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. Three different aspects of the scaffold were investigated: the effects of adding a linker between the carbocyclic and phenyl fragments, introduction of different substituents on the benzoyl residue and replacing the central carbocyclic ring with a benzyl group. Analogues of 20 ,30 -dideoxy-20 ,30 -didehydro-50 -nor-uridine, bearing 3,5-dichloro- or 3,5-dimethylbenzoyl groups, showed inhibitory activity against HIV-RT wild-type (IC50 5–10 mM) and mutants L100I (IC50 1.2–2.1 mM) and K103N (IC50 8–17 mM).