ABSTRACT
ÐBSTRACTEsters of the antiherpetic drugs ganciclovir, penciclovir with the bile acids (cholic, chenodeoxycholic and deoxycholic) and amino acid esters of acyclovir were generated and evaluated for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The antiviral assays demonstrated that modified analogs of ACV and PCV are less active compared to the initial substances against HSV-1and HSV-2. CC50 for ganciclovir-deoxycholate corresponded to the CC50 of the other analogs and its activity is lower than ganciclovir. Obtained results show that tested modification do not improve bioavailability of nucleoside analogs in cells.
Subject(s)
Acyclovir/pharmacology , Antiviral Agents/pharmacology , Ganciclovir/pharmacology , Guanine/pharmacology , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Acyclovir/chemical synthesis , Acyclovir/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cattle , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Ganciclovir/chemical synthesis , Ganciclovir/chemistry , Guanine/chemical synthesis , Guanine/chemistry , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
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 HSV-2. ACV-chenodeoxycholate presented a six-fold higher antiviral activity against HSV-2 with respect to ACV. Concerning EBV, the highest antiviral effect was demonstrated by ACV-chenodeoxycholate. Human plasma stability assays revealed that ACV-deoxycholate was more stable than the other two prodrugs. These results suggest that decorating the core structure of ACV with bile acids could deliver prodrugs with amplified antiviral activity.
