Table 1.

Flavonoids with antiviral properties against SARS-CoV-2 and viral infections with similar pathogenesis.

Phytochemical Name	Plant Source	Model	Dose/Concentration	Mechanisms/Outcomes	Reference
(−)-epigallocatechin 3-O-gallate	Limonium morisianum Arrigoni	Anti-HIV-1 RT and IN	-	↓ HIV-1 RT-associated RNase	[128]
				H activity: IC50 = 0.21 μM
				↓ IN catalytic function and IN-LEDGF-dependent activity: IC50 = 1.92 μM
2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone	Cleistocalyx operculatus (Roxb.) Merr. and L.M.Perry	HEK293 cells infected with the plasmid H1N1 or oseltamivir-resistant novel H1N1 (H274Y)	20–40 μM	↑ cell viability,	[67]
		MDCK cells infected with influenza H1N1 A/PR/8/34 and H9N2 A/Chicken/Korea/O1310/2001		↓ NA activity (IC50 = 5.07 to 8.84 μM), viral replication, and CPE
3-Deoxysappanchalcone	Caesalpinia sappan L.	MDCK, A549, and THP-1 cells infected with influenza virus A/PR/8/34 (H1N1)	30 µM	↓ viral genomic replication, DNA fragmentation, CCL5, CXCL10, IL-6, IL-1β, caspase 3/7, 8, and 9 activity and HA copy number (IC50 = 3.9 µM)	[68]
3-deoxysappanchalcone, Sappanchalcone and rhamnetin	Caesalpinia sappan L.	MDCK cells infected with influenza A/Guangdong/243/72 (H3N2), A/PR/8/34 (H1N1) and B/Jiangsu/10/2003	-	↓ NA activity: IC50 = 13.9–24.1 μg/mL ↓ CPE: IC50 = 1.06–15.4 μg/mL CC50 = 12.83–115.47 μg/mL SI = 6.23–16.27	[129]
5,7,4′-Trihydroxy-8-methoxyflavone	-	MDCK cells infected with influenza A/PR/8/34 (H1N1), A/Guizhou/54/89 (H3N2), and B/Ibaraki/2/85	-	↓ Sialidase activity:	[130]
				IC50 = 6.58–9.78 µg/mL
6-hydroxyluteolin 7-O-β-d-glucoside	Salvia plebeia R.Br.	MDCK cells infected with influenza A/PR/8/34 (H1N1)	20, 50 μM	↓ NA activity and CPE, ↑ cell viability	[131]
8-Prenylkaempferol	Sophora flavescens Aiton	A549 cells infected with influenza A/PR/8/34 (H1N1) virus	1–30 μM	↓ RANTES production, NF-κB, IRF-3, PI3K activity, Akt phosphorylation, and IκB degradation	[111]
Agathisflavone	Anacardium occidentale L.	Mice infected with wild-type and oseltamivir-resistant influenza virus		IC50 = 20 to 2.0 µM, EC50 = 1.3 µM	[132]
				↓ NA activity and virus replication
Apigenin 7-O-β-d-(4′-caffeoyl)glucuronide	Chrysanthemum morifolium Ramat.	MT-4 cells infected with HIV-IIIIB	-	↓ HIV-1 integrase activity:	[133]
				IC50 = 7.2 µg/mL
				CPE:
				EC50 = 41.86µg/mL,
				SI ≥ 3.58
Baicalein	-	A549 cells infected with influenza H5N1 virus strains (A/Thailand/1(Kan-1)/04 and A/Vietnam/1203/04)	40–100 µM	↓ viral nucleoprotein: IC50 = 18.79 µM	[53]
				CC50 = 109.41 µM
				SI = 5.82
		Primary human monocyte-derived macrophages (MDM) infected with influenza A/Thailand/1(Kan-1)/04		↓ virus titer, caspase-3 activation, NA activity,
				↓ IL-6 and IL-8
				↓ viral replication, IL6, CXCL10, and TNF-α
Baicalin	-	Human lung epithelial A549 cells infected with influenza A/Jingfang/01/1986	20 μg/mL	↓ viral NP, M1 protein levels, viral titer, miR-146a expression, virus replication and viral copy number (EC50 = 17.04, 19.31 μg/mL), ↑ TRAF6 level, IFN-α, and IFN-β	[54]
		(H1N1) and A/Lufang/09/1993 (H3N2)		↓miR-146a expression and virus copy number
		Balb/C mice inoculated intranasally with the influenza A H1N1 virus		↑ survival rate, IFN-α and IFN-β
Baicalin	Scutellaria baicalensis Georgi	A549 and Ana-1 cells infected with influenza virus A3/Beijing/30/95 (H3N2)	12.5–50 μg/mL	↑ mTOR phosphorylation, ↓ autophagy, Atg5–Atg12 complex and LC3-II expression, EC50 = 15–15.6 µg/mL	[112]
Baicalin	-	A549 and MDCK cells infected with influenza virus A/H1N1/Eastern India/66/pdm09 (H1N1-pdm09)	0.5–320 µM	TD50 = 220 µM	[55]
				IC50 = 0.5 and 18 µM
				↓ NP transcription, RIG-1, PKR, NS1 expression, viral replication, TNF-α, IL-8, p-85b–NS1 binding, p-Akt, M1 protein, ↑ IRF-3, IFN-γ, and IFN-β
		BALB/c mice infected intranasally with H1N1-pdm09	(10–120 mg/kg/day) twice daily for 3 days	↓ viral titer:
				MIC50 ≈ 80 mg/kg/day
				↓ p-Akt and M1 protein expression
Baicalin	Scutellaria baicalensis Georgi	MDCK and A549 cells infected with influenza A/FM1/1/47 (H1N1) and A/Beijing/32/92 (H3N2)	20–80 µg/mL (in MDCK cells)	↑ cell viability, ↓ virus replication, and CPE:	[71]
				EC50 = 40.3 and 104.9 µg/mL
			5–40 µg/mL (in A549 cells)	SI: 2.1–8.6
		ICR mice infected with influenza A/FM1/1/47 (H1N1) virus		↓ NA activity:
			50–200 mg/kg/d for 5 days, i.v injection	IC50 = 52.3 and 85.8µg/mL
				↓ death rate, weight loss, ↑ mean day to death, survival rates, and improved the lung parameters
Baicalin	Scutellaria baicalensis Georgi	Hos/CD4/CCR5 or Hos/CD4/CXCR4 cells infected with recombinant vaccinia virus vTF7-3	0.04 to 400 µM	↓ X4 and R5 HIV-1 Env-mediated fusion, CAT activity, CD4/CXCR4, CD4/CCR5, and HIV-1 entry	[134]
Baicalein, Baicalin	-	Vero CCL-81 cell line infected with SARS-CoV-2	20 µM	↓ viral RdRp and viral replication	[49]
				CC50 = 86–100 µM
				EC50 = 1–9 µM
Baicalein	-	Vero E6 cells infected with SARS-CoV-2	0.1 μM	↓ body weight loss, the replication of the virus, relieved the lesions of lung tissue, inflammatory cell infiltration, IL-1β and TNF-α	[66]
		hACE2 transgenic mice infected with SARS-CoV-2	200 mg/kg	↑ respiratory function
Biochanin A	-	A549 cells infected with influenza H5N1 virus strains (A/Thailand/1(Kan-1)/04 and A/Vietnam/1203/04)	40 µM	↓ viral nucleoprotein: IC50 = 8.92 µM	[53]
				CC50 = 49.91 µM
				SI = 5.60
		Primary human monocyte-derived macrophages (MDM) infected with influenza A/Thailand/1(Kan-1)/04		↓ virus titer, caspase-3 activation, NFκB p65 accumulation, IL-6, IL-8, CXCL10 production, phosphorylation of AKT and ERK 1/2 and ↑ IκB levels
				↓ IL6, CXCL10, and TNF-α
Catechin	-	A549 cells infected with influenza A H1N1	5–50 μM	↓ NA and HA activity, viral load, and virus-induced autophagy	[135]
Catechins	Camellia sinensis (L.) Kuntze	MDCK cell infected with influenza A/Chile/1/83 (H1N1), A/Sydney/5/97 (H3N2), and B/Yamagata/16/88	30–1200 µM	↓ plaque formation:	[136]
				EC50 = 22.2–318 µM
				↓ NA activity, HA activity, and viral RNA synthesis
Catechins (EGCG, ECG and C5G)	Camellia sinensis (L.) Kuntze	MDCK cells infected with influenza A/Victoria/503/2013,	50–100 µM	↓ NA activity	[137]
				IC50 = 100.3–173 µM
		A/SouthAustralia/21/2013 and A/Perth/25/2013		CC50 = 274–551.3 µM
				↓ plaque number
				EC50 = 28.4–34.3 µM
Catechins with a galloyl moiety	-	HIV-1 integrase assay kit	0.1–100 μM	↓ HIV-1 integrase activity IC50 = 0.56–3.02 μM	[138]
Cirsimaritin	-	MDCK and THP-1 cells infected with influenza A/Fort Monmouth/1/1947(H1N1), A/tianjinjinnan/15/2009(H1N1) and A/JiangXi/312/2006(H3N2)	2.5–20 μg/mL	↓ CPE:	[59]
				IC50 = 5.8, 6.3, 11.1 μg/mL, SI = 24.3, 26.4, 13.8, and TC50 = 153.3
				↓ viral replication, M2 viral protein expression, intracellular
				p65/NF-κB protein, p65/NF-κB phosphorylation, TNF-α, IL-1β,
				IL-8, IL-10, COX-2 expression, phospho-p38 MAPK, and ↓ phospho-JNK
C-methylated flavonoids	Cleistocalyx operculatus (Roxb.) Merr. and L.M.Perry	MDCK and 293T cells infected with influenza A/PR/8/34 (H1N1), A/Chicken/Korea/O1310/2001 (H9N2), A/Sw/Kor/CAH1/04 (H1N1, KCTC 11165BP), novel H1N1 (WT) and Oseltamivir-resistant novel H1N1 (H274Y)	-	↓ CPE:	[139]
				EC50 = 4.90–8.79 µM
				SI = 10.15 to > 24.49
				↓ NA activity:
				IC50 = 2.55–93.77 µM
