MOLECULAR SIMULATION OF 5,6-SUBSTITUTED 1-[(2-HYDROXYETHOXY)METHYL]URACILS WITH ANTI-HIV-1 ACTIVITY

The dioxypyrimidine ring of 5,6-substituted 1-[(2-hydroxyethoxy)methyl ]uracils is an extended 'partial pi system' with ring distortion. PM3- MM+ geometry optimization suggested a lipophilic 'butterfly-like' orie ntation which was also found in other non-nucleoside inhibitors that i nteract with the HIV-1 reverse transcriptase. Multivariate QSAR has sh own that discrimination between the antiviral response and undesired c ytotoxicity is possible. Related to the C-6 thiophenyl ring substituen ts and to modifications at the C-5 position, the antiviral response de pends on hydrogen-bonding forces, steric parameters, and electronic pr operties. The cytotoxicity depends on the lipophilicity and steric par ameters.