Enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) is an important target for antimalarial agents that interfere with the FAS-II pathway of lipid synthesis, which is specific for the parasite. Recent studies showed that substituted analogs of triclosan (TCL) inhibit the purified PfENR enzyme with IC(50) values below 200 nM when the suboptimal 5-chloro group was replaced by larger hydrophobic moieties. We have used computer-assisted combinatorial techniques to design, focus and in silico screen a virtual library of TCL analogs substituted at positions 5, 4' and 2'. Our study can thus direct synthetic chemists working on the antimalarial FAS-II inhibitors towards the explored subset of the chemical space, which is predicted to contain compounds with PfENR inhibition potencies in the low nanomolar range and favorable ADME properties.