EGCG	Camellia sinensis (L.) Kuntze (green tea)	MDCK cells infected with influenza A/Puerto Rico/8/34 (H1N1) (PR8), A/Hong Kong/8/68 (H3N2) (HK), A/Brisbane/59/2007 (H1N1) (BB), A/Taiwan/1/1986 (H1N1) (TW), A/Korea/01/2009 (H1N1) (KR) and B/Panama/45/1990 (PNM)	10–100 µM	↓ CPE:	[140]
				EC50 = 8.9–17.3 µM
				↓ hemifusion events, viral membrane integrity, cell penetration capacity, NP protein, viral entry, and NA activity: IC50 = 133.2 to > 500 µM
EGCG	-	PBMCs, CD4+ T cells and macrophages infected with several clinical isolates of HIV-1	6–100 μM	↓ HIV-1 p24 antigen: IC50 = 4.5–12 μM	[141]
				↓ HIV-1 infectivity,
				HIV-1–glycoprotein 120 attachment to the CD4 molecule,
				CC50 > 100 μM
EGCG	-	CD4+ T cells	0.2–20 μM	↓ HIV-1 gp 120 binding to the CD4+ T cells	[142]
EGCG	Camelia sinensis (L.) Kuntze	Peripheral blood CD4+ T cells (by flow cytometry)	25–100 µM	↓ CD4 expression, anti-CD4 antibody binding to its antigen, gp120 binding to CD4, and HIV infection	[143]
EGCG	Camelia sinensis (L.) Kuntze	Peripheral blood lymphocytes infected with either LAI/IIIB or Bal HIV strains	1–50 µM	↓ virus replication, RT activity, and p24	[75]
EGCG	Camelia sinensis (L.) Kuntze	THP-1 and H9 cells infected with HIV-1	1–100 µM	↓ RT activity, protease activity, p24, viral entry, and viral production	[40]
Flavonoid aglycones (demethoxymatteucinol, matteucinol, matteucin, methoxymatteucin, and 3′-hydroxy-5′-methoxy-6,8-dimethylhuazhongilexone)	Pentarhizidium orientale (Hook.) Hayata	MDCK cells infected with influenza A/PR/8/34 (H1N1) or A/chicken/Korea/01210/2001 (H9N2)	-	↓ NA activities and CPE:	[144]
				IC50 = 23.1–31.3 μM, EC50 = 21.4–30.7 μM, CC50 = 77.6 μM (demethoxymatteucinol), CC50 => 100 μM (matteucin, methoxymatteucin, and 3′-hydroxy-5′-methoxy-6,8-dimethylhuazhongilexone)
Flavonoid compounds	-	SARS-CoV proteases (recombinant 3CLpro) expressed in Pichia pastoris GS115	200 µM	↓ 3CLpro activity:	[145]
				IC50 = 47–381 µM
Gallocatechin-7-gallate	Pithecellobium clypearia Benth	A549 and MDCK cells infected with influenza A/PR/8/34 (H1N1)	3–30 μM	↓ CPE:	[58]
				CC50 = above 100 μM, EC50 = 1.69 μM
				↓ NP and M2 expression levels, HA mRNA expression, M2/M1 levels, and phosphorylation of SF2/ASF and SC35
		ICR mice infected intranasally with influenza A H1N1 virus	30 mg/kg/d, i.v, for 5 days	↓ viral NP mRNA expression, TNF-α, IL-1β, IL-6, bodyweight loss, acute lung injury and lung virus titer, ↑ survival rate, T-lymphocyte stimulation index, B-lymphocyte stimulation index, and spleen and thymus indices
Genistein	-	Heterologously expression of viral protein U of HIV in Xenopus oocyte	20 µM	↓ Ba2+-sensitive current and blocked Vpu ion channels	[146]
Genistein	-	Primary human macrophages infected with HIV-1Ba-L Env expressed on 293 T cells	5–10 µg/mL	↓ R5 Env pseudotyped virus infection, HIV-1Ba-L Env expressing cells and macrophages cell-fusion, reporter gene expression, virus penetration, gp120-induced TNF-α secretion, virus replication	[76]
Ginkgetin	Ginkgo biloba L. and Cephalotaxus harringtonia K. Koch	MDCK cells infected with influenza A/PR/8/34 (H1N1), A/Guizhou/54/89 (H3N2), and B/Ibaraki/2/85	-	↓ sialidase activity:	[130]
				IC50 = 9.78 to > 100 µg/mL
Herbacitrin	Drosera peltata Thunb.	HIV-1 infected MT-4 and MT-2 cell culture	21.5 µM	↓ HIV-1 replication, HIV-1 RT activity, IN activity, and p24 level	[77]
Hesperidin	-	R5-type HIV-1 in CD4+ NKT cells and human Vδ1+ cells in PBMCs	30–100 µg/mL	↑ IL-2, IL-5, IL-13, MIP-1α, MIP-1β, RANTES, CFSE, and CD25 expression, and ↓ viral replication	[104]
