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

SEVER B., TÜRKEŞ C., ALTINTOP M. D., Demir Y., AKALIN ÇİFTÇİ G., BEYDEMİR Ş.

ARCHIV DER PHARMAZIE, vol.354, no.12, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 354 Issue: 12
  • Publication Date: 2021
  • Doi Number: 10.1002/ardp.202100294
  • Journal Name: ARCHIV DER PHARMAZIE
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database, Index Chemicus (IC)
  • Keywords: acetylcholinesterase, Alzheimer's disease, carbonic anhydrase, piperidine, thiazolyl-pyrazoline, CARBONIC-ANHYDRASE I, CALCIUM-CHANNEL BLOCKERS, BIOLOGICAL EVALUATION, POTENTIAL ACETYLCHOLINESTERASE, SILICO EVALUATION, ACCURATE DOCKING, VITRO, DERIVATIVES, CHOLINESTERASE, DISCOVERY
  • Anadolu University Affiliated: Yes

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 K-I 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 Schrodinger Small-Molecule Drug Discovery Suite to elucidate the potential binding modes of the new hybrid inhibitors against these metabolic enzymes.