Design, Synthesis, and Biological Evaluation of Novel 3,5-Disubstituted-1,2,6-Thiadiazine-1,1-Dione Derivatives as HIV-1 NNRTIs.

On the basis of structural features, binding mode, and structure-activity relationship studies of two pyrimidine-derived non-nucleoside reverse-transcriptase inhibitors, DABOs, and diaryl pyrimidines, a novel class of 1,2,6-thiadiazine-1,1-dione derivatives were rationally designed using the strategies of bioisosterism and molecular hybridization, synthesized, and evaluated for their anti-HIV activity in MT4 cell cultures. Three compounds were found to have moderate activity against HIV-1 replication with EC50 values ranging from 23 to 32 μm. To further confirm the binding target, compound IIg was selected to conduct an HIV-1 reverse-transcriptase inhibitory assay. In addition, preliminary structure-activity relationship analysis among the newly synthesized compounds was discussed, and the binding mode of the active compound IIg was rationalized by molecular docking and physicochemical studies.