Hesperidin	-	Influenza A virus (H1N1) induced lung injury in male Sprague-Dawley rats, by the intrathecal route	200 and 500 mg/kg/d, i.p., for 5 days	↑ pulmonary function,	[94]
				↓ Local numbers of immune cells, TNF-α, IL-6, and IFN-α
		H1N1 infected pulmonary microvascular endothelial cells	1 mg/mL	↓ TNF-α, IL-6, IFN-α, phosphorylated p38 and JNK
Hexamethoxyflavone (5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone)	Marcetia taxifolia (A. St.-Hil.) DC.	MT4 cells infected with HIV-1 (HTLV-IIIB/H9)	45 µM	↓ HIV-1 RT activity: IC50 = 4.1 µM,	[147]
				EC50 = 0.04 μM, CC50 > 50 μM
Hispidulin	Salvia plebeia R. Br.	MDCK cells infected with influenza strain H1N1 A/PR/8/34 virus	20–50 μM	↓ CPE and NA activity:	[148]
				IC50 = 19.83 μM, EC50 = 22.62 μM, SI > 8.90
				↑ cell survival rate recovered the chromosome condensation
Homoplantaginin	Salvia plebeia R.Br.	MDCK cells infected with influenza A/PR/8/34 (H1N1)	20, 50 μM	↓ NA activity and CPE, ↑ cell viability	[131]
IND02	Cinnamomum zeylanicum Blume	MAGI cells and PBMCs infected with HIV-1 LAI and NL4-3	5–30 μM	↓ gp120 binding to HS (IC50 = 7 μM), gp120 binding to CD4 (IC50 = 20 μM), and envelope binding to CD4	[149]
IND02-trimer	Cinnamomum zeylanicum Blume	MAGI cells and PBMCs infected with HIV-1 LAI, NL4-3, Ba-L and clinical isolates (HIV-1 92UG029(A-X4), HIV-1 92HT599 (B-X4), HIV-1 96USHIPS4 (B-X4/R5) and HIV-1 98IN017 (C-X4))	2–20 μM	↓ gp120 binding to HS (IC50 = 7.5 μM), EC50 = 0.8–7 μM, CC50 = 96 and 23	[149]
		HIV-1-infected CD4+ and CD8+ T cells	0.46–46.3 μM	↓ up-modulation of Tim-3 and PD-1
Isoliquiritigenin	-	SARS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21	-	↓ PLpro activity: IC50 = 24.6 µM, Deubiquitination activity = 17.2, DeISGylation activity = 12.6,	[37]
				↓ 3CLpro activity:
		MERS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21		IC50 = 61.9 µM
				↓ PLpro activity: IC50 = 82.2 µM,
				↓ 3CLpro activity: IC50 = 33.9 µM
Isoquercetin	-	MDCK or Vero cells infected with influenza A viruses from pigs (A/swine/OH/511445/2007 [H1N1], Oh7) and human (A/PR/8/34 [H1N1], PR8), and human influenza B virus (B/Lee/40)	1–5 µM	↓ viral replication and CPE:	[79]
				ED50 = 1.2 µM
			2–10 mg/kg/day, i.p.	TD50 = 45 µM
		BALB/c mice infected with influenza A/PR/8/34, H1N1virus		SI = 38
				↓ IFN-γ, iNOS, RANTES, virus titers, viral bronchitis, and bronchiolitis
Isorhamnetin	-	MDCK cells infected with influenza virus A/PR/08/34 (H1N1)Embryonated chicken eggs infected with influenza virus A/PR/08/34 (H1N1)	50 µM	↑ cell viability	[113]
				EC50 = 23 µM
				CC50 > 280 µM
				SI > 12
		C57BL/6 mice infected with influenza A/PR/8/34 (H1N1)	1 mg/kg/day for 5 days (intranasal route)	↓ autophagy, ROS generation, ERK phosphorylation, cytoplasmic lysosome acidification, NA and HA expression, and NA activity
				↓ virus titer, adsorption onto RBCs and RBCs hemolysis
				↓ lung virus titer and body weight loss,
				↑ survival rate
Quercetin	Elaeagnus rhamnoides (L.) A.Nelson (synonym: Hippophae rhamnoides L.)	ACE2h cells infected with SARS-CoV-2	50 µM	↓ Viral entry	[65]
Isorhamnetin				↓ Viral Binding affinity to ACE2
Kaempferol	-	SARS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21	-	↓ PLpro activity: IC50 = 16.3 µM, Deubiquitination activity = 61.7, DeISGylation activity = 71.7,	[37]
				↓ 3CLpro activity:
		MERS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21		IC50 = 116.3 µM
				↓ PLpro activity: IC50 = 206.6 µM,
				↓ 3CLpro activity: IC50 = 35.3 µM
Kaempferol derivatives	-	Heterologously expression of 3a protein of SARS-CoV in Xenopus oocyte	10–20 µM	↓ Ba2+-sensitive current and 3a-mediated current, blocked 3a-protein channel IC50 = 2.3 µM (for juglanin)	[36]
