Evaluation of the inhibitory activity on serine and aspartic proteases of 4-amino-4H-1,2,4-triazole and 5-aminothiazole derivatives structurally related to beta-lactam antibiotics.
Twenty new derivatives of 4-amino-4H-1,2,4-triazole and 5-aminothiazole have been examined for their inhibitory potential towards serine and aspartic proteases. Upon prolonged incubation with enzyme, the phenylacetylaminothiazolium salts exhibit progressive, time-dependent inhibition of chymotrypsin according to a first-order process. The formation of a tetrahedral transition state-like complex by attack of the active-site serine at the C2-position of the pseudobase form of the thiazolium may be responsible for the observed effect. Triazolium salts appeared to be simple competitive inhibitors of this enzyme, effective in the mM range concentration. Poor inhibitions of trypsin and pepsin were also obtained in the triazolium series. In spite of their structural analogy with beta-lactams, the selected derivatives failed to inhibit human leucocyte elastase.
Vilain
A C
AC
Laboratoire d'Enzymologie Moléculaire et Fonctionelle, Institut Jacques Monod, Université de Paris VII, France.
Pirotte
B
B
Vergely
I
I
Boggetto
N
N
Masereel
B
B
Schynts
M
M
Delarge
J
J
Reboud-Ravaux
M
M
D000595:Amino Acid Sequence; D000640:Amitrole / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002417:Cattle; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D006801:Humans; D019272:Leukocyte Elastase; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D010434:Pepsin A / Q000037:antagonists & inhibitors; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000494:pharmacology; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D014361:Trypsin Inhibitors; D047090:beta-Lactams; D002918:Chymotrypsin; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D013917:Thrombin; D016282:Aspartic Acid Endopeptidases; D010434:Pepsin A; D000640:Amitrole