The Plasmodium falciparum cysteine proteases, falcipains, have been established as novel targets for antimalarial drug design. Using the de novo design approach, several trisubstituted thiazole analogs were generated as potential inhibitors of these enzymes. A general and convenient synthetic approach for these novel trisubstituted thiazoles is reported here. Substituents at the 4th and 5th positions of the target thiazoles were introduced by a Hantzsch reaction, and the chain at the second position was extended through a Sandmeyer reaction, formylation, and Wittig olefination. In vitro enzyme inhibition studies have identified three inhibitors (14, 16, 23) of the falcipains with one (14) showing dual activity against both falcipain-2 and falcipain-3 and IC50 values of 6.6 and 29.4 μM, respectively.