Linarin	-	R5-type HIV-1 in CD4+ NKT cells and human Vδ1+ cells in PBMCs	10–100 µg/mL	↑ IL-2, IL-5, IL-13, MIP-1α, MIP-1β, RANTES, CFSE, and CD25 expression, ↓ viral replication	[104]
Luteolin	-	MDCK, Calu-3, and Vero cells infected with influenza A/Jiangxi/312/2006 (H3N2) and A/Fort Monmouth/1/1947 (H1N1)	3.75–240 μM	↓ CPE:	[60]
				IC50 = 6.89, 7.15 μM, CC50 = 148–240 μM
				↓ M2 viral protein expression, virus absorption, and internalization
Luteolin	Salvia plebeia R. Br.	MDCK cells infected with influenza strain H1N1 A/PR/8/34 virus	50 μM	↓ NA activity: IC50 = 17.96 μM, EC50 = cytotoxic	[148]
Luteolin	-	PBMCs, TZM-bl reporter, and Jurkat cellsinfected with wild–type HIV (NLENY1) or VSV-HIV-1	5–10 µM	↓ clade-B- and -C -Tat-driven LTR transactivation, reactivation of latent HIV-1 infection, HIV-1 gene expression, LTR activity, PBMC cell aggregation/syncytia, viral entry	[150]
Luteolin and luteolin 7-methyl ether	Coleus parvifolius Benth.	MT-4 cells infected with HIV-1 (HTLV IIIB)	-	↓ HIV-1 integrase activity:	[151]
				IC50 = 11–70 µM
				↓ viral replication
Myricetin	-	TZM-bl cell infected with HIV-1 BaL (R5 tropic), H9 and PBMC cells infected with HIV-1 MN (X4 tropic), and the dual tropic (X4R5) HIV-1 89.6,	0.01–100 μM	↓ p24 antigen:	[152]
				IC50 = 1.76–22.91 μM, CC50 = 804.94–1214.72 μM,
		Anti-HIV-1 RT		↓ HIV-1 RT: IC50 = 203.65 μM
Myricetin	-	TZM-bl cell infected with HIV-1 BaL (R5 tropic), H9 and PBMC cells infected with HIV-1 MN (X4 tropic), and the dual tropic (X4R5) HIV-1 89.6,	0.01–100 µM	↑ cell viability,	[152]
				↓ p24 antigen:
				IC50 = 1.76–22.91 μM, CC50 = 804.94–1214.72 μM,
				↓ HIV-1 RT:
		Anti-HIV-1 RT		IC50 = 203.65 μM
Myricetin-3-O-(6″-O-galloyl)-β-D-galactopyranoside	Limonium morisianum Arrigoni	Anti-HIV-1 RT and IN	-	↓ HIV-1 RT-associated RNase	[128]
				H activity: IC50 = 10.9 μM
				↓ IN catalytic function and IN-LEDGF-dependent activity: IC50 = 6.47 μM
Myricetin derivatives	Marcetia taxifolia (A. St.-Hil.) DC.	MT4 cells infected with HIV-1 (HTLV-IIIB/H9)	-	↓ HIV-1 RT activity: IC50 = 7.6–13.8 µM, EC50 = 45–230 μM, SI > 1.3–7	[153]
Myricetin-3′,5′-dimethylether 3-O-β-D-galactopyranoside	Cleistocalyx operculatus (Roxb.) Merr. and L.M.Perry	HEK293 cells infected with the plasmid H1N1 or oseltamivir-resistant novel H1N1 (H274Y)	40 μM	↑ cell viability,	[67]
		MDCK cells infected with influenza H1N1 A/PR/8/34 and H9N2 A/Chicken/Korea/O1310/2001		↓ NA activity (IC50 = 6.50 to 9.34 μM), viral replication and CPE
Naringenin	-	Vero E6 cells infected with HCoVOC43, HCoV229E, and SARS-CoV-2	62.5, 250 μM	↓ TPC2, CPE activity	[74]
Nepetin	Salvia plebeia R. Br.	MDCK cells infected with influenza strain H1N1 A/PR/8/34 virus	20–50 μM	↓ CPE and NA activity:	[148]
				IC50 = 11.18 μM, EC50 = 17.45 μM, SI = ~11.47,
				↑ cell survival rate
Nepitrin	Salvia plebeia R.Br.	MDCK cells infected with influenza A/PR/8/34 (H1N1)	20, 50 μM	↓ NA activity and CPE, ↑ cell viability	[131]
Oroxylin A	-	MDCK and A549 cells infected with influenza A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2), and oseltamivir-resistant	40–50 μM	↓ CPE:	[52]
				IC50 = 270.9, 245.0, 241.4 μM, EC50 = 44.6, 36.1, 109.4 μM
		A/FM/1/47-H275Y (H1N1-H275Y) viruses H1N1-H275Y and A/Anhui/1/2013-R294 K (H7N9-R294 K)	100 μM	↓ viral mRNA and M1 protein expression
				↓ NA activity, IC50 = 241.4 and 203.6 μM
		ICR mice infected intranasally with the A/FM/1/47 (H1N1)	100 mg/kg/d, p.o.	↑ IFN-β, IFN-γ and survival rate ↓ body weight loss, lung injury, lung indexes and lung scores
Oroxylin A	Scutellaria baicalensis Georgi	CHME5 cells and primary human macrophages infected with HIV-1-D3	5–20 µM	↓ phosphorylation of PI3K, PDK1, Akt, activation of GSK3β, m-TOR, and Bad	[114]
