DNA viruses have DNA genomes that are replicated by either host or virally encoded DNA polymerases. DNA viruses with a large genome, particularly the families of Herpesviridae
, encode a number of proteins that counter host defenses. [48
] Double-stranded DNA viruses can be subdivided into three groups: (1) those with a small size DNA genome (<10 kb), such as polyomaviruses and papillomaviruses; (2) those with a medium-sized DNA genome (ca., 35 kb), such as adenoviruses; and (3) those with a large DNA genome (ca., 130–250 kb), such as herpesviruses and poxviruses [49
4.1.1. Quinoxaline Derivatives Active against Herpesviridae
are a ubiquitous worldwide family responsible for viral infections. Among its members frequently encountered are, herpes simplex viruses (HSV-1 and HSV-2), human cytomegalovirus (HCMV), and Epstein Barr virus (EBV) [28
]. Usually, these infections remain latent and patients are often asymptomatic, particularly immunocompetent populations. However, in immunocompromised patients especially (e.g., AIDS, cancer, etc.), there can be clinical symptoms such as meningitidis or pneumoniae leading to death. Treatments against HSV or HCMV like ganciclovir, valganciclovir, foscarnet, or cidofovir, are currently available but they are limited by toxicity and/or poor oral bioavailability [28
]. In addition, drug resistance is emerging. Hence there is a need to identify improved agents that circumvent one or more of these problems.
In 2012, a series of new [1,2,4]triazolo[4,3-a
]quinoxaline derivatives and their pyrimido-quinoxaline isosters were synthesized and evaluated as potential antiviral agents. Twenty-two novel compounds were obtained. Among them, 1-(4-chloro-8-methyl[1,2,4]triazolo[4,3a
]quinoxaline-1-yl)-3-phenyl thiourea 1
showed the highest antiviral activity in a plaque-reduction assay against Herpes simplex virus grown on Vero African monkey kidney cells, reducing the number of plaques by 25% at 20 µg/mL (Figure 3
). Nine other compounds reduced the number of plaques by less than 25% at 80 µg/mL, leading the authors to the conclusion that the thiourea moiety may be responsible for antiviral activity and highlighting the importance of the moieties selected in developing antiviral activity [29
]. However, antiviral activity remained disappointing compared to positive control aphidicolin, which reduced the number of plaques by 100% at 5 µg/mL, even though compound 1
showed lower cytotoxicity.
The synthesis of four new aldehydo-sugar-N-(3-phenylquinoxalin-2-yl)hydrazones 2a-d
and their acyclic C-nucleoside analogues, 1-(4-phenyl-[1,2,4]triazolo[4,3-a
) indicated that these compounds exhibited very weak antiviral activity against HSV-1 in a plaque reduction infectivity assay in comparison to aphidicolin taken as reference [30
Recently, nine novel quinoxaline derivatives were synthetized via different nucleophilic reactions using ethyl (6,7-dimethyl-2-oxo-3,4-dihydroquinoxalin-3-yl)acetate 4
and ethyl (6-methyl-2-oxo-3,4-dihydroquinoxalin-3-yl)acetate 5
)-one, and 1,4-dihydroquinoxaline-2,3-dione as precursors [31
] (Table 3
). When their antiviral activity against HCMV was compared to the standard drug ganciclovir (EC50
= 0.059 µM), two derivatives demonstrated higher activity, each with EC50
< 0.05 µM. Notably, the toxicity of 4
= 108.47 and >150 µM, respectively) was comparable to the reference drug (CC50
>150 µM) and compound 6
showed the poorest safety profile with CC50
= 2.34 µM.
Four other compounds showed promising antiviral activity. Antiviral activity was observed to depend on varying chemical characteristics, like the presence of a dimethylquinoxalinyl methylene nucleus as a common structural feature and the presence of a lipophilic ester function (Figure 5
In addition, several quinoxaline derivatives are of current interest as anti HCMV agents [28
]. Some 2-aryl-2-hydroxy ethylamine substituted 1H
]quinoxaline-6-carboxamides were synthetized and tested (Figure 6
In this study, the pyridoquinoxaline nucleus proved to be a useful nucleus, as some of the synthetized compounds showed a favorable profile for established drugs like as ganciclovir, acyclovir, foscarnet, and aphidicolin [28
] (Table 4
The morpholinomethyl side chain afforded good levels of both enzymatic and antiviral activity whereas the benzofuran moiety resulted in extremely potent enzymatic and antiviral activity. However, despite excellent biological activity, the calculated log P of compound 10 proves the need to continue pharmacomodulation efforts aimed at improving its hydrosolubility.
Finally, EBV is a very common virus that can increase the risk of developing certain rare cancers. The malignant transformation of normal human epithelial cells results from exposure to EBV and that transformation is dependent on the presence of phorbol esters, which stimulate cell proliferation through rapid activation of protein kinase C [32
]. Novel 3-amioquinoxalin-2(1H
)-one derivatives and derivatives with pyrimidine ring linked to quinoxaline through sulfur (Figure 7
) exhibited properties against EBV antigen activation.
On a series of 22 original compounds, six derivatives demonstrated stronger inhibitory effect on EBV than oleanolic acid as reference, without showing any cytotoxicity. The structure–activity relationship proved that disubstitution with alkyl groups on both nitrogen of hydrazine and quinoxaline was crucial for activity especially for the allyl group. This high activity could result from a hydrophobic interaction between the alkyl group and the hydrophobic region of the binding site of the receptor. The presence of a methoxy group on the phenyl group and substitution with a pyrimidine nucleus linked to quinoxaline through sulfur were also conducive to activity [32