ABSTRACT
A new series of imidazothiadiazine dioxides, including the first acyclonucleosides derived from this heterocycle moiety, has been synthesized. A wide-spectrum antiviral screening was performed. Some of the N-1 benzyl imidazothiadiazines and the new acyclonucleosides showed interesting anti-CMV or anti-HIV activity. These structures could be considered as new lead compounds for antiviral drug research.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Thiadiazines/chemical synthesis , Thiadiazines/pharmacology , Antiviral Agents/chemistry , Cell Line , Cell Survival/drug effects , Humans , Microbial Sensitivity Tests , Molecular Structure , Thiadiazines/chemistryABSTRACT
The first acyclonucleosides based on the benzothiadiazine dioxide system were synthesized following the silylation procedure. Several acyclic moieties, including acetoxyethoxymethyl, benzyloxymethyl, and propargyloxymethyl groups, were introduced. Two synthetic strategies were designed to selectively obtain the N-1 or N-3 derivatives. Lipase-mediated deacylation was used for the deprotection of the acyclonucleosides. Some of the benzothiadiazine dioxide acyclonucleosides, in particular 16, proved active against human cytomegalovirus (CMV) at concentrations slightly higher than that found for ganciclovir [50% inhibitory concentration (IC50) = 3. 5-3.7 micrograms/mL, cytotoxicity (CC50) >/= 40 micrograms/mL, MCC = 20 micrograms/mL]. Additionally, compound 16 inhibited the replication of human immunodeficiency virus type 1 (HIV-1) and HIV-2 in CEM cells at concentrations that were 5-fold lower than its cytotoxic concentration.
Subject(s)
Antiviral Agents/chemical synthesis , Benzothiadiazines/chemical synthesis , Cyclic S-Oxides/chemical synthesis , Cytomegalovirus/drug effects , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzothiadiazines/chemistry , Benzothiadiazines/pharmacology , Cell Line , Cyclic S-Oxides/chemistry , Cyclic S-Oxides/pharmacology , HIV-1/drug effects , HIV-2/drug effects , Humans , Inhibitory Concentration 50 , Models, Molecular , Structure-Activity Relationship , Virus ReplicationABSTRACT
New acyclonucleosides derived from 1,2,6-thiadiazine dioxide systems have been synthesized. Lipase-mediated deacylation procedure was used to obtain the deprotected derivatives. All the newly prepared compounds were tested as antiviral agents, but none of them showed significant activity.
