Modifications on the heterocyclic base of ganciclovir, penciclovir, acyclovir - syntheses and antiviral properties (original) (raw)
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Journal of Medicinal Chemistry, 1983
Several water-soluble ester derivatives of acyclovir [9-[ (2-hydroxyethoxy)methyl]guanine], i.e., the 2'-O-glycyl-, 2'-0-a-alanyl-, Z'-O-fi-alanyl-and 2'-0-3-carboxypropionyl esters, were synthesized and evaluated for their antiviral activity in cell culture. The compounds were all prepared directly from acyclovir by application of the usual esterification methods with the appropriate acyl precursors and isolated as their hydrochloride or sodium salts. When assayed in primary rabbit kidney cell cultures against various herpes simplex virus type 1 and type 2 strains, the four acyclovir esters proved almost as active as acyclovir itself, suggesting that they were readily hydrolyzed to release the parent compound.
Amino acids, 2018
Bile acid prodrugs have served as a viable strategy for refining the pharmaceutical profile of parent drugs through utilizing bile acid transporters. A series of three ester prodrugs of the antiherpetic drug acyclovir (ACV) with the bile acids cholic, chenodeoxycholic and deoxycholic were synthesized and evaluated along with valacyclovir for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The in vitro antiviral activity of the three bile acid prodrugs was also evaluated against Epstein-Barr virus (EBV). Plasma stability assays, utilizing ultra-high performance liquid chromatography coupled with tandem mass spectrometry, in vitro cytotoxicity and inhibitory experiments were conducted in order to establish the biological profile of ACV prodrugs. The antiviral assays demonstrated that ACV-cholate had slightly better antiviral activity than ACV against HSV-1, while it presented an eight-fold higher activity with respect to ACV against H...
Activity of penciclovir in antiviral assays against herpes simplex virus
Journal of Antimicrobial Chemotherapy, 1996
The effect of penciclovir and acyclovir on the replication of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) strains was determined in MRC-5 cells infected with 0.01 pfu/cell and exposed to the drugs for 72 h to allow multiple cycles of replication. Penciclovir was significantly more active than acyclovir against three strains of HSV-1 and three strains of HSV-2 at 1 mg/L (P = 0.009), 3 mg/L (P < 0.001) and lOmg/L (P = 0.001). Further comparisons between the compounds were made in MRC-5 cells infected with HSV-1 strain SCI6 using four different antiviral assays namely, the 24 h virus yield reduction assay, plaque reduction assay, viral antigen inhibition assay, and a viral DNA inhibition assay, to determine the relative merits of each. Penciclovir and acyclovir shared similar activities in the plaque reduction assay (with 50% effective concentrations, EC», being 0.8 and 0.6 mg/L, respectively) and in the viral antigen inhibition assay (EQoS, 0.6 and 0.7 mg/L, respectively). The EC» of penciclovir in the 24 h viral DNA inhibition assay was 0.01 mg/L compared with 0.06 mg/L of acyclovir. In the 24 h virus yield reduction assay in which MRC-5 cells were infected with 0.3 pfu/cell, penciclovir was more active than acyclovir with 99% effective concentrations of 0.6 mg/L and 1.1 mg/L, respectively. The activity of penciclovir in the 24 h virus yield reduction and antigen inhibition assays was inversely related to the multiplicity of infection, whereas this had considerably less effect on the inhibition of viral DNA synthesis. These results suggest that famciclovir, which is the oral form of penciclovir, will be at least as effective as acyclovir in treating infections caused by HSV-1 and HSV-2.
A new homodimer of aciclovir as a prodrug with increased solubility and antiviral activity
2009
Aciclovir (ACV) is the drug of choice against herpes simplex virus type 1 (HSV-1) infection. However, its limited solubility in water and limited oral bioavailability represent the main limitations of this drug. Utilising a plaque reduction assay, this study assessed the antiherpetic activity of a new homodimer of ACV (ACVp 2 ACV) with a higher water solubility. ACVp 2 ACV markedly inhibited HSV-1 replication in Vero cells [50% effective concentration (EC 50 ) of 2.8 M vs. 6.6 M for ACV] and was non-toxic in the cells at concentrations ≤15 M. ACVp 2 ACV encapsulated in erythrocytes provides effective protection against HSV-1 replication in human macrophages and also partially against the HSV-1 thymidine kinase-deficient strain.
