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. New hybrid thiazolyl–pyrazoline derivatives (4a–k) were designed, synthesized, and investigated as multitarget inhibitors of human carbonic anhydrase (hCA) isoforms I and II and acetylcholinesterase (AChE). All derivatives showed KI values for hCAs and AChE in the low nanomolar range. The observed structure–activity relationships were rationalized by in silico docking simulation.