Design, synthesis, and enzymatic evaluation of N1-acyloxyalkyl- and N1-oxazolidin-2,4-dion-5-yl-substituted beta-lactams as novel inhibitors of human leukocyte elastase.
Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be responsible for the onset of chronic obstructive pulmonary disease (COPD). A novel series of C-3-, C-4-, and N-1-substituted azetidin-2-ones were prepared as potential mechanism-based inhibitors of HLE to restore the protease/antiprotease imbalance. N-Acyloxyalkylazetidin-2-ones, 4, and their carbamate counterparts, 5, are weak HLE inhibitors, being 5 times less active than their bicyclic oxazolidin-2,4-dione-substituted analogues, 6, containing an electron-withdrawing substituent at C-4. Compounds 6 containing a C-4 substituent exist as two diastereomeric pairs of enantiomers, each pair presenting similar inhibitory activity against HLE. Comparative docking experiments with the C-4-substituted oxazolidin-2,4-dione inhibitors 6 suggest that only the 4R,5'S and 4S,5'S diastereomers consistently interact with the beta-lactam carbonyl carbon atom accessible to the serine hydroxyl oxygen.
Moreira
Rui
R
CECF, Faculdade de Farmácia, Universidade de Lisboa, Av. Forças Armadas, 1600-083 Lisboa, Portugal. rmoreira@ff.ul.pt
Santana
Ana Bela
AB
Iley
Jim
J
Neres
João
J
Douglas
Kenneth T
KT
Horton
Peter N
PN
Hursthouse
Michael B
MB
D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001384:Azetidines; D007769:Lactams; D010080:Oxazoles; D019272:Leukocyte Elastase