Antiviral activity of cyclosaligenyl prodrugs of the nucleoside analogue bromovinyldeoxyuridine against herpes viruses

A series of 42 lipophilic bromovinyldeoxyuridine monophosphates (BVDUMPs) are presented as potential prodrugs of the antiviral agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU). The 5'-cycloSal-masking group technique has been applied to this cyclic nucleoside analogue to achieve delivery of the monophosphate of BVDU inside the target cells. The new substances have been tested for their antiviral activity against herpes simplex virus types 1 and 2 (HSV-1 and -2), thymidine kinase-deficient (TK(-)) HSV-1, varicella-zoster virus (VZV), human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). The XTT-based tetrazolium reduction assay EZ4U (for HSV), the plaque inhibition test (for VZV and HCMV) and a DNA hybridisation assay (for EBV) were used to assess antiviral activity. The results indicate that cycloSal-BVDUMP triesters proved to be potent and selective inhibitors of HSV-1 comparable with aciclovir. VZV replication was inhibited by very low concentrations, and two substances had a slightly better anti-VZV activity than the parent compound BVDU. No antiviral effect could be demonstrated against TK(-)-HSV-1, HSV-2 and HCMV, most likely owing to the lack of phosphorylation to BVDU diphosphate. Most remarkably, several cycloSal-BVDUMP triesters yielded promising anti-EBV activity whereas the parent compound BVDU was entirely inactive.     

Synthesis and in vitro antiviral activity of 3'-O-acyl derivatives of 5'-amino-5'-deoxythymidine: potential prodrugs for topical application

A series of 3'-O-acyl derivatives of 5'-amino-5'-deoxythymidine (5'-NH2-TdR) (IIIa-j) was synthesized by acylation of 5'-azido-5'-deoxythymidine (I). The resulting acetoxy azides were reduced by catalytic hydrogenation to give the corresponding amines. The antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro, the aqueous solubilities, and the octanol-water partition coefficients of these compounds were determined. All these derivatives have shown potency against HSV-1 virus similar to the parent compound, except the aromatic and highly branched aliphatic esters, IIIi and IIIj, which are less active. Because of their markedly improved lipophilicity, these compounds are believed to penetrate the biological membranes more easily, and thus, would be more effective for the topical treatment of cutaneous herpes virus infections.     

Effect of mono- and di-acylation on the ocular disposition of ganciclovir: physicochemical properties, ocular bioreversion, and antiviral activity of short chain ester prodrugs

A series of short-chain carboxylic mono- and diesters of ganciclovir were synthesized in our laboratory. Physico-chemical properties, i.e., solubility (pH 4.2), partition coefficient in 1-octanol/phosphate buffer (pH 7.4), aqueous stability at various pH values, bioreversion kinetics in various ocular homogenates and effectiveness against various Herpes viruses in vitro were determined. The compounds exhibited a decrease in solubility as the ester length ascended with a corresponding increase in the octanol/buffer partition coefficient values. All of the prodrugs exhibit stability profiles typical of a carboxylic ester with maximum stability at neutral or slight acidic pH (4.0-7.0). Apparent first-order rate constants associated with prodrug to drug hydrolysis in the ocular homogenates varied depending on the size of the promoiety, lipophilicity of the compound, and the ocular tissue studied. The acetyl and butyryl mono and diesters were screened against various Herpes viruses. The monobutyrate ester of ganciclovir exhibits excellent activity against HSV-2 and VZV and provides a very high selectivity index against most of the viruses studied.     

Synthesis and antiviral activity of phosphonoacetic and phosphonoformic acid esters of 5-bromo-2'-deoxyuridine and related pyrimidine nucleosides and acyclonucleosides

Phosphonoacetic acid (PAA, 1) was coupled with various acyclonucleosides, 2'-deoxyuridines, cytidines, and arabinosyluracils, with 2,4,6-triisopropylbenzenesulfonyl chloride (TPS) or dicyclohexylcarbodiimide (DCCI) as condensing agents, to give a range of phosphonate esters. The carboxylic ester linkage of PAA to the 5'-position of 5-bromo-2'-deoxyuridine (BUdR, 3) was achieved via the mixed anhydride formed from (diethylphosphono)acetic acid and trifluoroacetic anhydride. Phosphonoformic acid (PFA, 2) was coupled with BUdR by using the DCCI method to give the phosphonate ester. Of these compounds only phosphonate esters in the 2'-deoxyuridine series showed significant activity against herpes simplex virus types 1 and 2. The BUdR-PAA derivative and the BUdR-PFA derivative were highly active, especially the latter, which was more active than the parent nucleoside BUdR against the type 2 virus. The active compounds may exert their effects by extracellular or intracellular hydrolysis to the corresponding antiviral agents, but an intrinsic component of antiviral activity may also be involved.     

