INDEX antiviral activity

Antiviral activity. Epigallocatechin-3-gal-late, administered to Hep2 cells in culture, produced a therapeutic index of 22 and an ICjf, of 25 pM. The agent was the most effective when added to the cells during the transition from the early to the late phase of viral infection suggesting that the polyphenol inhibits one or more late steps in virus infection " . 

Since the dose-dependent curves for cytotoxicity and antiviral activity are almost parallel, it was possible to calculate the ratio cell-/Z)50/virus-//t50. As shown in Table 4, the Therapeutic index (= 77) increased from 2.5 for distamycin/A, to 7.0 for distamycin/4 and to 7.7 for distamycin/5. 

In spite of obtaining a 1000 fold improvement in IC50, the best compounds did not show a significant therapeutic index (TD50/EC50 of > 10-fold) in cellular assays and therefore did not warrant claims of antiviral activity. The lack of cellular activity despite IC50 s in the 3-10 nM range necessitated a close examination of possible explanations. 

Several studies using molecular connectivity have been performed on antiviral data. Tamm et al. developed data for the antiviral activity of alkyl-substituted benzimidazoles against the Lee strain of the flu virus. Hall and Kier have analyzed that data using chi indexes.It is found that the activity depends heavily on arrangement of substituents but not on the atom count. This analysis is revealed in the following QSAR. 

Compound Cy totox icity( 11>50 mg/ml)k Antiviral activity (ED50, pg/ml)c Selectivity index (ID50/ED50)... 

The nucleoside derivatives having in vitro anti-HIV activity are listed in Table 1. The particular activities, toxicities and, thus, selectivity indexes of the tested compounds depend on the in vitro assay system used, and vary significantly according to the target cells, multiplicity of infection and other factors. Compounds shown in Table 1 have been evaluated by different groups, under different conditions. Although all of them showed selective antiviral activities, usually determined by a selectivity index > 10, the results cannot be directly compared. 

A. S. Mayhoub et.al. [104] s)mthesized a sequence of third-generation referents of methyl 4-(dibromomethyl)-2-(4-chlorophenyl)thiazole-5-carboxylate 120, which had the highly potent antiviral activity comparable to the first and second generation derivatives, have been s)mthesized and verified against yellow fever virus consuming a cell-based assay. The compounds were aimed at the objectives of enlightening metabolic stability, therapeutic index, and antiviral potency. The biological effects of C4 and C5 substitution were studied. The... 

Primo et al. (2001) examined in vitro the antiviral activity of the EO from the Lamiaceae Minthostachys verticillata (Griseb.) Epling against HSV-1 and PrV using the viral plaque-reduction assay. The EO influences HSV-1 and PrV multiplication, an activity which is attributed to the main constituents of the EO, namely menthone (39.5%) and especially pulegone (44.6%). The therapeutic index values attained 10.0 and 9.5 for HSV-1 and PrV, respectively. 

The use of complexes of cisplatin with modified nucleosides such as acyclovir has also been proposed for antiviral applications [23]. This approach is similar to that described for antitumour responses in Chapter 3. For antiviral effects, the fact that many of the antiviral nucleoside analogues are not very specific must be considered a disadvantage in this approach. Thus, although there is a distinct synergy between say, are-C, and cisplatin in antitumour effects, the therapeutic index of ara-C for a virus is almost unity and thus toxic side effects may not be overcome. The complex d5-[Pt(NH3)2(Guo)2] has also been reported to have antiviral activity [23], and also to have some antitumour activity (Section 3.5) [24]. However, the carrier approach may be more effective in antiviral therapy than in destroying tumour cells. 

The antiviral activities of the test compounds/extracts are measured with the CPE inhibition assay (Liu et al. 2008b). Viral suspension (200 TCIDj ml, 100 pi) is added to each well of a 96-well plate containing a confluent cell monolayer. After incubation at 37°C for 2 h, the virus solution is removed, and 100 pi of consecutive threefold serial dilutions of the test compounds/extracts and reference compounds are added to each well, using the MNCC as the highest concentration. An infection control without samples is also included. The plates are incubated at 37°C in a humidified CO atmosphere (5% CO ) for 24 h, after which the CPE is assessed. The virus-induced CPE is scored as follows 0=no CPE, 1=0-25% CPE, 2=25-50% CPE, 3 = 50-75% CPE, and 4 = 75-100% CPE. The reduction in virus multiplication is calculated as a percentage of the virus control (% virus control = CPE Z 100). The IC, of the CPE with respect to the virus control is estimated using the Reed-Muench method. The selective index (SI) is calculated as the ratio CC /IC... 

