Tetrahydroquinazole-based secondary sulphonamides as carbonic anhydrase inhibitors: synthesis, biological evaluation against isoforms I, II, IV, and IX, and computational studies

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1874-1883. doi: 10.1080/14756366.2021.1956913.

Abstract

A library of variously decorated N-phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure-activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.

Keywords: Carbonic anhydrases inhibitors; secondary sulphonamides; structure–activity relationships; tetrahydroquinazole derivatives; tumour-related CA IX isoform.

MeSH terms

  • Carbon-13 Magnetic Resonance Spectroscopy
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Computational Biology / methods*
  • Drug Evaluation, Preclinical
  • Isoenzymes / antagonists & inhibitors*
  • Molecular Docking Simulation
  • Proton Magnetic Resonance Spectroscopy
  • Quinazolines / chemistry*
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Quinazolines
  • Sulfonamides

Grants and funding

This work was supported by University of Campania Luigi Vanvitelli under Grant VALERE: Vanvitelli per la Ricerca, ANIMA and VALEREPlus projects, Campania and Regional Government Technology Platform Lotta alle Patologie Oncologiche under Grant iCURE, University of Pisa under Grant PRA_2020_58 and Italian MIUR under Grant PRIN 2017, 2017XYBP2R.