The human immunodeficiency virus (HIV) pandemic remains a significant problem, especially in developing nations where the social and economic impacts are severe. Until a cure or vaccine for the disease is found, a constant supply of new compounds to fill the drug development pipeline is a requirement, given the tendency for the virus to rapidly develop resistance to current therapies. Here we disclose our efforts to improve upon the efficacy of cyclopropyl-indole derivatives developed as NNRTIs in our laboratories. To this end, modifications to the functionality occupying the small Val179 pocket have resulted in nearly two orders of magnitude increase in potency.