Antiviral activity of Australian tea tree oil and eucalyptus oil against herpes simplex virus in cell culture

The antiviral effect of Australian tea tree oil (TTO) and eucalyptus oil (EUO) against herpes simplex virus was examined. Cytotoxicity of TTO and EUO was evaluated in a standard neutral red dye uptake assay. Toxicity of TTO and EUO was moderate for RC-37 cells and approached 50% (TC50) at concentrations of 0.006% and 0.03%, respectively. Antiviral activity of TTO and EUO against herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) was tested in vitro on RC-37 cells using a plaque reduction assay. The 50% inhibitory concentration (IC50) of TTO for herpes simplex virus plaque formation was 0.0009% and 0.0008% and the IC50 of EUO was determined at 0.009% and 0.008% for HSV-1 and HSV-2, respectively. Australian tea tree oil exhibited high levels of virucidal activity against HSV-1 and HSV-2 in viral suspension tests. At noncytotoxic concentrations of TTO plaque formation was reduced by 98.2% and 93.0% for HSV-1 and HSV-2, respectively. Noncytotoxic concentrations of EUO reduced virus titers by 57.9% for HSV-1 and 75.4% for HSV-2. Virus titers were reduced significantly with TTO, whereas EUO exhibited distinct but less antiviral activity. In order to determine the mode of antiviral action of both essential oils, either cells were pretreated before viral infection or viruses were incubated with TTO or EUO before infection, during adsorption or after penetration into the host cells. Plaque formation was clearly reduced, when herpes simplex virus was pretreated with the essential oils prior to adsorption. These results indicate that TTO and EUO affect the virus before or during adsorption, but not after penetration into the host cell. Thus TTO and EUO are capable to exert a direct antiviral effect on HSV. Although the active antiherpes components of Australian tea tree and eucalyptus oil are not yet known, their possible application as antiviral agents in recurrent herpes infection is promising.     

Antiviral effect of octyl gallate against DNA and RNA viruses

The effects of gallic acid (3,4,5-trihydroxybenzoic acid) and its alkyl esters on virus growth and virion infectivity were examined. All the compounds tested showed an inhibitory effect on the growth of herpes simplex virus type 1 (HSV-1) in HEp-2 or Vero cells. The antiviral activity of gallic acid alkyl esters was enhanced by increasing the number of carbon in the alkyl moieties of the compounds, reaching maximum at a carbon number of 12 (lauryl gallate), but both cytocidal activity and cytopathic effect of the compounds were also significantly increased simultaneously. Among these compounds, octyl gallate showed a marked antiviral effect with a relatively moderate cytotoxity. In addition, octyl gallate suppressed the multiplication of RNA viruses, such as vesicular stomatitis virus and poliovirus. Quantitative characterization of the HSV-1 infection in the presence of octyl gallate revealed that: (1) this reagent can directly inactivate HSV-1 (virucidal activity), (2) it suppresses both the intracellar multiplication and the release of the virus, (3) it selectively accelerates death of the virus-infected cells and (4) the addition of the reagent even at 6-h post infection completely abolishes the formation of progeny virus in the infected cells.     

Synthesis and antiviral evaluation of novel cyclopropyl nucleosides, phosphonate nucleosides and phosphonic acid nucleosides

Novel phenyl-branched cyclopropyl nucleosides, phosphonates, and phosphonic acid analogues were designed and synthesized as potential antiviral agents. Coupling of the mesylate 10 with natural bases (U, T, C, A) and desilylation/hydrolysis afforded a series of novel cyclopropyl nucleosides 15-18. Phosphonate and phosphonic acid nucleosides 22-29 were also readily synthesized from the mesylate 21. The synthesized compounds were evaluated for their antiviral activity against various viruses such as HIV-1, HSV-1, HSV-2, and HCMV.     