Pentamethoxyflavone(5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone)	Marcetia taxifolia (A. St.-Hil.) DC.	MT4 cells infected with HIV-1 (HTLV-IIIB/H9)	45 µM	↓ HIV-1 RT activity: IC50 = 0.4 µM, EC50 = 0.05 μM, CC50 > 50 μM	[154]
Pongamones A–E	Pongamia pinnata (L.) Pierre	In vitro inhibitory activity against HIV-1 RT	-	↓ RT activity	[155]
				IC50 > 10 µg/mL
Prenylisoflavonoids	Erythrina senegalensis DC.	In vitro inhibitory activity against recombinant HIV-1 protease	-	↓ HIV-1 protease activity	[44]
				IC50 = 0.5–30.1 µM
Purified chalcones	Angelica keiskei (Miq.) Koidz.	SARS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21	-	↓ 3CLpro activity:	[156]
				Cell-free cleavage: IC50 = 11.4–129.8 µM,
				Cell-based cleavage: IC50 = 5.8–50.8 µM, SI = 0.4–9.2
				↓ PLpro activity: IC50 = 1.2–46.4 µM, Deubiquitination activity = 2.6–44.1, DeISGylation activity = 1.1–11.3
Purified flavanone glucosides	Thevetia peruviana SCHUM.	HIV-1 IN protein expressed in E. coli,		↓ HIV-1 RDDP activity: IC50 = 20–43 µM	[157]
		RDDP and DDDP inhibitory activity assay		↓ HIV-1 DDDP activity: IC50 = 42 and 69 µM
				↓ HIV-1 IN activity: IC50 = 5–45 µM
Purified flavones	Kaempferia parviflora Wall. ex Baker	In vitro inhibitory activity against HIV-1 protease	-	↓ HIV-1 protease	[158]
				IC50 = 19.04–160.07 µM
Purified flavonoids	Pithecellobium clypearia Benth	A549 cells infected with influenza A/PR/8/34 (H1N1), A/Sydney/5/97 (H3N2) and B/Jiangsu/10/2003	3–30 μg/mL	↓ NA activity:	[105]
				IC50 = 29.77–39.15 µg/mL
				↓ IL-6 and MCP-1
Purified flavonoids	-	NAs from influenza A/PR/8/34 (H1N1), A/Jinan/15/90 (H3N2), andB/Jiangshu/10/2003	-	↓ NA activity:	[159]
				IC50 = 22–87.6 μM
				↓ CPE:
		MDCK cells infected with influenza A/Jinan/15/90 (H3N2)		IC50 = 4.74–24.70 µM
				SI = 1.82–9.64
Purified flavonoids	Elsholtzia rugulosa Hemsl.	NAs from influenza viruses A/PR/8/34(H1N1), A/Jinan/15/90(H3N2) and B/Jiangsu/10/2003	-	↓ NA activity:	[160]
				IC50 = 7.81–28.49 μM
				↓ viral replication and CPE:
		MDCK cells infected with influenza A/Jinan/15/90 (H3N2)		IC50 = 1.43 to > 500 µM,
				SI = 1.73–7.48
Purified flavonoids (Ochnaflavone 7″-O-methyl ether and 2″,3″dihydroochnaflavone 7″ methyl ether)	Ochna integerrima (Lour.) Merr.	1A2 cell line infected with ∆Tat/revMC99 virus	200 µg/mL	↓ RT activity:	[161]
				IC50 = 2.0 and 2.4 µg/mL
				↓ HIV-1 activities:
				EC50 = 2 and 0.9 µg/mL
				IC50 = 6.3 and 2.9 µg/mL
				SI = 3.1 and 3.2
Purified flavonol glycosides	Zanthoxylum piperitum (L.)	MDCK cells infected with influenza A/NWS/33 (H1N1)	7.8–1000 μg/mL	↓ NA activity:	[162]
				IC50 = 211–434 μg/mL
				↓ PFU
Purified flavonols	Rhodiola rosea L.	MDCK cells infected with influenza A/PR/8/34 (H1N1) and A/Chicken/Korea/MS96/96 (H9N2)	-	↓ CPE:	[163]
				EC50 = 6.25–145.4 µM
				SI = 1.6 to > 48
		Recombinant influenza A virus H1N1(rvH1N1)		↓ NA activity:
				IC50 = 2.2–56.9 μg/mL
Purified flavonoids	Broussonetia papyrifera (L.) L’Hér. ex Vent.	SARS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21	-	↓ PLpro activity: IC50 = 3.7–66.2 µM, Deubiquitination activity = 7.6–74.8, DeISGylation activity = 8.5–70.8,	[37]
				↓ 3CLpro activity:
				IC50 = 30.2–233.3 µM
		MERS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21		↓ PLpro activity: IC50 = 39.5–171.6 µM,
				↓ 3CLpro activity: IC50 = 27.9–193.7 µM
Quercetin	-	SARS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21	-	↓ PLpro activity: IC50 = 8.6 µM, Deubiquitination activity = 20.7, DeISGylation activity = 34.4,	[37]
