title: Design, synthesis and biological evaluation of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives as HIV-1 NNRTIs.
abstract: A series of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives (PTTDs) was designed and synthesized by a facile route. The biological assay results showed that five most potent compounds displayed inhibitory activity against HIV-1 at low micromolar concentrations (EC50=5.1-8.9 μM). Structure-activity relationship analysis indicated that N2-(3-halogenated-benzyl) analogues were more potent than N2-(unsubstituted-benzyl) analogues. The N4-substitutions contributed to the antiviral activity in the following order: 2-/3-cyano substituted benzyl > 2-/3-halogenated benzyl > non-substituted benzyl > 4-halogenated benzyl. Docking studies of the representative compound revealed the binding conformation of these compounds and provided critical insights for the further development of PTTD analogues.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44, West Culture Road, 250012 Jinan, Shandong, PR China.
authors.forename: Wenmin
authors.initials: W
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011758:Pyrroles; D018894:Reverse Transcriptase Inhibitors; D014227:Triazines; D054303:HIV Reverse Transcriptase
keywords: Drug design; HIV; Heterocycle; NNRTIs; Pyrrolothiatriazine; Reverse transcriptase; Thienothiadiazine