ABSTRACT
A range of 2'-fluoro and 2',3'-difluoro analogues of pyrimidine deoxyribonucleosides have been synthesized and evaluated against human immunodeficiency virus (HIV-1) in a human lymphoblastoid cell line. Among these compounds, 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12), 2',3'-didehydro-2',3'-dideoxy-2'-fluorocytidine (35), 1-(2,3-dideoxy-2,3-difluoro-beta-D-arabinofuranosyl)cytosine (41), and 3'-deoxy-2',3'-didehydro-2'-fluorothymidine (45) were found to have significant antiviral activity, with IC50 values of 0.65, 10, 10, and 100 microM, respectively. The structure-activity relationships are discussed.
Subject(s)
Antiviral Agents/pharmacology , Deoxyribonucleosides/pharmacology , Fluorine , HIV-1/drug effects , Pyrimidine Nucleosides/pharmacology , Antiviral Agents/chemical synthesis , Cell Line , Cell Survival/drug effects , Chemical Phenomena , Chemistry , Deoxyribonucleosides/chemical synthesis , Dideoxynucleosides/chemical synthesis , Dideoxynucleosides/pharmacology , Humans , Lymphocytes/drug effects , Molecular Structure , Pyrimidine Nucleosides/chemical synthesis , Structure-Activity Relationship , Zalcitabine/analogs & derivatives , Zalcitabine/chemical synthesis , Zalcitabine/pharmacologyABSTRACT
The rational design and synthesis of nucleotide analogues as inhibitors of herpes simplex virus (HSV) thymidine kinase is described. Starting from thymidine, product analogues which included phosphates, phosphonates, sulphonates, sulphonamides and carboxamides were prepared. The carboxamide series showed good structure-activity relationships and afforded a lead structure which inhibited the HSV-2 enzyme in the low micromolar range. Replacing the 5-methyl group in thymidine by ethyl enhanced the potency of the lead structure 10-fold. Further optimization of the carboxamide moiety afforded inhibitors active in the sub-nanomolar range and finally the introduction of a 2'-beta-fluoro substituent improved the potency a further twofold. The low water solubility of the most potent inhibitor was overcome by conversion to the 3'-valyl ester, which had good oral bioavailability and showed activity by the oral route in murine models of infection.
Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Herpesvirus 1, Human/enzymology , Herpesvirus 2, Human/enzymology , Thymidine Kinase/antagonists & inhibitors , Animals , Cell Line , Cricetinae , Humans , Mass SpectrometryABSTRACT
A series of carboxamide derivatives of 5'-amino-2',5'-dideoxy-5-ethyluridine has been prepared as inhibitors of HSV-TK (herpes simplex virus thymidine kinase). The most potent compounds were derived from xanthene, thioxanthene and dihydroanthracene carboxylic acids. The lead compounds show subnanomolar IC(50) values against HSV TKs.