumestan, soya beans, alfalfa | [33] | |
| Curcumin (56) | CPA, PRA, viral adsorption assay, viral penetration assay | At 30 µM, 85% inhibition of HSV-1 and 68% of HSV-2 CPE, PRA 92% for HSV-1 and 88% for HSV-2 |
Curcuma longa Inhibits HSV adsorption and replication |
[52] | |
| Vero cells, HSV-1 CPE ACV CC50 > 200 ± 0.4 μg/mL |
CC50 49.8 ± 0.4 μg/mL | Dietary phenols Low activity, questionable results |
[39] | ||
| Imperatorin (57) | Vero cells, HSV-1 CPE ACV – full inhibition of replication of HSV-1 at 250 μg/mL |
57 decreases titer of HSV-1 by 55.6% at 31.25 μg/mL | Furanocoumarin of Apiaceae family | [53] | |
| Pinoresinol (58) | IP (%) | IP: 26% | Dietary phenolics | [29] |
HSV-1: herpes simplex virus type 1; HSV-2; herpes simplex virus type 2; ACV: acyclovir; CPE: cytopathic effect; IC50: 50% inhibitory concentration; EC50: 50% effective concentration; ED50: 50% effective dose; CC50: 50% cytotoxic concentration; PRA: plague reduction assay; YRA: yield reduction assay; SI: selectivity index = CC50/EC50 or CC50/IC50 (cytotox./antiviral); PFU: plaque forming units; IPF: inhibition of plaque formation; TRA: titer reduction assay; MTT assay: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide; Vero cells used for assay if not stated in methods; F, KOS, 29-R—viral strains.