Table 2.

Antiviral properties of flavonoids against human cytomegalovirus with various mechanisms of action.

Type of Study, Method, Virus, and Cells	Results (Compound, Concentration, or Dose)	Mechanisms	Reference
In vitro. Plaque-reduction assay and multiple biochemical analyses. HCMV–Towne. HFF cells.	Quercetin and isoquercitrin potently hindered the replication of HCMV with IC50 values of 5.9 and 1.9 µg/mL, respectively.	Inhibition of HCMV-IE gene expression. Suppression of the transcript levels of HCMV UL122 (IE), UL44 (E) and UL83 (L). Inhibition of MIEP activation by interfering with the JNK pathway.	[102]
In vitro. mCherry (a marker of infection), eGFP (a marker of late viral replication) fluorescence assays, and various biochemical analyses. Recombinant HCMV (ganciclovir-resistant strain) TB40/EmCherry-UL99eGFP. NuFF-1 cells.	Treatment of HCMV-infected NuFF-1 cells with deguelin at high (moi = 1.0) or low (moi = 0.01) multiplicities potently suppressed the HCMV lytic replication, with IC50 values of 55.8 and 23.4 nM, respectively.	Deguelin (250 nM) effectively repressed E and L viral gene transcriptions and reduced the expressions of IE2-86 and IE2-60 proteins.	[114]
In vitro. Plaque-reduction assay coupled with multiple biochemical tests. HCMV–Towne. HEL fibroblast cells.	Tricin suppressed the replication and infection of HCMV at a concentration of 10 µM.	Reduction of IE1 and UL54 (encoding DNA polymerase) genes expression. Inhibition of CCL2-CCR2 axis expressions in the HCMV replication cycle.	[115]
In vitro. Plaque assay combined with various biochemical analyses. HCMV–Towne. HEL fibroblast cells.	Treatment with tricin (10 µM) showed considerable inhibition of HCMV replication.	Inhibition of IE1 and UL54 gene expressions. Suppression of CCL5 protein expression.	[116]
In vitro and in silico. Plaque-reduction assay and various biochemical and molecular docking analyses. HCMV–Towne. HEL fibroblast cells.	Tricin and flavopiridol (synthetic flavonoid and standard inhibitor of CDK) exhibited notable anti-HCMV properties, with EC50 values of 2.09 µM and 15.8 nM, respectively.	In vitro (tricin and flavopiridol repressed the activity of CDK9, with IC50 values of 1.38 µM and 8.20 nM, respectively). The anti-CDK9 activity of tricin is related to the phosphorylation of the carboxy-terminal domain of RNA polymerase II. In silico (tricin was found to bind to the ATP-binding site of CDK9).	[118]
In vitro and in silico. Plaque-reduction assay and multiple biochemical and molecular docking simulations assays. HCMV–Towne. HEL fibroblast cells.	The anti-HCMV activities of tricin and 6F-tricin were determined, with EC50 values of 54.3 and 0.13 nM, respectively.	In silico (tricin and 6F-tricin were detected to bind to the ATP-binding site of CDK9, and significant binding affinity was observed with 6F-tricin).	[119]

CCL2, CC-motif chemokine ligand 2; CCL5, CC-motif chemokine ligand 5; CCR2, a CCL2-specific receptor; CDK9, cyclin-dependent kinase 9; EC₅₀, 50% effective concentration; HCMV, human cytomegalovirus; HEL, human embryonic lung; HFF, human foreskin fibroblasts; IC₅₀, 50% inhibitory concentration; IE, immediate–early; JNK, c-jun N-terminal kinase; MIEP, major IE (MIE) enhancer/promoter; moi, multiplicity of infection; NuFF-1, primary newborn human fibroblasts.