Synthesis, biological evaluation and molecular docking study of N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide derivatives as potent HIV-1 Vif antagonists

Eur J Med Chem. 2017 Mar 31:129:310-324. doi: 10.1016/j.ejmech.2017.01.010. Epub 2017 Jan 12.

Abstract

Viral infectivity factor (Vif) is protective against APOBEC3G (A3G)-mediated viral cDNA hypermutations, and development of molecules that inhibit Vif mediated A3G degradation is a novel strategy for blocking HIV-1 replication. Through optimizations of the central ring of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), we found a potent compound 12c with EC50 value of 1.54 μM, enhancing the antiviral activity more than 150-fold compared with RN-18 in nonpermissive H9 cells. 12c protected A3G from degradation by inhibiting Vif function. Besides, 12c suppressed different HIV-1 clinical strains (HIV-1KM018, HIV-1TC-1 and HIV-1WAN) and drug-resistant strains (NRTI, NNRTI, PI, and FI) with relatively high activities. Amidation of 12c with glycine gave a prodrug 13a, improving the water solubility about 2600-fold compared with 12c. Moreover, 13a inhibited the virus replication efficiently with an EC50 value of 0.228 μM. These results suggested that the prodrug 13a is a promising candidate agent for the treatment of AIDS.

Keywords: Antiviral activity; Nonpermissive; Vif antagonists; Vif mediated A3G degradation.

MeSH terms

  • APOBEC-3G Deaminase / metabolism
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Benzamides / chemical synthesis
  • Benzamides / pharmacology*
  • Cell Line
  • Drug Resistance, Viral
  • Humans
  • Molecular Docking Simulation
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacokinetics
  • Virus Replication / drug effects
  • vif Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*

Substances

  • Anti-HIV Agents
  • Benzamides
  • Prodrugs
  • vif Gene Products, Human Immunodeficiency Virus
  • vif protein, Human immunodeficiency virus 1
  • APOBEC-3G Deaminase