Design, synthesis and anti-HIV evaluation of novel diarylnicotinamide derivatives (DANAs) targeting the entrance channel of the NNRTI binding pocket through structure-guided molecular hybridization

Eur J Med Chem. 2014 Nov 24:87:52-62. doi: 10.1016/j.ejmech.2014.09.054. Epub 2014 Sep 17.

Abstract

Through a structure-based molecular hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 μM. Among them, compound 6b11 (EC50 = 0.027 μM, SI > 12518) and 6b5 (EC50 = 0.029 μM, SI = 2471) were identified as the most potent inhibitors, which were more potent than the reference drugs nevirapine (EC50 = 0.31 μM) and delavirdine (EC50 = 0.66 μM). Some DANAs were also active at micromolar concentrations against the K103N + Y181C resistant mutant. Compound 6b11 exhibited the highest enzymatic inhibition activity (IC50 = 20 nM), which is equal to that of efavirenz (EC50 = 20 nM) and 31 times higher than that of nevirapine (EC50 = 0.62 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new DANAs have been discussed.

Keywords: DANAs; Drug design; Entrance channel; HIV-1; Molecular hybridization; NNRTIs.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology*
  • Catalytic Domain
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Niacinamide / chemistry*
  • Protein Conformation
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • Niacinamide
  • HIV Reverse Transcriptase