title: Design, synthesis, and biological evaluation of novel 3,5-disubstituted-1,2,6-thiadiazine-1,1-dione derivatives as HIV-1 NNRTIs.
abstract: 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.
authors: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Educational Ministry of China), School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhuaxi Road, Jinan, 250012, China.
authors: Ye
authors: Y
authors: Tian
authors: Diwakar
authors: D
authors: Rai
authors: Peng
authors: P
authors: Zhan
authors: Christophe
authors: C
authors: Pannecouque
authors: Jan
authors: J
authors: Balzarini
authors: Erik
authors: E
authors: De Clercq
authors: Huiqing
authors: H
authors: Liu
authors: Xinyong
authors: X
authors: Liu
mesh_terms: D002460:Cell Line; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013829:Thiadiazines / Q000494:pharmacology*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D013829:Thiadiazines
keywords: 1,2,6-thiadiazine-1,1-dione; HIV-1; activity assay; non-nucleoside reverse-transcriptase inhibitors; reverse-transcriptase; synthesis