Inhibitory effect of cycloSaligenyl-nucleoside monophosphates (cycloSal-NMP) of acyclic nucleoside analogues on HSV-1 and EBV

The in vitro antiviral activity of a new series of cycloSal-pro-nucleotides derived from the acyclic nucleoside analogues aciclovir and penciclovir against herpes simplex virus type 1 (HSV-1), thymidine kinase deficient (TK-) HSV-1, and Epstein-Barr virus (EBV) was evaluated. Using the XTT-based tetrazolium reduction assay EZ4U, the cycloSal derivatives were examined for their antiviral and cytotoxic effects in HSV-1 as well as HSV-1-TK--infected Vero cells. The anti-EBV activity was assessed by means of an EBV DNA hybridization assay using a digoxigenin-labeled probe specific for the Bam H1-W-fragment of the EBV genome and by measuring viral capsid antigen (VCA) expression in P3HR-1 cells by indirect immunofluorescence. Among the new cycloSal-phosphotriesters the three aciclovir monophosphates proved to be potent and selective inhibitors of HSV-1 replication, EBV DNA synthesis and EB-VCA expression. Of interest is the retention of activity of the aciclovir monophosphates in HSV-1-TK--infected cells. Particularly 3-methyl-cycloSal-aciclovir monophosphate retained the same effectiveness, as compared to the wild type virus strain. In contrast to the aciclovir pro-nucleotides the penciclovir cycloSal-phosphotriesters exhibited at best only a marginal antiviral effect on HSV and EBV replication.     

Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir

The purpose of this study was to synthesize a series of diester prodrugs of ganciclovir (GCV), for improving ocular and oral bioavailability and therapeutic activity. Solubility, logP, pH stability profile, in vitro antiviral activity, cytotoxicity, inhibition profile and ocular tissue hydrolysis of the GCV prodrugs were measured. Val-Val-GCV and Val-Gly-GCV diesters were found to exhibit greater aqueous stability compared to Val-GCV and Gly-Val-GCV while ocular tissue hydrolysis demonstrated Val-Gly-GCV and Gly-Val-GCV to be more stable. Val-Val-GCV and Val-GCV diesters were the most lipophilic compounds and were predicted to possess a partition coefficient 295- and 12-fold greater than that of GCV, respectively. All the prodrugs possess much higher aqueous solubility than the parent drug GCV. Ex vivo uptake in the rabbit eye indicates that the prodrugs have high uptake potential. The prodrugs showed no increase in cytotoxicity compared to GCV, instead there was a marked increase in their potency against human cytomegalovirus (HCMV) as well as HSV-1 and HSV-2. This should allow therapeutic response to be seen at a lower concentration that can be achieved more easily, than the drugs currently being used. In conclusion, the diester GCV prodrugs demonstrated excellent chemical stability, high aqueous solubility and markedly enhanced antiviral potency against the herpes viruses without any increase in cytotoxicity.     

Antiviral activity of ganciclovir elaidic acid ester against herpesviruses

A fatty acid derivative of ganciclovir (GCV), elaidic acid ganciclovir (E-GCV), has been evaluated for its inhibitory activity against laboratory and clinical strains of herpes simplex type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV) and human cytomegalovirus (HCMV) in human embryonic lung fibroblasts. GCV, cidofovir, acyclovir (ACV), brivudin (BVDU) and foscarnet (PFA) were included as reference compounds. The viruses studied were wild-type, thymidine kinase-deficient (TK(-)) and PFA-resistant (PFA(r)) HSV strains. The IC(50) values obtained for E-GCV were 5- to 30-fold lower than those observed for GCV, the IC(50) value of E-GCV for HSV-1 strain KOS being 0.07 nM. A similarly increased activity of E-GCV (as compared to GCV) was noted for TK(-) and PFA(r) HSV-1 or HSV-2 strains. However, E-GCV did not exhibit superior activity over GCV to VZV or HCMV in vitro. The antiviral efficacy of E-GCV was also evaluated in vivo against intracerebral HSV-2 infection in NMRI mice. Animals were treated intraperitoneally or perorally with E-GCV, GCV or placebo once daily for 10 days, starting the day of infection. E-GCV compared to GCV at equimolar doses, proved markedly more efficacious than GCV in terms of reduction of mortality rate and delay of mean time of death. The elaidic acid ester of GCV should therefore be considered as a novel approach towards the treatment of HSV infections.     

