Synthesis, biological evaluation and in silico modeling of novel integrase strand transfer inhibitors (INSTIs)

Eur J Med Chem. 2020 Mar 1:189:112064. doi: 10.1016/j.ejmech.2020.112064. Epub 2020 Jan 13.


Although a relatively wide range of therapeutic options is currently available for the treatment of HIV/AIDS, it is still among the most serious and virulent diseases and is associated with a high mortality rate. Integrase strand transfer inhibitors (INSTIs), e.g., FDA-approved dolutegravir (DTG), bictegravir (BIC) and cabotegravir (CAB), have recently been included in standard highly active antiretroviral therapy (HAART) schemes as one of the five major components responsible for the most beneficial clinical outcome. In this paper, we describe a combinatorial amide synthesis, biological evaluation and in silico modeling of new INSTIs containing heteroaromatic bioisosteric substitution instead of the well-studied halogen-substituted benzyl fragment. With the focus on the mentioned diversity point, a medium-sized library of compounds was selected for synthesis. A biological study revealed that many molecules were highly active INSTIs (EC50 < 10 nM). Two compounds 1{4} and 1{26} demonstrated picomolar antiviral activity that was comparable with CAB and were more active than DTG and BIC. Molecular docking study was performed to evaluate the binding mode of compounds in the active site of HIV-1 IN. In rats, lead compound 1{26} showed two-fold greater bioavailability than CAB and had a similar half-life. Compound 1{26} and its sodium salt were considerably more soluble in water than the parent drugs. Both molecules were very stable in human liver microsomes and plasma, demonstrated high affinity towards plasma proteins and did not show cytochrome (CYP) inhibition. This benefit profile indicates the great potential of these molecules as attractive candidates for subsequent evaluation as oral long-acting drugs and long-acting nanosuspension formulations for intramuscular injection.

Keywords: Cabotegravir analogs; Combinatorial synthesis; HIV; HIV-1 integrase; In silico modeling; Medicinal chemistry.

MeSH terms

  • Animals
  • Computer Simulation*
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV Integrase / chemistry*
  • HIV Integrase Inhibitors / chemical synthesis*
  • HIV Integrase Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • Humans
  • Male
  • Models, Molecular*
  • Molecular Docking Simulation
  • Mutation
  • Oxazoles / chemical synthesis*
  • Oxazoles / pharmacology*
  • Pyridones / chemical synthesis*
  • Pyridones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Virus Replication


  • HIV Integrase Inhibitors
  • Oxazoles
  • Pyridones
  • HIV Integrase
  • cabotegravir