Indolylarylsulfones bearing phenylboronic acid and phenylboronate ester functionalities as potent HIV‑1 non-nucleoside reverse transcriptase inhibitors

Bioorg Med Chem. 2022 Jan 1:53:116531. doi: 10.1016/j.bmc.2021.116531. Epub 2021 Dec 3.

Abstract

To explore the chemical space around the entrance channel of the HIV-1 reverse transcriptase (RT) binding pocket, we innovatively designed and synthesized a series of novel indolylarylsulfones (IASs) bearing phenylboronic acid and phenylboronate ester functionalities at the indole-2-carboxamide as new HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) through structure-based drug design. All the newly synthesized compounds exhibited excellent to moderate potency against wild-type (WT) HIV-1 with EC50 values ranging from 6.7 to 42.6 nM. Among all, (3-ethylphenyl)boronic acid substituted indole-2-carboxamide and (4-ethylphenyl) boronate ester substituted indole-2-carboxamide were found to be the most potent inhibitors (EC50 = 8.5 nM, SI = 3310; EC50 = 6.7 nM, SI = 3549, respectively). Notably, (3-ethylphenyl)boronic acid substituted indole-2-carboxamide maintained excellent activities against the single HIV-1 mutants L100I (EC50 = 7.3 nM), K103N (EC50 = 9.2 nM), as well as the double mutant V106A/F227L (EC50 = 21.1 nM). Preliminary SARs and molecular modelling studies are also discussed in detail.

Keywords: Boronic acid; HIV-1; Indole-2-carboxamide; NNRTIs; SARs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Boronic Acids / chemistry
  • Boronic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Esters / chemistry
  • Esters / pharmacology*
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • HIV-1 / enzymology
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Solubility
  • Structure-Activity Relationship
  • Sulfones / chemistry
  • Sulfones / pharmacology*
  • Water / chemistry

Substances

  • Anti-HIV Agents
  • Boronic Acids
  • Esters
  • Indoles
  • Reverse Transcriptase Inhibitors
  • Sulfones
  • Water
  • indole
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • benzeneboronic acid