Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

Arch Pharm (Weinheim). 2021 Dec;354(12):e2100294. doi: 10.1002/ardp.202100294. Epub 2021 Sep 27.

Abstract

New hybrid thiazolyl-pyrazoline derivatives (4a-k) were obtained through a facile and versatile synthetic procedure, and their inhibitory effects on the human carbonic anhydrase (hCA) isoforms I and II as well as on acetylcholinesterase (AChE) were determined. All new thiazolyl-pyrazolines showed activity at nanomolar levels as hCA I, hCA II, and AChE inhibitors, with KI values in the range of 13.35-63.79, 7.01-115.80, and 17.89-48.05 nM, respectively. 1-[4-(4-Cyanophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4f) and 1-(4-phenylthiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4a) against hCAs and 1-[4-(4-chlorophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4d) and 1-[4-(4-nitrophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4b) against AChE were identified as highly potent inhibitors, superior to the standard drugs, acetazolamide and tacrine, respectively. Compounds 4a-k were also evaluated for their cytotoxic effects on the L929 mouse fibroblast (normal) cell line. Moreover, a comprehensive ligand-receptor interaction prediction was performed using the ADME-Tox, Glide XP, and MM-GBSA modules of the Schrödinger Small-Molecule Drug Discovery Suite to elucidate the potential binding modes of the new hybrid inhibitors against these metabolic enzymes.

Keywords: Alzheimer's disease; acetylcholinesterase; carbonic anhydrase; piperidine; thiazolyl-pyrazoline.

Publication types

  • Comparative Study

MeSH terms

  • Acetazolamide / pharmacology
  • Animals
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Cell Line
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Mice
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • Tacrine / pharmacology
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Cholinesterase Inhibitors
  • Pyrazoles
  • Thiazoles
  • Tacrine
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • Acetazolamide