ABSTRACT The incidence of measles virus (MV) infection has been significantly reduced in many nations through extensive vaccination; however, the virus still causes significant morbidity and mortality in developing countries. Measles outbreaks also occur in some developed countries that have failed to maintain high vaccine coverage rates. While vaccination is essential in preventing the spread of measles, case management would greatly benefit from the use of therapeutic agents to lower morbidity. Thus, the development of new therapeutic strategies is desirable. We previously reported the generation of a panel of small-molecule MV entry inhibitors. Here we show that our initial lead compound, although providing proof of concept for our approach, has a short half-life (<16 h) under physiological conditions. In order to combine potent antiviral activity with increased compound stability, a targeted library of candidate molecules designed on the structural basis of the first lead has been synthesized and tested against MV. We have identified an improved lead with low toxicity and high stability (half-life ≫ 16 h) that prevents viral entry and hence infection. This compound shows high MV specificity and strong activity (50% inhibitory concentration = 0.6 to 3.0 μM, depending on the MV genotype) against a panel of wild-type MV strains representative of viruses that are currently endemic in the field.