title: Inhibitory activity of 9-phenylcyclohepta[d]pyrimidinedione derivatives against different strains of HIV-1 as non-nucleoside reverse transcriptase inhibitors.
abstract: BACKGROUND
  The non-nucleoside reverse transcriptase inhibitor (NNRTI), as a major component of the highly active antiretroviral therapy (HAART) to HIV-1 (human immunodeficiency virus type 1) infected patients, required the development of new NNRTIs with improved resistance profile and decreased toxicity. Therefore, a series of novel compounds, 9-phenylcyclohepta[d]pyrimidinedione derivatives (PCPs), were designed based on the chemical structure of TNK-651, to detect anti-HIV-1 activity.
  
  
  RESULTS
  1-[(benzyloxy)methyl]-9-phenyl-cyclohepta[d] pyrimidinedione (BmPCP) among four PCPs has antiviral activity on laboratory-adapted HIV strains (HIV-1 SF33). The results showed 50% inhibition concentrations (IC50s) of BmPCP were 0.34 μM, 1.72 μM and 1.96 μM on TZM-bl, peripheral blood mononuclear cells (PBMCs) and MT4, respectively. It was also effective against infection by the predominant HIV-1 isolates in China, with IC50s at low μM levels. Its selectivity index (SI) ranged from 67 to 266 in different cells. The results of time-of-addition assay demonstrated that BmPCP inhibited HIV-1 infection by targeting the post entry of the HIV-1 replication cycle. For inhibition of HIV-1 reverse transcriptase activity, the IC50 values of BmPCP and NVP were 1.51 and 3.67 μM, respectively.
  
  
  CONCLUSIONS
  BmPCP with a novel structure acts as a NNRTI to inhibit HIV-1 replication and can serve as a lead compound for further development of new anti-HIV-1 drugs.
authors.affiliation: State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Chinese Center for Disease Control and Prevention (CDC), China. yshao@bbn.cn
authors.forename: Yang
authors.initials: Y
authors.lastname: Huang
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.forename: Weisi
authors.initials: W
authors.lastname: Xu
authors.forename: Tiejun
authors.initials: T
authors.lastname: Liu
authors.forename: Junyi
authors.initials: J
authors.lastname: Liu
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
authors.forename: Liying
authors.initials: L
authors.lastname: Ma
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003508:Cycloheptanes / Q000737:chemistry / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: C523060:9-phenylcyclohepta(d)pyrimidine-2,4-dione; D019380:Anti-HIV Agents; D003508:Cycloheptanes; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase