Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents

A study of the structure-activity relationship of a series of newly synthesized phosphonylmethoxyalkyl purine and pyrimidine derivatives revealed that several adenine derivatives substituted at the N9 position by a 2-phosphonylmethoxyethyl (PME) group inhibited human immunodeficiency virus (HIV)-induced cytopathogenicity and HIV antigen expression in vitro at concentrations significantly below the toxicity threshold for the host cells. In terms of anti-HIV potency in MT-4 cells, the PME 2,6-diaminopurine derivative (50% effective dose ED50], 1 microM) ranked first, followed by the PME adenine derivative (ED50, 2 microM MT-4]) and the PME 2-monoaminopurine derivative (ED50, 45 microM). Antiretroviral activity was also demonstrated in ATH8 and H9 cells, which were de novo infected with HIV, and extended to C3H mouse fibroblasts infected with Moloney murine sarcoma virus. Unlike 2',3'-dideoxyadenosine, these compounds were not found to be degraded by deaminases derived from bovine intestine.