Malaria is responsible for over a million deaths annually. These result primarily from rampant infection of erythrocytes with the Apicomplexan parasite Plasmodium falciparum. With the goal of developing novel antimalarials, our laboratories have focused on the structure-based design of triclosan-derived inhibitors of the fatty acid biosynthesis enzyme P. falciparum enoyl acyl carrier protein reductase (PfENR). Six X-ray structures of inhibitors bound to the PfENR:NAD+ complex were solved and found to demonstrate active site flexibility that was critical to analog design. Synthetic efforts were streamlined by the development and implementation of an aqueous Suzuki-Miyaura method. The protocol is amenable to the arylation of bromophenols using inexpensive Pd/C as a catalyst, with a reaction time of 15 min in a microwave reactor or conventional oil bath. Many of the novel triclosan derivatives exhibit low micromolar potency against in vitro cultures of drug-resistant and drug-sensitive parasite strains and inhibit purified PfENR (IC50 values < 200 nM). The SAR demonstrates the ability to enhance the in vitro potency of triclosan significantly by replacement of the suboptimal 5-chloro substituent with larger hydrophobic moieties.