A series of malaria plasmepsin (Plm) I and II inhibitors contg. a C2-sym. core structure have been synthesized and tested for protease inhibition activity. These compds. can be prepd. using a straightforward synthesis involving a phenol nucleophilic ring opening of a diepoxide. Exemplar compds. synthesized exhibited remarkable inhibitory activity against both Plm I and II, notably 15c with Ki values of 2.7 nM and 0.25 nM resp., as well as showing >100-fold selectivity against Cathepsin D. [on SciFinder (R)]