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

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.