(Acyloxy)benzophenones and (acyloxy)-4-pyrones. A new class of inhibitors of human neutrophil elastase

Abstract

A series of 4-(acyloxy)- and 4,4'-bis(acyloxy)benzophenones were synthesized. Some of them, pivalates (trimethylacetates) and isobutyrates in particular, were found to be potent and selective inhibitors of human neutrophil (leukocyte) elastase. A series of 2-[(acyloxy)methyl]-5-(acyloxy)-4-pyrones were synthesized regioselectively from kojic acid. The 4-pyrones bearing a long chain acyl group at the 2-position and either pivaloyloxy or isobutyryloxy at the 5-position were potent and selective inhibitors of the human elastase. A number of analogues and derivatives in both series were synthesized in order to study the structure-activity relationship as summarized in Tables I-VI and in Tables IX and X. The inhibition was selective to human neutrophil elastase. No inhibition of porcine pancreatic elastase or bovine pancreatic chymotrypsin (Tables VII and XI) was observed. The most likely mechanism of inhibition is discussed. The implication of these findings for the treatment of rheumatoid arthritis and emphysema is outlined.

One-pot chemoenzymatic preparation of coenzyme A analogues

“…The title compound was synthesized by amidation of pantothenic acid with 4-aminopivaloyloxybutanol. 4-Aminopivaloyloxybutanol was obtained from N a -Cbz-4-aminobutanol via esterification with trimethylacetylchloride [16], followed by HBr/AcOH deprotection and ether precipitation. Yield: 70%.…”

“…Yield: 73%. ES-MS (C16 H 30 N 2 O 5 S, MW 362.49): (ES þ ) 363.1[M + H] þ ; 385.2[M + Na] þ . 1 H NMR (MeOD): 3.88 (1H,s); 3.29-3.50 (4H,m); 3.01-3.05 (4H,m)…”

Synthesis of 1,2,3-Triazole Derivatives of 4,4’-Dihydroxybenzophenone and Evaluation of Their Elastase Inhibitory Activity

“…The derivatives 4-(pivaloyloxy)benzophenone and 4-(isobutyryloxy)benzophenone showed elastase inhibitory activity with half maximal inhibitory concentration (IC 50 ) of 0.62 and 0.25 µM, respectively. It was found that 4,4'-bis(acyloxy)benzophenones were more potent than the corresponding 4-(acyloxy)benzophenones, highlighting 4,4'-bis(2,2-dimethylpropanoate)benzophenone with IC 50 = 0.12 µM and inhibition constant (K i ) = 7.1 × 10 -8 M. 10 Serine proteases are involved in different branches of the immune system and play an important role in inflammation. In a recent investigation from our research group, Martins et al 11 reported in vitro inhibition of serine proteases by synthetic and natural benzophenones, which showed moderate to high inhibitory effects against all the enzymes.…”

“…Recently, studies have demonstrated that structural modifications carried out on this drug afforded substances with improved anti-inflammatory activity. 9 Miyano et al 10 synthesized a series of 4-(acyloxy)benzophenones and 4,4'-bis(acyloxy) benzophenones and evaluated their anti-inflammatory activity using human neutrophil elastase (HNE) as a template. The derivatives 4-(pivaloyloxy)benzophenone and 4-(isobutyryloxy)benzophenone showed elastase inhibitory activity with half maximal inhibitory concentration (IC 50 ) of 0.62 and 0.25 µM, respectively.…”

Modular Synthesis of Candidate Indole-based Insulin Mimics by Claisen Rearrangement

“…The preparation of a reactant to test this plan used known compounds 4 and 5 . Following alkylation of the kojic acid, the THP group can be removed and 6 subjected to pyrolysis (sealed reaction vessel, CEM Discover microwave reactor, IR temperature monitoring).…”