Scaffold hopping and optimisation of 3',4'-dihydroxyphenyl- containing thienopyrimidinones: synthesis of quinazolinone derivatives as novel allosteric inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H

J Enzyme Inhib Med Chem. 2020 Dec;35(1):1953-1963. doi: 10.1080/14756366.2020.1835884.

Abstract

Bioisosteric replacement and scaffold hopping are powerful strategies in drug design useful for rationally modifying a hit compound towards novel lead therapeutic agents. Recently, we reported a series of thienopyrimidinones that compromise dynamics at the p66/p51 HIV-1 reverse transcriptase (RT)-associated Ribonuclease H (RNase H) dimer interface, thereby allosterically interrupting catalysis by altering the active site geometry. Although they exhibited good submicromolar activity, the isosteric replacement of the thiophene ring, a potential toxicophore, is warranted. Thus, in this article, the most active 2-(3,4-dihydroxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one 1 was selected as the hit scaffold and several isosteric substitutions of the thiophene ring were performed. A novel series of highly active RNase H allosteric quinazolinone inhibitors was thus obtained. To determine their target selectivity, they were tested against RT-associated RNA-dependent DNA polymerase (RDDP) and integrase (IN). Interestingly, none of the compounds were particularly active on (RDDP) but many displayed micromolar to submicromolar activity against IN.

Keywords: Bioisosters; HIV-1 virus; RNase H; RNase H allosteric inhibitors; integrase.

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Catalytic Domain
  • Drug Design
  • HIV Reverse Transcriptase / metabolism*
  • Humans
  • Models, Molecular
  • Protein Binding
  • Protein Multimerization
  • Pyrimidinones / chemistry*
  • Quinazolinones / chemical synthesis*
  • Quinazolinones / pharmacology
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thiophenes / chemistry

Substances

  • Anti-HIV Agents
  • Pyrimidinones
  • Quinazolinones
  • Reverse Transcriptase Inhibitors
  • Thiophenes
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • Ribonuclease H, Human Immunodeficiency Virus

Grants and funding

A.C. research was funded by the Sardinian Regional Government grant LR07/17 [F76C18000800002]. SFJLG and JAB were supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.