New Analogues of Acyclovir – Synthesis and Biological Activity
Zeitschrift für Naturforschung C, 2010
New acyclovir esters with peptidomimetics were synthesized and evaluated in vitro for their antiviral activity against the replication of Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The infl uence of peptidomimetics containing oxazole and thiazolyl-thiazole moieties on the antiviral activity is also reported. The esters were synthesized using the coupling reagents N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N,N-dimethyl-4-aminopyridine (DMAP) as a catalyst.
1998
, are well known for the chemotherapy of human herpesviruses, e.g. herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicellazoster virus (VZV) or Epstein-Barr virus (EBV) (De Clercq, 1993). Antiherpesvirus agents all act on the viral DNA polymerase, but compounds differ from each other in the way in which they are metabolized to their active forms and the precise mechanism by which the latter forms interact with the viral DNA polymerase. As for other classes of nucleo-side analogues (De Clercq, 1984), intracellular phosphorylation of acyclic nucleoside analogues to their mono-, diand triphosphates is a prerequisite for the expression of their biological activity as competitive inhibitors/alternative substrates with respect to the natural substances for the DNA polymerase reaction. At the DNA polymerase level, these type of compounds interact as chain terminators (because their incorporation into DNA does not allow further chain elongation) or act as inhibitors of the HSV DNA polymerase. For example, ACVTP, the active form of ACV, which has a short intracellular half life of 0.7 h (Vere Hodge & Perkins, 1989), is an obligate chain termi
Antiviral activity of selected acyclic nucleoside analogues against human herpesvirus 6
Antiviral Research, 1995
Human herpesvirus 6 (HHV-6) was examined in vitro for its sensitivity to a broad range of nucleoside analogues, including acyclovir (ACV), ganciclovir (GCV), penciclovir (PCV), buciclovir (BCV), brivudin (BVDU), the NT-isomer of 6-deoxyganciclovir ($2242), foscarnet (phosphonoformic acid, PFA), and several acyclic nucleoside phosphonate (ANP) analogues such as (S)-HPMPA, (S)-HPMPC, PMEA and PMEDAP. Antiviral efficacy was monitored microscopically by the inhibitory effect of the compounds on HHV-6-induced cytopathic effect in human T-lymphoblastoid HSB-2 cells. In addition, a newly developed immunofluorescence/flow cytometric assay (FACS) was used to determine HHV-6-specific antigen expression. A close correlation was observed between the antiviral data obtained by the microscopic assay and the flow cytometric assay. Marked antiviral efficacy was noted for $2242, PFA and the ANP analogues (S)-HPMPA, (S)-HPMPC, (S)-cHPMPC, (S)-3-deaza-HPMPA, (S)-3-deaza-cHPMPA, (S)-HPMPG and (R)-HPMPG. Also, PMEA and PMEDAP proved highly active against HHV-6 infection, whereas (S)-FPMPA and (R)-PMPDAP were inactive. ACV was only slightly protective against HHV-6, and no activity was found for GCV, PCV, BCV and BVDU. Overall, the efficacy of the nucleoside analogues against HHV-6 appeared to correlate with their efficacy against human cytomegalovirus (HCMV).
Antimicrobial Agents and Chemotherapy, 1992
The metabolism and mode of action of penciclovir [9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; BRL 39123] were studied and compared with those of acyclovir. In uninfected MRC-5 cells, low concentrations of the triphosphates of penciclovir and acyclovir were occasionally just detectable, the limit of detection being about 1 pmol/10(6) cells. In contrast, in cells infected with either herpes simplex virus type 2 (HSV-2) or varicella-zoster virus (VZV), penciclovir was phosphorylated quickly to give high concentrations of the triphosphate ester. Following the removal of penciclovir from the culture medium, penciclovir-triphosphate remained trapped within the cells for a long time (half-lives, 20 and 7 h in HSV-2- and VZV-infected cells, respectively). In HSV-2-infected cells, acyclovir was phosphorylated to a lesser extent and the half-life of the triphosphate ester was only 1 h. We were unable to detect any phosphates of acyclovir in VZV-infected cells. (S)-Penciclovir-triphosphate i...