Inactivation of HSV-1 and HSV-2 and prevention of cell-to-cell virus spread by Santolina insularis essential oil

The essential oil obtained in toto from Santolina insularis was investigated for its antiviral activity on herpes simplex type 1 (HSV-1) and type 2 (HSV-2) in vitro. The IC(50) values, determined by plaque reduction assays, were 0.88 and 0.7 microg/ml for HSV-1 and HSV-2, respectively, while the CC(50) determined by the MTT test on Vero cells was 112 microg/ml, indicating a CC(50)/IC(50) ratio of 127 for HSV-1 and 160 for HSV-2. Results obtained by plaque reduction assays also indicated that the antiviral activity of S. insularis was principally due to direct virucidal effects. Antiviral activity against HSV-1 and HSV-2 was not observed in a post-attachment assay, and attachment assays indicated that virus adsorption was not inhibited. Up to 80% inhibition of HSV-1 was achieved at the concentration of 40 microg/ml by yield reduction assay. Furthermore, reduction of plaque formation assays also showed that S. insularis essential oil inhibits cell-to-cell transmission of both HSV-1 and HSV-2.     

朱砂七总蒽醌体外抗单纯疱疹病毒的研究

目的研究朱砂七总蒽醌(ZSQ)体外对单纯疱疹病毒的抑制作用。方法运用单纯疱疹病毒I型(HSV-Ⅰ)和Ⅱ型(HSV-Ⅱ),以非洲绿猴肾细胞(Vero细胞)为宿主细胞,通过观察感染病毒后的细胞变性反应(CPE)和MTI比色法,检测ZSQ对单纯疱疹病毒的抑制作用。结果与病毒对照组相比,朱砂七总蒽醌各质量浓度组均能有效地保护感染HSV-I和HSV-Ⅱ病毒的Vero细胞,抑制单纯疱疹病毒的复制,使病毒导致的细胞病变减弱。ZSQ抗HSV-I病毒作用IC50为0.004 7g.L-1,抗病毒有效率达90.83%,治疗指数(TI)为16.62;总蒽醌抗HSV-Ⅱ病毒作用IC50为0.006 7g.L-1,抗病毒有效率达90.06%,治疗指数(TI)为11.66。结论 ZSQ在体外显示出明显的保护宿主细胞、抵抗单纯疱疹病毒感染的活性。     

Oxanilic acids, a new series of orally active antiallergic agents.

A large number of oxanilic acid esters and N-heteroaryl oxamic acid esters were prepared and found to have antiallergic activity using the rat passive cutaneous anaphylaxis (PCA) test. Many of the oxanilic acid esters are active orally, with the most active species having an aryl 2'-carbamoyl group and a 3'-methoxy group. Hydrolysis of the ester from the oxanilic ester moiety causes a loss of oral activity.     

Synthesis and antiviral evaluation of cis-substituted cyclohexenyl and cyclohexanyl nucleosides

Starting from commercially available (rac)-3-cyclohexene-1-carboxylic acid, a series of purine and pyrimidine cis-substituted cyclohexenyl and cyclohexanyl nucleosides were synthesized through a key Mitsunobu reaction. Antiviral evaluations were performed on HIV, coxsackie B3, and herpes viruses (HSV-1, HSV-2, VZV, HCMV). Three compounds showed moderate activity against HSV-1 and coxsackie viruses. Specific computer modeling studies were performed on HSV-1 thymidine kinase in order to understand the enzyme activation of an analogue showing moderate antiviral activity.     

Modifications on the heterocyclic base of acyclovir: syntheses and antiviral properties

A group of compounds was prepared in which variations of the ring portion of the acyclovir (ACV) structure were made. These modifications included monocyclic (isocytosine, triazole, imidazole), bicyclic (8-azapurine, pyrrolo[2,3-d]pyrimidine, pyrazolo[3,4-d]pyrimidine) and tricyclic (linear benzoguanine) congeners. The derivatives were evaluated against herpes simplex virus type 1 (HSV-1) by the plaque-inhibition and plaque-reduction methods with only the 8-azapurine analogue 28 showing some activity. In a test measuring the ability of these compounds to inhibit the HSV-1 thymidine kinase, 28 and the tricyclic derivative 38 exhibited competition with ACV for binding to the enzyme. The inability of the group to exert significant antiherpetic action is attributed to their lack of phosphorylation to the requisite triphosphate stage.     

