Table 1.
Chemical compounds and their anti-HSV activity. CC50 = 50% cytotoxic concentration, EC50 = 50% effective concentration, IC50 = 50% inhibitory concentration, SI = selectivity index, HSV = herpes simplex virus, CPE = cytopathogenic effect, XTT = 2,3-bis[2-methoxy-4-nitro-5-sulphophenyl]-5-[(phenylamino)carbonyl-2H-tetrazolium hydroxide], ELISA = enzyme-linked immunosorbent assay, MAPK = mitogen-activated protein kinase, CCECs = cerebral capillary vessel endothelial cells, PMNs = polymorphonuclear leukocytes, TK = thymidine kinase.
| No. | Group | Compound | Plant/Other | Assay Employed; Cell Line | CC50 | HSV-1 EC50/IC50; SI |
HSV-2 EC50/IC50; SI |
Virus | Mechanism of Action/Target Structure | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Alkaloid | Harmine | Peganum harmala | CPE; Hec-1-A cells | >300 µM | 4.56 µM | 1.47 µM | HSV-1 F; HSV-2 G | Tyrosine phosphorylation-regulated kinase inhibitor; downregulation of cellular NF-κB and MAPK pathways. |
[15,16] |
| 2 | Anthraquinone | Emodin | Rheum tanguticum | CPE; HEp-2 cells | >1000 µg/mL (>3.7 mM) | n/A | n/A | HSV-1 F; HSV-2 (333) | Inhibition of viral replication. | [17] |
| 3 | Catechin | Epigallocatechin (EGC) | Thea sinensis L. | CPE; Vero cells | 500 µM | 4 μM; 125 | 63 μM; 7.9 | HSV-1 KOS; HSV-2 G | Glycoproteins B and D. | [18,19] |
| 4 | Palmitoyl-EGCG (p-EGCG) | Plaque assay; Vero cells | >75 µM | <50 µM | n/A | HSV-1 UL46 | Glycoprotein D expression is reduced. | [20] | ||
| 5 | Samarangenin B (Sam B) | Limonium sinense L. | >100 μM | 11.4 μM | n/A | HSV-1 KOS | Suppresses expression of ICP0 and ICP4 genes and viral DNA-polymerase (ß transcripts). | [21,22] | ||
| 6 | Ellagitannin | Casuarinin | Terminalia arjuna Linn | Plaque assay; Vero cells | 89 ± 1 µM | n/A | 1.5 μM; 59 | HSV-2 (196) | Inhibition of viral attachment and penetration. | [23] |
| 7 | Flavonoid | Baicalein | Scutellaria baicalensis | Plaque assay; Vero cells | >200 µM | n/A | 12.4 µM; >16.1 | HSV-1 F | Inactivation of free viral particles and downregulating cellular NF-κB. | [24] |
| HaCat cells | >200 µM | n/A | 20.1 µM; >9.95 | |||||||
| 8 | (−)-epigallocatechin 3-O-gallate (EGCG) | Camellia sinensis | Titer reduction; Vero cells | n/A | 102.0/104.4 reduction at 100 μM | 104.0–5.0/104.0 reduction at 100 μM | HSV-1 F; HSV-2 (333) | Glycoproteins B and D. | [25] | |
| 9 | Galangin | Helichrysum aureonitens | CPE; Vero cells | 1000 µM | 2.5 μM; 400 | n/A | HSV-1 KOS | Inhibition of of viral adsorption. | [18] | |
| 10 | Houttuynoid A | Houttuynia cordata | Plaque assay; Vero cells | 166.36 ± 9.27 μM | 23.50 ± 1.82 μM | HSV-1 F | Blocking viral attachment. | [26] | ||
| 11 | Isoquercitrin | Houttuynia cordata | >100 µg/mL (215.34 µM) | 0.42 µg/mL (0.9 µM); >512.8 | Downregulation of cellular NF-κB. | [27] | ||||
| 12 | Quercetin | Caesalpinia pulcherrima | XTT; BCC-1/KMC cells | 496.9 µg/mL (16.44 mM) | 22.6 ± 4.2 µg/mL (74.78 ± 13.89 µM); 22.0 | 86.7 ± 7.4 µg/mL (286.86 ± 24.48); 5.7 | HSV-1 KOS; HSV-2 (196) | Downregulation of cellular NF-κB and blocks viral entry (gD cellular binding site). | [27,28] | |
