A novel series of substituted 2-Amino-4,6-diarylpyrimidines (DAPY’s)as Non-nucleoside reverse transcriptase inhibitors (NNRTIs) were designed, synthesized and evaluated for in vitro reverse transcriptase (RT) inhibition activity. Out of the reported compounds, 4a, 4i, 4j and 4n showed potent anti-HIV activity as compared to standard rilpivirine. The other compounds displayed moderate activity against HIV-1. Binding affinities of the designed NCEs were studied on reverse transcriptase enzyme using docking studies and showed possible horseshoe conformation as required for the DAPY category of RT inhibitors. A correlation was found between the anti-HIV activity and the electrostatic energy interaction with Lys 101 residue.