We have identified acridinyl derivatives as potent aspartic protease inhibitors by virtual screening of in-house library of synthetic compounds. Enzyme inhibition experiments showed that both compounds inhibit human cathepsin D and Plasmodium falciparum plasmepsin-II in nanomolar ranges. The IC(50) values against cathepsin D and plasmepsin-II of compound-Nar103 were found to be 9.0+/-2.0 and 4.0+/-1.0nM and of compound-Nar110 were 0.5+/-0.05 and 0.13+/-0.03nM, respectively. Ligand docking predicted the binding of acridinyl derivatives at the substrate-binding cleft, where hydrazide part of the inhibitors interact with the S1-S1' subsite residues including catalytic aspartates. The phenyl ring and acridinyl moiety of the inhibitors were predicted to interact with S2/S3 and S2'/S3' subsite residues.