| 13 | Glycosides | Pterocarnin A | Pterocarya stenoptera | XTT; Vero cells | 31.7 ± 1.6 μM | n/A | 5.4 ± 0.3 μM; 5.9 | HSV-2 (196) | Inhibition of of viral attachment. | [29] |
| 14 | Harmaline | 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (HM) | Ophiorrhiza nicobarica Balkr | Plague assay; Vero cells | 30 µg/mL (120.14 µM) | 1.1 ± 0.1 µg/mL (4.41 ± 0.4 µM); 27.27 | 1.5 ± 0.1 µg/mL (6.01 ± 0.4 µM); 20 | HSV-1 F; HSV-2 G | Suppression of viral immediate early gene expression. | [30,31] |
| 15 | Monoterpenoid | Geraniol | Thymus bovei | Titer reduction; Vero cells | >210 µg/mL (1361.42 µM) | n/A | 1.92 ± 0.84 µg/mL (12.45 ± 5.45 µM); >109.38 | HSV-2 | In silico: Interacts with HSV-2 protease. | [32] |
| 16 | Oleanane triterpenoid | Glycyrrhetinic acid methylester | Glycyrrhiza glabra | Plaque assay; Vero cells | >207 µM | 8.1 ± 0.2 µM/mL; >26 | n/A | HSV-1 KOS | Inhibition of HSV-1 replication. | [33] |
| 17 | Glycyrrhetinic acid | 84.0 ± 2.8 µM | 21.7 ± 0.6 µM; 3.9 | Induces the autophagy activator Beclin 1 → blocks HSV replication. | [33] | |||||
| 18 | Glycyrrhizin | >608 µM | 225 ± 24.1 µM/mL; >2.7 | Reduces adhesion force between CCECs and PMNs. | [33,34] | |||||
| 19 | Phenolic acid | Chebulinic acid | Terminalia chebula | Plaque assay; Vero cells | >200 µg/mL | 17.02 ± 2.82 µM; 18.62 | 0.06 ± 0.002 μg/mL | HSV-1 KOS; HSV-2 G | Prevention of HSV-1 glycoprotein-mediated cell fusion events and attachment of HSV-2. | [35,36] |
| 20 | Gallic acid | Galla | Plaque assay; Vero cells and GMK AH1 | 668.7 ± 54.5 μM | 57.1 ± 2.3 μM; 11.72 | 33.56; 64.35 μM (during; after infection) | HSV-1 KOS; HSV-2 (333) | Inhibition of ICP2, gC, gD, and VP5 expression (effects on viral attachment). | [37,38] | |
| 21 | Phenolic | Curcumin | The curry spice turmeric | CPE; Vero cells | 49.8 ± 0.4 µg/mL (135.18 ± 1.09 µM) | n/A | n/A | HSV-1 (17) | P300/CBP histone acetyltransferase. | [39,40] |
| 22 | Phenylpropanoid | Verbascoside | Lepechinia speciosa | Plaque assay; Vero cells | >200 µg/mL (320.21 µM) | 58 µg/mL (92.86 µM); >3.4 | 8.9 µg/mL (14.25 µM); >22.4 | HSV-1; HSV-2 (clinical isolates) | HSV-1: prevention of viral adsorption, intracellular viral inhibition; HSV-2: inhibition of attachment and penetration. | [41] |
| 23 | Polysaccharide | MI-S | Agaricus brasiliensis | Plaque assay; Vero cells | 2415.29 ± 389.21 µg/mL (134.18 ± 21.61 µM) | 1.24 ± 0.05 µg/mL (0.07 µM), 1948; 5.50 ± 0.58 µg/mL (0.31 ± 0.03 µM), 439 (during; after infection) | 0.39 ± 0.17 µg/mL (0.02 ± 0.01 µM), 6193; 4.30 ± 0.36 µg/mL (0.24 ± 0.02 µM), 562 (during; after infection) | HSV-1 KOS; HSV-2 333 | Inhibition of attachment, penetration and cell-to-cell spread. | [42] |
| 24 | Scleroglucan | Scierotium glucanicum | CPE; Vero cells | 400 µg/mL (559.83 µM) | 5 µg/mL (7 µM); 80 | n/A | HSV-1 F | Glycoproteins of HSV-1 (inhibits adsorption step). | [43] | |