				↓ 3CLpro activity:
		MERS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21		IC50 = 52.7 µM
				↓ 3CLpro activity: IC50 = 34.8 µM
Kaempferol		Vero E6 cells infected with SARS-CoV	125, 62.5, and 31.25 μM	↓ Virus-induced cell death, 3CLprotease	[35]
Quercetin	-	MDCK and A549 cells infected with influenza A/Puerto Rico/8/34 (H1N1), A/FM-1/47/1 (H1N1) and A/Aichi/2/68 (H3N2)	12.5–100 µg/mL (50 µg/mL)	↓ CPE:	[62]
				IC50 = 2.738–7.756 µg/mL, IC90 = 8.24–24.58 µg/mL,
				↓ HA mRNA transcription, viral NP protein synthesis, viral HA expression and virus infection rate, target the membrane fusion process during virus entry
Quercetin	-	Inhibitory activity against recombinant HIV-1 protease	-	↓ HIV-1 protease activity:	[45]
				IC50 = 58.8 µM
Quercetin 3-O-(6″-feruloyl)-β-D-galactopyranoside	Polygonum viscosum Buch.-Ham. ex D. Don	In vitro anti-HIV-1 activity	-	↓ RT activity	[164]
				IC50 = 25.61 µg/mL
Quercetin 3-rhamnoside	Houttuynia cordata Thunb.	MDCK cells infected with influenza A/WS/33	10–100 µg/mL	↓ CPE, viral mRNA synthesis, virus replication and virus infection	[80]
Quercetin 3-β-O-D-glucoside	-	Vero E6 epithelial	10 μM	↓ virus replication (EC50 = 5.3 µM, EC90 = 9.3 µM), viral titers and entry of Ebola viruses	[81]
		cells infected with EBOV-Kikwit-GFP, EBOV-Makona
		and SUDV or VSV-EBOV, and VSV-SUDV	50 mg/kg every other day, i.p.	↓ virus replication and body weight loss,
		BALB/c or C57BL/6 mice infected with mouse-adapted Ebola virus		↑ survival rate
Quercetin-3-O-α-L-rhamnopyranoside	Rapanea melanophloeos (L.) Mez	MDCK cells infected with A/Puerto Rico/8/1934 (H1N1)	150 μg/mL	↓ CPE:	[106]
				CC50 = 200 μg/mL, EC50 = 25 μg/mL, EC90 = 100 μg/mL
				↓ NP and M2 genes copy numbers, viral titer, HA titer and TNF-α,
				↑ IL-27 protein level and cell viability
Quercetin-7-O-glucoside	Dianthus superbus var. longicalycinus (Maxim.) F.N.Williams	MDCK cells infected with influenza A/Vic/3/75 (H3N2), A/PR/8/34 (H1N1), B/Maryland/1/59 and B/Lee/40 viruses	10 μg/mL	↓ CPE:	[50]
				IC50 = 3.10 μg/mL to 8.19 μg/mL, CC50 > 100 μg/mL, SI = 12.21 to 32.25,
				↓ ROS, autophagy, viral RNA synthesis and viral RNA polymerase
Quercetin-β-galactoside	-	SARS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21	-	↓ PLpro activity: IC50 = 51.9 µM, Deubiquitination activity = 136.9, DeISGylation activity = 67.7,	[37]
				↓ 3CLpro activity:
				IC50 = 128.8 µM
		MERS-CoV proteases (3CLpro and PLpro) expressed in E. coli BL21		↓ PLpro activity: IC50 = 129.4 µM,
				↓ 3CLpro activity: IC50 = 68.0 µM
Santin	Artemisia rupestris L.	MDCK and THP-1 cells infected with influenza strain A/Fort Monmouth/1/1947 (H1N1) and A/Wuhan/359/1995	60 µM	↓ CPE:	[61]
				IC50 = 27.68, 37.20 μM, SI = 14.45, 10.75, TC50 > 400 μM
				↓ M2 viral protein expression, phosphorylation of p38 MAPK,
		(H3N2)		JNK/SAPK, ERK, NF-κB, TNF-α, IL-1β, IL-6, IL-8, and IL-10 production
Scutellarin	Erigeron breviscapus (Vant.) Hand.-Mazz	C8166 cells infected with HIV-1IIIB and HIV-1IIIB/H9,	54–541 µM	↓ HIV-1 replication:	[165]
		MT-2 cells infected with HIV-174V,		EC50 = 15–253 µM
		PBMC cells infected with HIV-1KM018		CC50 = 336 -> 1082 µM
		Purified recombinant HIV-1 RT		↓ RT activity, HIV-1 particle attachment and fusion
Tectorigenin	Pueraria thunbergiana (Siebold and Zucc.) Benth.	CHME5 cells and primary human macrophages infected with HIV-1-D3	5–20 µM	↓ phosphorylation of PI3K, PDK1, Akt, activation of GSK3β, m-TOR, and Bad	[114]
Theaflavins	Camellia sinensis (L.) Kuntze (black tea)	MDCK andA549 cells infected with influenza A/PR/8/34(A/H1N1), A/Sydney/5/97(A/H3N2) and B/Jiangsu/10/2003	0.1 to 30 µg/mL	↓ NA:	[108]
