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This paper reports the synthesis and the antiviral activities of a series of 6-arylmethyl-1-(allyloxymethyl)-5-alkyluracil derivatives, which can be viewed as analogues of the anti-HIV-1 drug emivirine (formerly MKC-442) from which they differ in the replacement of the ethoxymethyl group with variously allyloxymethyl moieties. The most active compounds N-1 allyloxymethyl- and N-1 3-methylbut-2-enyl substituted 5-ethyl-6-(3,5-dimethylbenzyl)uracils (12 and 13) showed activity against HIV-1 wild-type in the picomolar range with selective index of greater than 5 x 10(6) and activity in the submicromolar range against the clinically important Y181C and K103N mutant strains known to be resistant to emivirine. Structure-activity relationship studies established a correlation between the anti-HIV-1 activity and the substitution pattern of the N-1 allyloxymethyl group.

Background: Since 1985, donors of organs or tissues for transplantation in the United States have been screened for human immunodeficiency virus type 1 (HIV-1), and more than 60,000 organs and 1 million tissues have been transplanted. We describe a case of transmission of HIV-1 by transplantation of organs and tissues procured between the time the donor became infected and the appearance of antibodies. The donor was a 22-year-old man who died 32 hours after a gunshot wound; he had no known risk factors for HIV-1 infection and was seronegative., Methods: We reviewed the processing and distribution of all the transplanted organs and tissues, reviewed the medical histories of the donor and HIV-1-infected recipients, tested stored donor lymphocytes for HIV-1 by viral culture and the polymerase chain reaction, and tested stored serum samples from four organ recipients for HIV-1 antigen and antibody., Results: HIV-1 was detected in cultured lymphocytes from the donor. Of 58 tissues and organs obtained from the donor, 52 could be accounted for by the hospitals that received them. Of the 48 identified recipients, 41 were tested for HIV-1 antibody. All four recipients of organs and all three recipients of unprocessed fresh-frozen bone were infected with HIV-1. However, 34 recipients of other tissues--2 receiving corneas, 3 receiving lyophilized soft tissue, 25 receiving ethanol-treated bone, 3 receiving dura mater treated with gamma radiation, and 1 receiving marrow-evacuated, fresh-frozen bone--tested negative for HIV-1 antibody. Despite immunosuppressive chemotherapy, HIV-1 antibody appeared between 26 and 54 days after transplantation in the three organ recipients who survived more than four weeks., Conclusions: Although rare, transmission of HIV-1 by seronegative organ and tissue donors can occur. Improvements in the methods used to screen donors for HIV-1, advances in techniques of virus inactivation, prompt reporting of HIV infection in recipients, and accurate accounting of distributed allografts would help to reduce further this already exceedingly low risk.