Structure-activity study of 6-substituted 2-pyranones as inactivators of alpha-chymotrypsin.
A series of 2-pyranones, bearing halogens or electron-withdrawing groups at the 6-position and alkyl, aryl, or aralkyl groups at positions 3, 4, and 5, were synthesized to investigate their binding to and inactivation of chymotrypsin. Both binding and inactivation by 2-pyranones are sensitive to substitutions on positions 3, 4, 5, and 6. Binding was poorest with alkyl substituents on position 3 and best with phenyl substitution, with benzyl or benzyl-like substitution falling in between. The sequence of binding of 6-substituted pyrones is Cl greater than Br greater than H greater than CF3. 6-Chloro-2-pyranones bearing 4-phenyl or 3-(2-naphthylmethyl) substituents effected rapid inactivation of chymotrypsin, while those having 3-benzyl or 3-(1-naphthylmethyl) substituents gave slow inactivation and those with 3-phenyl or 3-alkyl substituents gave no inactivation. Only the 6-halopyrones demonstrated inactivation, with chloro-substituted ones acting faster than bromo-substituted ones.
D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D011714:Pyrans / Q000138:chemical synthesis*; D011753:Pyrones / Q000138:chemical synthesis* / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011480:Protease Inhibitors; D011714:Pyrans; D011753:Pyrones; D002918:Chymotrypsin