Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3

Hwang, Tsong‐Long; Wang, Wenhui; Wang, Ting‐Yi; Yu, Huang-Ping; Hsieh, Pei‐Wen

doi:10.1016/j.bmc.2014.12.056

Cited by 27 publications

(32 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 2 anthranilate derivatives-(E)-4-(N-{2-[1-(hydroxyimino)ethyl]phenyl}sulfamoyl)phenyl pivalate (HFP031) and butyl 2-[2-(2-fluorophenyl)acetamido] benzoate (HFP034)-have been reported to have antiinflammatory potency. HFP031 (in our previous study) showed dual inhibitory effects on human neutrophil elastase and proteinase 3 (19). HFP034 (in our previous study) exhibited a potent inhibitory effect on the N-formyl-Lmethionyl-L-leucyl-phenylalanine-induced release of O 2 ×2 and phosphodiesterase (PDE)4 activity by using human neutrophils as the inflammation cell models (20).…”

mentioning

confidence: 91%

Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte‐derived chemokine expression and neutrophil infiltration

et al. 2018

View full text Add to dashboard Cite

Psoriasis is an inflammatory autoimmune skin disorder possessing a complex etiology related to genetic and environmental triggers. Keratinocytes show a potential role for the origin of psoriasis. In this study, we estimated the efficiency of 2 anthranilate derivatives-(E)-4-( N-{2-[1-(hydroxyimino)ethyl]phenyl}sulfamoyl)phenyl pivalate (HFP031) and butyl 2-[2-(2-fluorophenyl)acetamido]benzoate (HFP034)-on psoriasis amelioration in a mouse model. The results showed that topical treatment with both compounds could attenuate epidermal thickness and scaling in an imiquimod (IMQ)-induced psoriasis mouse model via decreased expression of cytokines and chemokines [C-X-C chemokine ligand (CXCL)1 and CXCL2], leading to the reduction of neutrophilic abscess in the skin. The in vivo cutaneous absorption of HFP034 was 7.6-fold greater than that of HFP031. Both compounds caused negligible irritation on healthy mouse skin. In addition, we examined the effect of the anthranilate derivatives on chemokine expression in IMQ-treated HaCaT keratinocytes. Our results elucidated a mechanism for anti-inflammatory activity of HFP034 that involved the elevation of intracellular cAMP concentration, suppression of NF-κB activity, and attenuation of neutrophil chemoattractant expression. These results suggest that HFP034 could increase the cutaneous concentration of cAMP to suppress neutrophil infiltration into the skin. Topically applied HFP034 may demonstrate a potential for future clinical application as a novel therapy for psoriasis treatment.-Lin, Z.-C., Hsieh, P.-W., Hwang, T.-L., Chen, C.-Y., Sung, C. T., Fang, J.-Y. Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte-derived chemokine expression and neutrophil infiltration.

show abstract

mentioning

confidence: 91%

Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte‐derived chemokine expression and neutrophil infiltration

et al. 2018

View full text Add to dashboard Cite

show abstract

“…All assays were performed as described previously 58 59 . Neutrophils isolated from the blood of healthy volunteers (20–30 years old) were resuspended in a Ca 2+ -free HBSS buffer (pH 7.4) at 4 °C before use.…”

Section: Methodsmentioning

confidence: 99%

Ilex kaushue and Its Bioactive Component 3,5-Dicaffeoylquinic Acid Protected Mice from Lipopolysaccharide-Induced Acute Lung Injury

Chen

Hwang

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

Acute lung injury (ALI) is a severe respiratory disease with high mortality rates worldwide. Recent reports suggest that human neutrophil elastase (HNE) plays a key role in the inflammatory response that is characteristic of ALI, which indicates that the development of HNE inhibitors could be an efficient treatment strategy. In the current study, an enzyme-based screening assay was used to identify effective HNE inhibitors from a number of traditional Chinese medicines (TCMs). Among them, a water extract of Ilex kaushue (IKWE) effectively inhibited HNE activity (IC50, 11.37 ± 1.59 μg/mL). Using bioactivity-guided fractionation, one new compound and 23 known compounds were identified. Compound 6 (identified as 3,5-dicaffeoylquinic acid; 3,5-DCQA) exerted the most potent and selective inhibitory effect on HNE activity (IC50, 1.86 ± 0.06 μM). In a cell-based assay, 3,5-DCQA not only directly reduced superoxide generation and elastase activity but also attenuated the Src family kinase (SRKs)/Vav signaling pathway in N-formyl-L-Met-L-Leu-L-Phe (fMLF)-stimulated human neutrophils. In an animal disease model, both 3,5-DCQA and standardized IKWE protected against lipopolysaccharide-induced ALI in mice, which provides support for their potential as candidates in the development of new therapeutic agents for neutrophilic inflammatory diseases.

show abstract

“…After dilution with ice-cold water, the precipitate was filtered and washed with water (10-20 mL) to obtain the final compounds 3d-f, which were purified by crystallization from ethanol. To a suspension of intermediate 1g (Crocetti et al, 2013) (0.64 mmol) in 5 mL of anhydrous pyridine, 1.92 mmol of 4-(chlorosulfonyl)phenyl pivalate 2 (Hwang et al, 2015) was added. The mixture was stirred at room temperature for 4 h. The solvent was concentrated in vacuo to obtain the final compound 3g, which was purified by crystallization from ethanol.…”

Section: General Procedures For Compounds (3d-f)mentioning

confidence: 99%

Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors

et al. 2020

View full text Add to dashboard Cite

Human neutrophil elastase (HNE) is involved in a number of essential physiological processes and has been identified as a potential therapeutic target for treating acute and chronic lung injury. Nevertheless, only one drug, Sivelestat, has been approved for clinical use and just in Japan and the Republic of Korea. Thus, there is an urgent need for the development of low-molecular-weight synthetic HNE inhibitors, and we have developed a wide variety of HNE inhibitors with various chemical scaffolds. We hypothesized that substitution of the active fragment of Sivelestat into these HNE inhibitor scaffolds could modulate their inhibitory activity, potentially resulting in higher efficacy and/or improved chemical stability. Here, we report the synthesis, biological evaluation, and molecular modeling studies of novel compounds substituted with the 4-(sulfamoyl)phenyl pivalate fragment necessary for Sivelestat activity. Many of these compounds were potent HNE inhibitors with activity in the nanomolar range (IC 50 = 19-30 nM for compounds 3a, 3b, 3f, 3g, and 9a), confirming that the 4-(sulfamoyl)phenyl pivalate fragment could substitute for the N-CO group at position 1 and offer a different point of attack for Ser195. Results of molecular docking of the these pivaloyl-containing compounds into the HNE binding site supported the mechanism of inhibitory activity involving a nucleophilic attack of Ser195 from the catalytic triad onto the pivaloyl carbonyl group. Furthermore, some compounds (e.g., 3a and 3f) had a relatively good stability in aqueous buffer (t 1/2 > 9 h). Thus, this novel approach led to the identification of a number of potent HNE inhibitors that could be used as leads for the further development of new therapeutics.

show abstract

Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3

Cited by 27 publications

References 30 publications

Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte‐derived chemokine expression and neutrophil infiltration

Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte‐derived chemokine expression and neutrophil infiltration

Ilex kaushue and Its Bioactive Component 3,5-Dicaffeoylquinic Acid Protected Mice from Lipopolysaccharide-Induced Acute Lung Injury

Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors

Contact Info

Product

Resources

About