In the present study, we have designed and synthesized 16 novel 1,3-dioxoisoindole 4(a-p) derivatives as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors. Lipinski rule of five parameters and molecular parameters like drug likeness and drug scores were calculated for the designed analogs using online servers like Molinspiration and Osiris property explorer. Designed analogs were synthesized using a known synthetic protocol. Synthesized compounds were characterized using FT-IR 1H NMR Mass and Elemental analysis. The compounds were evaluated for their HIV-1 Reverse Transcriptase (RT) inhibitor activity by HIV-1 RNA dependent DNA polymerase activity assay at 2 and 20μM concentrations. Among the designed analogs, 4a, 4c, 4d, 4h, 4l, 4m and 4p showed weak Reverse Transcriptase inhibitory activity at 20μM concentration. For the designed compounds, there was no correlation observed between molecular modeling and in-vitro studies.