Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds
ARCHIV DER PHARMAZIE, vol.354, no.12, 2021 (SCI-Expanded, Scopus)
- 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.