In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8(S) , 11(S) , and 12(S) showed anti-HIV-1 activity with a 50% inhibitory concentration (IC(50) ) = 123.8 µM (selectivity index, SI > 3), IC(50)  = 12.1 µM (SI > 29), IC(50)  = 17.4 µM (SI > 19), respectively. Enantiomers 8(R) , 11(R) , and 12(R) were inactive against the HIV-1 strain III(B) . Hydrazones 8(S) , 11(S) , and 12(S) which were active against HIV-1 wild type showed no inhibition against a double mutant NNRTI-resistant strain (K103N;Y181C). Molecular docking calculations of R- and S-enantiomers of 8, 11, and 12 were performed using the hydrazone-bound novel site of HIV-1 RT.