Identification of novel quinazolin-4(3 H)-ones as inhibitors of thermolysin, the prototype of the M4 family of proteinases

• Published in: Bioorganic & medicinal chemistry 2010-06, Vol.18 (12), p.4317-4327
• Main Authors: Khan, Mahmud Tareq Hassan, Khan, Rasool, Wuxiuer, Yimingjiang, Arfan, Mohammad, Ahmed, Manzoor, Sylte, Ingebrigt
• Format: Article
• Language: English
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Binding Sites; Biological and medical sciences; Chemical array-based approach; Computer Simulation; Inhibition; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Quinazolin-4(3 H)-one structure analogues; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Quinazolinones - chemical synthesis; Quinazolinones - chemistry; Quinazolinones - pharmacology; Structure-Activity Relationship; Thermolysin; Thermolysin - antagonists & inhibitors; Thermolysin - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.083

Interaction of compound 3 [3-phenyl-2-(trifluoromethyl) quinazolin-4(3 H)-one] with thermolysin. A combinatorial series of novel quinazolin-4(3 H)-ones were synthesised and their structures were established based on spectroscopic data (IR, NMR, EI-MS, and FAB-MS). The compounds were tested for inhibition of the zinc metalloproteinase thermolysin (TLN) utilizing a chemical array-based approach. Some of the compounds were found to inhibit TLN, with IC 50 values ranging from 0.0115 μM (compound 3) to 122,637 μM (compound 29). Compound 3 [3-phenyl-2-(trifluoromethyl) quinazolin-4(3 H)-one] (IC 50 = 0.0115 μM) and compound 35 [3-(isopropylideneamino)-2,2-dimethyl-2,3-dihydroquinazolin-4 (1 H)-one] (IC 50 = 0.2477 μM) were found to be the most potent inhibitors.