ABSTRACT
Several 2-anilino- and 2-benzylamino-3-deaza-6-oxopurines [3-deazaguanines] and selected 8-methyl and 8-aza analogs have been synthesized. 7-Substituted N(2)-(3-ethyl-4-methylphenyl)-3-deazaguanines were potent and selective inhibitors of Gram+ bacterial DNA polymerase (pol) IIIC, and 7-substituted N(2)-(3,4-dichlorobenzyl)-3-deazaguanines were potent inhibitors of both pol IIIC and pol IIIE from Gram+ bacteria, but weakly inhibited pol IIIE from Gram- bacteria. Potent enzyme inhibitors in both classes inhibited the growth of Gram+ bacteria (MICs 2.5-10µg/ml), and were inactive against the Gram- organism Escherichia coli. Several derivatives had moderate protective activity in Staphylococcus aureus-infected mice.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , DNA Polymerase III/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Guanine/analogs & derivatives , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , DNA Polymerase III/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Escherichia coli/drug effects , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/enzymology , Guanine/chemistry , Guanine/pharmacology , Guanine/therapeutic use , Mice , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapyABSTRACT
Herpes B virus (B virus [BV]) is a macaque herpesvirus that is occasionally transmitted to humans where it can cause rapidly ascending encephalitis that is often fatal. To understand the low susceptibility of BV to the acyclonucleosides, we have cloned, expressed, and characterized the BV thymidine kinase (TK), an enzyme that is expected to "activate" nucleoside analogs. This enzyme is similar in sequence and properties to the TK of herpes simplex virus (HSV), i.e., it has a broad substrate range and low enantioselectivity and is sensitive to inhibitors of HSV TKs. The BV enzyme phosphorylates some modified nucleosides and acyclonucleosides and l enantiomers of thymidine and related antiherpetic analogs. However, the potent anti-HSV drugs acyclovir (ACV), ganciclovir (GCV), and 5-bromovinyldeoxyuridine were poorly or not phosphorylated by the BV enzyme under the experimental conditions. The antiviral activities of a number of marketed antiherpes drugs and experimental compounds were compared against BV strains and, for comparison, HSV type 1 (HSV-1) in Vero cell cultures. For most compounds tested, BV was found to be about as sensitive as HSV-1 was. However, BV was less sensitive to ACV and GCV than HSV-1 was. The abilities of thymidine analogs and acyclonucleosides to inhibit replication of BV in Vero cell culture were not always proportional to their substrate properties for BV TK. Our studies characterize BV TK for the first time and suggest new lead compounds, e.g., 5-ethyldeoxyuridine and pencyclovir, which may be superior to ACV or GCV as treatment for this emerging infectious disease.
Subject(s)
Antiviral Agents , Herpesvirus 1, Cercopithecine/drug effects , Nucleosides , Thymidine Kinase/metabolism , Acyclovir/analogs & derivatives , Acyclovir/chemistry , Acyclovir/pharmacology , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Chlorocebus aethiops , Deoxyuridine/analogs & derivatives , Deoxyuridine/chemistry , Deoxyuridine/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Guanine , Herpesvirus 1, Cercopithecine/enzymology , Herpesvirus 1, Cercopithecine/genetics , Microbial Sensitivity Tests/methods , Molecular Sequence Data , Nucleosides/chemistry , Nucleosides/metabolism , Nucleosides/pharmacology , Phosphorylation , Substrate Specificity , Thymidine/analogs & derivatives , Thymidine/metabolism , Thymidine Kinase/antagonists & inhibitors , Thymidine Kinase/chemistry , Thymidine Kinase/genetics , Vero CellsABSTRACT
7-Substituted-N(2)-(3,4-dichlorobenzyl)guanines potently and competitively inhibit DNA polymerases IIIC and IIIE from Gram(+) bacteria. Certain derivatives are also competitive inhibitors of DNA polymerase IIIE from Gram(-) bacteria.