Rotation Locular Countercurrent Chromatography and Quantitative 1H-Nuclear Magnetic Resonance Spectroscopy of the Phorbol Ester Constituents of Croton Oil.

The toxic components of the seed oil of CROTON TIGLIUM L. (Euphorbiaceae), croton oil, are known to be cocarcinogenic phorbol-12, 13-diesters and cryptic cocarcinogenic phorbol-12, 13, 20-triesters. For a rapid isolation of mixtures of these phorbol esters from the oil rotation locular countercurrent chromatography (RLCC) was used. The eluted fractions were analysed by thin layer chromatography (TLC) and (1)H-nuclear magnetic resonance spectroscopy ( (1)H-NMR). The phorbol diesters were separated from the triesters although no baseline separation could be achieved, and the diesters as well as the triesters were completeley extracted from the oil. In a simple methanolic extraction procedure, on the contrary, the phorbol triesters were partially lost. A qualitative as well as a quantitative physico-chemical evaluation method was developed for the phytochemical screening of these cocarcinogenic and cryptic cocarcinogenic compounds in biological material using (1)H-NMR spectroscopy. It was possible to quantify the phorbol esters in mixtures, in semi-purified samples, or even in the complete oil, and to determine at the same time the proportion of diand triesters. Because of its speed and accuracy, this technique provides a valuable alternative for the less versatile biological methods, to screen for known classes of compounds (like e. g. phorbol esters).     

CycloSal-BVDUMP pronucleotides: how to convert an antiviral-inactive nucleoside analogue into a bioactive compound against EBV

Novel cycloSal-BVDUMP triesters 2-4 5-[(E)-2-bromovinyl]-2'-deoxyuridine (BVDU, 1) have been studied with regard to their potential anti-EBV activity. In addition to the 3'-unmodified cycloSal-BVDUMP triesters 2a-f, the 3'-hydroxyl function has been esterified with different aliphatic carboxylic acids (3a-g) and alpha-amino acids having natural and nonnatural Calpha-configuration (4a-m). In addition to the synthesis of these compounds, different physicochemical properties of the new derivatives will be reported, i.e., lipophilicity and hydrolysis behavior. It could be proven that the monophosphate BVDUMP and not 3',5'-cyclic BVDUMP was delivered from most of the compounds by chemical hydrolysis in phosphate buffers at pH 6.8 and 7.3 as well as P3HR-1 cell extracts. Finally, the new compounds were tested for their anti-EBV activity. As a result, the prototype compounds and particularly triesters 2c,d exhibited pronounced anti-EBV activity making these compounds promising candidates for further development. However, the 3'-ester derivatives were devoid of any antiviral activity while the 3'-aminoacyl derivatives showed an antiviral activity dependent upon the amino acid and the Calpha-configuration     

Antiviral activity of Spirulina maxima against herpes simplex virus type 2

Spirulina has been used in a variety of practical applications in biotechnology and medical sciences. This paper presents the antiviral activity found in a hot water extract (HWE) of a commercial preparation of Spirulina maxima, studied by a microplate inhibition assay, using several viruses. The HWE inhibited the infection for: herpes simplex virus type 2 (HSV-2), pseudorabies virus (PRV), human cytomegalovirus (HCMV), and HSV-1, and the 50% effective inhibition doses (ED(50)) were 0.069, 0.103, 0.142, and 0.333 mg/ml for each virus, respectively. For adenovirus the inhibition was less than 20%, and no inhibition was found for measles virus, subacute sclerosing panencephalitis virus (SSPE), vesicular stomatitis virus (VSV), poliovirus 1 and rotavirus SA-11, at concentrations of 2 mg/ml of the HWE. The highest antiviral activity was for HSV-2, with a selectivity index of 128. The antiviral activity was not due to a virucidal effect. Herpesvirus infection was inhibited at the initial events (adsorption and penetration) of the viral cycle. To initiate the isolation and identification of the compound that exhibits the antiviral activity of S. maxima, some extracts made by using several solvents with different polarity were evaluated by microplate inhibition assay using HSV-2. The highest antiviral activity was detected in the methanol-water 3:1, which suggests that the antiviral activity is probably due to highly polar compounds.     

