Potent inhibition of human leukocyte elastase by 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based sulfonamide derivatives.
The design, synthesis, and in vitro biochemical evaluation of a class of mechanism-based inhibitors of human leukocyte elastase (HLE) that incorporate in their structure a 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold with appropriate recognition and reactivity elements appended to it is described. The synthesized compounds were found to be efficient, time-dependent inhibitors of HLE. The interaction of the inhibitors with HLE is postulated to lead to the formation of a highly reactive N-sulfonyl imine (a Michael acceptor) that arises from an enzyme-induced sulfonamide fragmentation cascade. Subsequent reaction ultimately leads to the formation of a relatively stable acyl enzyme. The results cited herein demonstrate convincingly the superiority of the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold over other scaffolds (e.g., saccharin) in the design of inhibitors of (chymo)trypsin-like serine proteases.
Lai
Zhong
Z
Department of Chemistry, Wichita State University, Wichita, Kansas 67260, USA.
Gan
Xiangdong
X
Wei
Liuqing
L
Alliston
Kevin R
KR
Yu
Hongyi
H
Li
Yue H
YH
Groutas
William C
WC
D003499:Cyclic S-Oxides / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry*
C428430:1,2,5-thiadiazolidin-3-one 1,1-dioxide; D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; D019272:Leukocyte Elastase