Taurultams incorporating arylsulfonamide: First in vitro inhibition studies of α-, β- and γ-class Carbonic Anhydrases from Vibrio cholerae and Burkholderia pseudomallei

Eur J Med Chem. 2021 Jul 5:219:113444. doi: 10.1016/j.ejmech.2021.113444. Epub 2021 Apr 15.

Abstract

A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibitory activity in vitro against the Carbonic Anhydrases from Vibrio cholerae (VchCA-α, VchCA-β and VchCA-γ) and Burkholderia pseudomallei (BpsCA-β and BpsCA-γ). Among the compounds tested, derivatives 4, 5, 7, 10, 12, and 16 resulted in highly effective VchCAα inhibitors (KI values spanning within the 6.1-9.6 nM range) and endowed with excellent Selectivity Indexes (SIs; KI VchCA-α/KI hCA II) all comprised between 0.04 and 0.09. Potent in vitro inhibitors for the BpsCA-γ were also identified (KIs of 18.9-19.5 nM). The results here reported may represent the blueprint for the future development of a new generation of CA-based antibiotics integrated with free of resistance mechanisms of action adopted from known drugs.

Keywords: Benzensulfonamide; Burkholderia pseudomallei; Carbonic anhydrase inhibitors (CAIs); Taurine; Taurultam; Vibrio cholerae.

MeSH terms

  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / metabolism*
  • Burkholderia pseudomallei / enzymology*
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / metabolism
  • Carbonic Anhydrases / chemistry
  • Carbonic Anhydrases / metabolism*
  • Drug Design
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Kinetics
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Thiadiazines / chemistry*
  • Vibrio cholerae / enzymology*

Substances

  • Bacterial Proteins
  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Sulfonamides
  • Thiadiazines
  • Carbonic Anhydrases
  • taurultam