[Study of the specific toxic effects of the substance 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil, the original non-nucleoside inhibitor of human immunodeficiency virus type 1 (Retroviridae; Orthoretrovirinae; Lentivirus: Human immunodeficiency virus 1) reverse transcriptase]

Vopr Virusol. 2021 Sep 18;66(4):279-288. doi: 10.36233/0507-4088-59.
[Article in Russian]

Abstract

Introduction: Combination antiretroviral therapy is currently the main component of treatment for human immunodeficiency virus (HIV) infected patients. At the same time, the high mutational potential of the virus and the frequency of side effects of existing drugs dictate the need for the development and preclinical study of new, more effective and safer compounds.The aim of the study is to evaluate the specific types of toxicity of a new non-nucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RNA-dependent DNA revertase) (NNRTI) based on the substance 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil, a benzophenone derivative.

Material and methods: The study investigated reproductive toxicity, embryotoxicity, immunotoxicity, genotoxic (in micronucleus test in and comet assay) and allergenic properties of the test itemcompound. It was tested on three species of animals in two doses: the estimated therapeutic dose (1 TD) and its tenfold equivalent (10 TD). Taking into account the metabolic coefficients, the doses for rats (Rattus) were 9 and 90 mg/kg, for mice (Mus musculus), 21 and 210 mg/kg, and for guinea pigs (Cavia porcellus), 8 and 80 mg/kg, respectively.

Results and discussion: According to the obtained results, a favorable safety profile of the tested compound was established. Negative effects on the immune system, reproductive function, the body of pregnant animals and the fetus were not observed, as well as the compound did not have genotoxic and allergenic properties.

Conclusion: These data allows to consider the studied compound as a promising therapeutic candidate for the treatment of HIV-1 infection.

MeSH terms

  • Animals
  • Anti-HIV Agents* / therapeutic use
  • Anti-HIV Agents* / toxicity
  • Guinea Pigs
  • HIV Infections* / drug therapy
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / pharmacology
  • HIV Reverse Transcriptase / therapeutic use
  • HIV-1* / genetics
  • Humans
  • Lentivirus
  • Mice
  • RNA-Directed DNA Polymerase / pharmacology
  • RNA-Directed DNA Polymerase / therapeutic use
  • Rats
  • Retroviridae
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Reverse Transcriptase Inhibitors / toxicity
  • Uracil / analogs & derivatives

Substances

  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • Uracil
  • 6-methyluracil
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase