Molecular design, synthesis and biological evaluation of BP-O-DAPY and O-DAPY derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors

Eur J Med Chem. 2013 Jul:65:134-43. doi: 10.1016/j.ejmech.2013.04.052. Epub 2013 May 3.


This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation.

Keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide; 50% cell culture infectious dose; 50% cytotoxic concentration; 50% effective concentration; 50% inhibitory concentration; AZT; Antiviral activity; BPs; Benzophenone; CC(50); CCID(50); DAPYs; DLV; Diarylpyrimidine; EC(50); EFV; ESI; HIV-1; HIV-1 RT; Human immunodeficiency virus type 1 reverse transcriptase; IC(50); K(d); MTT; Molecular hybridization; NNIBP; NNRTIs; NVP; OD; SI; TMC125; TMC278; TMS; USFDA; United States Food and Drug Administration; benzophenone derivatives; delavirdine; diarylpyrimidine derivatives; dissociation constant; efavirenz; electrospray ionization; etravirine; nevirapine; non-nucleoside RT inhibitors; non-nucleoside inhibitor binding pocket; non-nucleoside reverse transcriptase inhibitors; optical density; rilpivirine; selectivity index; tetramethylsilane; wild-type; wt; zidovudine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Benzophenones / chemical synthesis
  • Benzophenones / chemistry
  • Benzophenones / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • HIV-2 / drug effects
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship


  • Anti-HIV Agents
  • Benzophenones
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • benzophenone
  • HIV Reverse Transcriptase
  • pyrimidine