In an effort to obtain more insight into the interaction between HIV-1 reverse transcriptase (RT) and MKC-442 analogues, a new series of compounds was synthesized and evaluated for inhibition of HIV-1 replication. The modifications include bulky alkenyl substituents at the C-5 position of the uracil ring. Analogues with reactive centers (aldehyde and epoxide functionalities) at C-5 were also synthesized in an attempt to develop HIV drugs with improved activity against the Y181C mutants by forming a covalent bond to the mercapto group in cysteine in the hydrophobic pocket of the mutated RT. Difficulties in the syntheses show that the epoxides are chemically reactive, whereas the aldehydes are more stable. One of the alkenyl analogues showed activity against HIV-1 in the same range as MKC-442, whereas the reactive analogues were not active against HIV with the mutation Y181C in RT.