3-Aminobenzenesulfonamides incorporating acylthiourea moieties selectively inhibit the tumor-associated carbonic anhydrase isoform IX over the off-target isoforms I, II and IV

Bioorg Chem. 2019 Feb:82:123-128. doi: 10.1016/j.bioorg.2018.10.006. Epub 2018 Oct 4.

Abstract

We describe the synthesis of a series of novel 1-aroyl/acyl-3-(3-aminosulfonylphenyl) thioureas (4a-k) acting as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. Reaction of alkyl/aryl isothiocyanates with 3-aminobenzenesulfonamide afforded a series of the title compounds incorporating a variety of short as well as highly lipophilic long tails. The newly synthesized sulfonamides were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IV, and IX). Several compounds showed interesting inhibitory activity. The tumor-associated hCA IX was the most sensitive isoform to inhibition with these compounds, with KIs in the range of 21.5-44.0 nM and selectivity ratios over the major cytosolic isoform hCA II in the range of 3.35-37.3. The sulfonamides incorporating the phenylacetylthioureido and pentadecanoylthioureido moieties were the most hCA IX-selective inhibitors detected in this work, making them of interest for further investigations.

Keywords: 3-Aminobenzenesulfonamide; Acyl-thioureas; Carbonic anhydrase; Inhibitors; Isothiocyanates; Thioureas.

MeSH terms

  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / chemistry*
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Humans
  • Isoenzymes / chemical synthesis
  • Isoenzymes / chemistry
  • Molecular Structure
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Thiourea / analogs & derivatives*
  • Thiourea / chemical synthesis

Substances

  • Aniline Compounds
  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Sulfonamides
  • Thiourea