| 25 | Spiroketal-enol ether derivative | (E)-2-(2,4-hexa-diynyliden)-1,6dioxaspiro[4.5] dec-3-ene | Tanacetum vulgare | Time-of-addition assay; Vero cells | >30 µg/mL (>149.83 µM) | 0.146 ± 0.013 µg/mL (0.73 ± 0.06 µM); >205 | 0.127 ± 0.009 µg/mL (0.63 ± 0.04 µM); >236 | HSV-1 (AY240815.1); HSV-2 (HM011430.1) | Suppression of viral RNA synthesis. | [44] |
| 26 | Steroid | Halistanol sulfate | Petromica citrina | Plaque assay; Vero cells | 13.83 ± 3.75 µg/mL (20.08 ± 5.44 µM) | 5.63 ± 1.3 µg/mL (8.17 ± 1.89 µM); 2.46 | n/A | HSV-1 KOS | Inhibition of attachment and penetration. Impairs HSV-1 gD and ICP27 levels. | [45] |
| 27 | Stilbenoid and 2-arylbenzofuran | Kuwanon X | Moru salba L. | Plaque assay; Vero cells | 80.3 ± 3.2 µg/mL (128.15 ± 5.12 µM) | 2.2 ± 0.1 µg/mL (3.5 ± 0.16 µM); 37 | 2.5 ± 0.3 µg/mL (3.99 ± 0.48 µM); 32 | HSV-1 (15577); HSV-2 (333) | Downregulation of cellular NF-κB and viral RNA/DNA synthesis. | [46] |
| 28 | Oxyresveratrol | Artocarpus lakoocha | >100 µM | 63.5 μM | 55.3 μM | HSV-1; HSV-2 | Inhibition of early and late replication. | [47,48] | ||
| 29 | Taxol derivative | n-benzoyl-(2’R,3’S)-3’phenylisoserine | Lactarius | CPE; Vero cells | >500 µg/mL | 21.7 µg/mL (76.06 µM); >23 | n/A | HSV-1 (McIntyre) | Inhibition of HSV-1 replication (possibly related to mitotic division). | [49] |
| 30 | Terpene | 28-Deacetylsendanin (28-DAS) | Melia azedarach | ELISA; Vero cells | >400 µg/mL (696.11 µM) | 1.46 µg/mL (2.54 µM) | n/A | HSV-1 (McIntyre) | Reduces activity of TK. | [50] |
| 31 | Isoborneol | Salvia fruticosa | Plaque assay; Vero cells | n/A | n/A | HSV-1 F | Affected TK-independent glycosylation process of viral glycoproteins B and D. | [51] | ||
| 32 | 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM) | Melia azedarach | Plaque assay; HCLE cells | >100 µM | 0.78 µM | HSV-1 KOS | Inhibition of glycoproteins B, gC, gD intracellular trafficking and downregulates cellular NF-κB. | [52,53,54] | ||
| 33 | Triptofordin C-2 | Tripterygium wilfordii | Plaque assay; HeLa cells | 89 ± 9.5 µg/mL (145.76 ± 15.56 µM) | 3.7 ± 0.90 µg/mL (6.06 ± 1.47 µM); 24 ± 3.2 | HSV-1 HF | Suppression of viral immediate early gene expression. | [55] | ||
| 34 | β-orcinol depsidone | Psoromic acid | Usnea | Plaque assay; Vero cells | >310 µM | 1.9 ± 0.42 µM; >163.2 | 2.7 ± 0.43 μM; 114.8 | HSV-1 KOS; HSV-2 (A234) | Inhibition of HSV replication: HSV-1 DNA-polymerase in vitro; HSV-2 DNA-polymerase in silico. | [56] |
| 35 | Peptide | Griffithsin | Griffithsia | Plaque assay; CaSki | no cytotoxic effect | n/A | 2.3 μg/mL (0.18 µM) | HSV-2 (333) | Inhibition of viral attachment (cell-to-cell spread). | [57] |
| 36 | Subtilosin | Bacillus amyloliquefaciens | Plaque assay; Vero cells | 314 µg/mL (92.3 µM) | 9.6 µg/mL (2.82 µM); 33 | 18.2 µg/mL (5.35 µM); 17.4 | HSV-1 F; HSV-2 G | Late stages of the viral replicative cycle and intracellular glycoprotein transport. | [58,59] | |
| 37 | Trichosanthin (TCS) | Trichosanthes kirilowii | ELISA; Vero cells | 416.5 ± 34.5 µg/mL (15.42 ± 1.28 µM) | 38.4 ± 17.5 µg/mL (1.42 ± 0.65 µM); 10.8 | n/A | HSV-1 F | Suppression of p38 MAPK protein and Bcl-2 gene activity, replication (E and L), DNA expression and viral release. | [60,61,62] |