Structure-activity relationships of pyrimidine nucleosides as antiviral agents for human immunodeficiency virus type 1 in peripheral blood mononuclear cells

Abstract

The structure-activity relationships of several pyrimidine nucleosides related to 3''-azido-3''-deoxythymidine (AZT) were determined in human immunodeficiency virus type 1 (HIV-1) infected human peripheral blood mononuclear cells. These studies indicated that nucleosides with a 3''-azide group on the sugar ring exhibited the most potent antiviral activity. Substitution at C-5 with H, CH3, and Cl2H5 produced derivatives with the highest potency, whereas alkyl functions greater than C2, including bromovinyl substitution reduced the antiviral potency significantly. Changing the 3''-azido function to an amino or iodo gropu reduced the antiviral activity. Replacement of the uracil ring by cytosine or 5-methylcytosine produced analogues with high potency and low toxicity. Modification of the 5''-hydroxy group markedly reduced the antiviral activity. Similarly, various C-nucleoside analogues related to AZT and 2'',3''-dideoxycytidine were inactive and nontoxic. From these systematic studies 3''-azido-2'',3''-dideoxyuridine (5a), 3''-azido-5-ethyl-2'',3''-dideoxyuridine (5c), and 3''-azido-2-,3''-dideoxycytidine (7a) and its 5-methyl analogue (7b) were identified as potent and selective anti-HIV-1 agent in primary human lymphocytes.