Abstract Antiretroviral therapy (ART) for HIV/AIDS is effective in the clinical treatment of HIV-1 infections. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a class of anti-retrovirals playing a major role in the success of ART. However, the emergence of drug resistant viruses has limited the usefulness of the NNRTIs in many patients. Thus, new NNRTIs are needed to overcome current NNRTI resistant HIV strains. The goal of this study is to identify new NNRTIs effective for drug resistant viruses. We have previously discovered two classes of NNRTIs, diarylanilines (DAANs) and diarylpyridinamines (DAPAs), which are structurally different from the approved diarylpyrimidine (DAPY)-type drugs etravirine and rilpivirine. Each of the chemical classes can fully overcome some prevalent NNRTI resistant mutations. However, none of them was effective for all the prevalent NNRTI resistant HIV-1 variants. To fully overcome the NNRTI resistance, we have identified the key structural features from each of the chemical classes that are required for effectiveness against drug resistant viruses. We hypothesize that a compound with structural features effective for drug resistant viruses can be synthesized and will be effective for viruses resistant to current NNRTIs. To test our hypothesis and to accomplish our goal, we propose to carry out the following two Specific Aims. Aim 1 is to design and synthesize new diarylaniline (DAAN) and diarylpyridinamine (DAPA) derivatives to overcome HIV-1 variants resistant to NNRTIs. This aim will be achieved by designing new NNRTIs that include favorable structural features for overcoming drug resistance selected from DAANs/DAPAs. Aim 2 is to establish the pharmacological profiles of the new NNRTIs effective against drug resistant HIV-1. The pharmacological study is aimed at establishing basic/initial pharmacological profiles to pave the way for future more comprehensive drug-target interaction studies and clinical drug development. Achieving this aim will provide the essential information to advance the compounds for further preclinical drug development to mitigate NNRTI resistance. Our chemical synthesis will be supported by conventional medicinal chemistry and modern molecular modeling. The lead optimization will be guided by well- established primary and secondary biological testing against wild-type and NNRTI resistant virus, respectively. The research team is positioned uniquely to conduct this endeavor based on over two decades of anti-HIV research. With confirmed promising leads already on-hand, coupled with the availability of established bioassay systems, we feel confident that we can discover and develop new NNRTIs to overcome the prevalent NNRTI resistant viruses.