A new series of potential nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) based on the carbocyclic 50 -nor-uracil scaffold were designed and synthesized. Binding modes in the active site of the enzyme were studied computationally to provide insight on potential interactions. Several of the 20 ,30 dideoxy-20 ,30 -didehydro-50 -nor-uridine analogues showed inhibitory activity against wild-type and mutant (L100I) HIV-RT with Ki 13–18 mM and 1–11 mM, respectively.