				IC50 = 10.67–49.6 µM
				↓ CPE:
				CC50 = 76.7–177.1 µM
				↓ HA activity, IL-6 and vRNP nuclear localization,
Theaflavins	-	SARS-CoV proteases (3CLpro) expressed in E. coli	-	↓ 3CLpro activity	[43]
				IC50 = 3–9.5 µM
Tricin	-	MDCK cells infected with influenza A/Solomon islands/3/2006 (H1N1), A/Hiroshima/52/2005 (H3N2), A/California/07/2009 (H1N1pdm), A/Narita/1/2009 (H1N1pdm) and B/Malaysia/2506/2004	3.3–30 µM	↓ HA and matrix protein, mRNA expression, virus titer (EC50 = 3.4–10.2 µM)	[63]
		DBA/2 Cr mice infected intranasally with influenza A/PR/8/34 virus	20–100 µg/kg, p.o.	↓ Body weight loss,
				↑ Survival rate
Wogonin	Scutellaria baicalensis Georgi	MDCK and A549 cells infected with human influenza virus A/Puerto-Rico/8/34 (H1N1) PR8, seasonal H1N1, H3N2 and B (yamagata lineage)	10 μg/mL	↓ NA and NS1 levels, viral replication, Akt phosphorylation, ↑ IFN-β, IFN-λ1, MxA, OAS, AMPK phosphorylation, phospho-IRF-3 expression, cleaved PARP, and caspase-3 expression and apoptosis	[95]
				↓ Plaque formation: IC50 = 10 μg/mL

Abbreviations: HA: hemagglutinin; NA: neuraminidase; MDCK: Madin-Darby canine kidney; HIV: human immunodeficiency virus; CD: cluster of differentiation; NKT: natural killer T cells; CPE: cytopathic effect; IC50: inhibitory concentration 50%; CC50: cytotoxic concentration 50%; THP-1: Human acute monocytic leukemia; SI: selectivity index; TC50: 50% toxicity concentration; MAPK: Mitogen-activated protein Kinase; JNK: c-Jun N-terminal kinase; SAPK: stress-activated protein kinase; ERK: extracellular signal-regulated kinase; NF-κB: Nuclear factor kappa B; IL: interleukin; TNF-α: tumor necrosis factor; PBMCs: Peripheral Blood Mononuclear Cells; RT: reverse transcriptase; RNase H: Ribonuclease H; IN: integrase; NP: nucleoprotein; mir-146a: microRNA-146a; EC50: effective concentration 50%; TRAF6: TNF receptor-associated factor 6; IFN: Interferon; COX-2: Cyclooxygenase-2; NS1: nonstruc-tural protein 1; AMPK: 5′ adenosine monophosphate-activated protein kinase; IRF-3: Interferon regulatory factor 3; PARP: Poly (ADP-ribose) polymerase; SARS-CoV: Severe acute respiratory syndrome coronavirus; PLpro: papain-like protease; 3CLpro: 3-chymotripsin-like protease; SPR: Surface plasmon resonance; IC90: inhibitory concentration 90%; EBOV: Ebola virus; ROS: Reactive oxygen species; HS: heparan sulphate; HA: hemagglutinin; NA: neuraminidase; HIV: human immunodeficiency virus; CD: cluster of differentiation; NKT: natural killer T cells; CPE: cytopathic effect; IC50: inhibitory concentration 50%; CC50: cytotoxic concentration 50%; EC50: effective concentration 50%; EGCG: Epigallocatechin gallate; ECG: Epicatechin gallate; C5G: Catechin-5-gallate; PI3K: phosphoinositide 3-kinase; PDLKI1: pyruvate dehydrogenase lipoamid kinase isozyme 1; GSK3 β:glycogen synthase kinase-3β; LC3B:light chain 3-B; ROS: reactive oxygen species; MAP1: microtubule associated protein1; SI: selective index; G1,2: group 1,2; orf3a: open-reading-frame 3a; RT: reverse transcriptase; PBMC: peripheral blood mononuclear cells; IFN:interferon; NS1: non-structural protein 1; TF: theaflavin; TF-3-G:theaflavin-3-gallate; TF-3′-G:theaflavin-3′-G; TF-3,3′-DG: theaflavin-3,3′-DG; 3-DSC: 3-deoxysappanchalcone; GCG: gallocatechin gallate; Q3R: quercetin 3-rhamnoside; HMB: 2-hydroxy-3-methyl-3-butenyl alkyl; RANTES: regulated activation; normal T cell expressed and secreted; CG: catechin gallate; SEVI: semen-derived enhancer of virus infection; Env: envelope protein; gp: glycoprotein; TF2B: 3-isotheaflavin-3-gallate; TF3: theaflavin-3,3′-digallate; TPC: endo-lysosomal Two-Pore Channels.