Teratogenic phthalate esters and metabolites activate the nuclear receptors PPARs and induce differentiation of F9 cells

Industrial plasticizers such as phthalates can induce peroxisome proliferation. Some phthalates such as di-2-ethyl-hexyl-phthalate (DEHP) and its metabolites mono-2-ethyl-hexyl-phthalate and 2-ethyl-hexanoic acid are also known teratogens. Recently, we introduced two in vitro test systems consisting of F9 teratocarcinoma cell differentiation and activation of peroxisome proliferator-activated receptor (PPAR)-ligand-binding domain in Chinese hamster ovary-reporter cells for the detection of teratogenic compounds related to the antiepileptic drug valproic acid. We now applied these methods to the class of phthalate esters and their metabolites by testing 2 diphthalate esters and 19 monophthalate esters in vitro. In the F9 cell assay only five compounds, mono-2-ethyl-hexyl-phthalate, mono-1-methyl-heptyl-phthalate, mono-benzyl-phthalate, benzyl-butyl-phthalate, and 2-ethyl-hexanoic acid were found to induce F9 cell differentiation. The other test compounds were not able to induce differentiation of F9 cells. Three compounds (mono-methyl-phthalate, mono-ethyl-phthalate, and mono-2,2-dimethyl-1-phenyl-propyl-phthalate, and phthalic acid di-methyl-ester were found not to interact with any PPARs. All other phthalate esters activated PPARs. Most compounds activated PPARalpha and PPARgamma. Interestingly PPARgamma in most cases was activated stronger than PPARalpha. Only the five test compounds, mono-2-ethyl-hexyl-phthatate, mono-1-methyl-heptyl-phthalate, mono-benzyl-phthalate, benzyl-butyl-phthalate, and 2-ethyl-hexanoic acid activated PPARdelta and interacted with a specific PPARdelta-response element. These are the same compounds that induced F9 cell differentiation and three of them are known teratogenic compounds. It is concluded that phthatate esters are acting like hormones by activating PPARs. The combination of F9 cell differentiation assay and PPARdelta activation assay detected possible teratogenic phthalate-ester and derivatives. Therefore the test systems seem useful for a screening test system in the early development of new plasticizers.     

Structure-antiviral activity relationship in the series of pyrimidine and purine N-[2-(2-phosphonomethoxy)ethyl] nucleotide analogues. 1. Derivatives substituted at the carbon atoms of the base.

A series of dialkyl esters of purine and pyrimidine N-[2-(phosphonomethoxy)ethyl] derivatives substituted at position 2, 6, or 8 of the purine base or position 2, 4, or 5 of the pyrimidine base were prepared by alkylation of the appropriate heterocyclic base with 2-chloroethoxymethylphosphonate diester in the presence of sodium hydride, cesium carbonate, or 1,8-diazabicyclo[5,4, 0]undec-7-ene (DBU) in dimethylformamide. Additional derivatives were obtained by the transformations of the bases in the suitably modified intermediates bearing reactive functions at the base moiety. The diesters were converted to the corresponding monoesters by sodium azide treatment, while the free acids were obtained from the diester by successive treatment with bromotrimethylsilane and hydrolysis. None of the PME derivatives in the pyrimidine series, their 6-aza or 3-deaza analogues, exhibited any activity against DNA viruses or retroviruses tested, except for the 5-bromocytosine derivative. Substitution of the adenine ring in PMEA at position 2 by Cl, F, or OH group decreased the activity against all DNA viruses tested. PMEDAP was highly active against HSV-1, HSV-2, and VZV in the concentration range (EC50) of 0.07-2 microg/mL. Also the 2-amino-6-chloropurine derivative was strongly active (EC50 = 0.1-0. 4 microg/mL) against herpes simplex viruses and (EC50 = 0.006-0.3 microg/mL) against CMV and VZV. PMEG was the most active compound of the whole series against DNA viruses (EC50 approximately 0.01-0.02 microg/mL), though it exhibited significant toxicity against the host cells. The base-modified compounds did not show any appreciable activity against DNA viruses except for 7-deazaPMEA (IC50 approximately 7.5 microg/mL) against HIV-1 and MSV. The neutral (diisopropyl, diisooctyl) diesters of PMEA were active against CMV and VZV, while the corresponding monoesters were inactive. The diisopropyl ester of the 2-chloroadenine analogue of PMEA showed substantially (10-100x) higher activity against CMV and VZV than the parent phosphonate. Also, the diisopropyl and diisooctyl ester of PMEDAP inhibited CMV and VZV, but esterification of the phosphonate residue did not improve the activity against either MSV or HIV.