We designed several reverse transcriptase inhibitors (RT) using our novel model of the non-nucleoside inhibitor binding pocket of HIV RT which combines high resolution crystal structure information from 9 NNRTI-RT complexes. We hypothesize that our binding pocket model can be used to design potent NNRTI inhibitors of RT and to predict how well they will bind to RT. Our SPECIFIC AIM 1 is to design and synthesize phenethylthiazolylthiourea derivatives containing alkoxy-substituted phenyl groups or halo-substituted phenyl groups for the inhibition of HIV reverse transcriptase. Under SPECIFIC AIM 2, we will evaluate the in vitro anti-HIV activity of novel phenethyl-thiazolylthiourea derivatives. Under SPECIFIC AIM 3, we will attempt to improve the composite binding pocket model of RT based on RT inhibition data obtained from compounds designed using the composite model. The successful completion of the proposed studies may provide the foundation for an effective salvage treatment program for multidrug resistant AIDS patients.