The essential oil from Santolina insularis was also inhibited virus replication against HSV-1 and HSV-2 in vitro (Schnitzler et al. 2008). Its antiviral activity was principally due to direct virucidal effects (De Logu et al. 2000). Lemon balm oil, the essential oil of Melissa officinalis, is capable of exerting a direct antiviral effect on HSV-1 and HSV-2. Considering the lipophilic nature of essential oils, which enable it to penetrate the skin, and a high selectivity index, essential oils might be suitable for topical treatment of herpetic infections (Schnitzler et al. 2008). 

Nucleosides in which the ribofiiranosyl oxygen is replaced by a methylene to result in a cyclopentane ring are referred to as carbocyclic nucleosides. The first such conopound was carbocyclic adenosine (1, aristeromycin), which was synthesized in its racemic form prior to isolation of the (-)-enantiomer from Streptomyces citricolor. The antiviral activity of has stimulated the search for other carbocyclic nucleosides that would display a more favorable therapeutic index. ... 

As another example of Stille chemistry directed towards macrocycles, 1,6-naphthyridines (106) were constructed from active acyclic precursors 105 (Scheme ll.ll) based on the crystal structure, which revealed a proximity between substituents on the naphthyridine and phenyl rings. The antiviral activity of the 14- and 15-membered cyclic compounds proved to be 25-to 150-fold higher than the linear counterpart against human cytomegalovirus (HCMV) strains with one analogue 450-fold better versus ganciclovir-resistant isolates with a selectivity index of 3000. 

Bellenamine, (R)-3,6-diamino-V-(aminomethyl)hexanamide is a (very) small-molecular-weight (MW 174) antibiotic produced by Streptomyces nashvillensis. It has only weak antibacterial activity but inhibits HIV-1 infection at an IC50 of 0.62 pg/ml (3.6 iM). With a CC50 of > 2 mg/ml (11.5 mM), the selectivity index of bellenamine can be estimated at well above 2000. Similarl to the well-established glycosylation inhibitors castanospermine and 1-deoxynojirimycin, bellenamine inhibits the secondary spread of HIV, although, unlike the glycosylation inhibitors, bellenamine had no apparent inhibitory effect on the glycosylation process. Therefore, its antiviral mechanism remains to be elucidated. 

Mendiratta, S. and Madan, A.K. (1994). Structure-Activity Study on Antiviral 5-Vinylpyrimidine Nucleoside Analogs Using Wiener s Topological Index. J.Chem.Inf.Comput.ScL, 34,867-871. Menziani, M.C. and De Benedetti, P.G. (1992). Molecular Mechanics and Quantum Chemical QSAR Analysis in Carbonic Anhydrase Heterocyclic Sulfonamide Interactions. Struct. CherrL,... 

Table 4. Antiviral and cytotoxic activities of some distamycin derivatives. The activity of distamycin derivatives was tested on mouse embryo cells infected or not with MSV (M), ID o Inhibiting dose 50% 77 = therapeutic index, 77>so-cell/72)50-virus...

Several biologically active polypeptides such as levomycin, ac-tinoleukin, and echinomycin have been shown to possess one or more quinoxalinoyl residues.Echinomycin (45) possesses antitumour, antiviral, and antibacterial activities, but its low therapeutic index has precluded any medicinal uses. The structure for echinomycin was deduced from NMR and mass spectral measurements and is a revision of an earlier proposal in which the linking sulfur atoms were incorporated in a dithiapyran ring. Echinomycin has been shown to inhibit the synthesis of RNA by Staphylococcus aureus. ... 

In vivo testing of any new in vitro active antiviral agent is considered the key step before any human clinical trials. This model should predict efficacy in human and should mimic the natural disease as close as possible. The therapeutic index of any antiviral agent to be in vivo tested should be adequate so that appropriate, non-toxic dose for the animal could be considered. Animal models are useful in ... 

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