Further modifications of 1H‐pyrrolo[2,3‐b]pyridine derivatives as inhibitors of human neutrophil elastase

Giovannoni, Maria Paola; Cantini, Niccolò; Crocetti, Letizia; Guerrini, Gabriella; Iacovone, Antonella; Schepetkin, Igor A.; Vergelli, Claudia; Khlebnikov, Аndrei I.; Quinn, Mark T.

doi:10.1002/ddr.21539

Cited by 8 publications

(6 citation statements)

References 32 publications

(51 reference statements)

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“…Sivelestat, a known HNE inhibitor, was used as a positive control. The inhibition assay was performed, as described previously [ 29 ]. Briefly, a solution containing 200 mM Tris-HCl (pH 7.5), 0.01% bovine serum albumin, 0.05% Tween-20, and 20 mU/mL of human neutrophil elastase was added to black, flat-bottom 96-well microtiter plates containing different concentrations of test compounds.…”

Section: Methodsmentioning

confidence: 99%

Chemical Composition and Immunomodulatory Activity of Hypericum perforatum Essential Oils

Schepetkin

Özek

et al. 2020

Biomolecules

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Hypericum L. (Hypericaceae) extracts have been used for their therapeutic effects; however, not much is known about the immunomodulatory activity of essential oils extracted from this plant. We isolated essential oils from the flowers and leaves of H. perforatum and analyzed their chemical composition and innate immunomodulatory activity. Analysis of flower (HEOFl) versus leaf (HEOLv) essential oils using gas chromatography–mass spectrometry revealed that HEOFl was comprised mainly of monoterpenes (52.8%), with an abundance of oxygenated monoterpenes, including cis-p-menth-3-en-1,2-diol (9.1%), α-terpineol (6.1%), terpinen-4-ol (7.4%), and limonen-4-ol (3.2%), whereas the sesquiterpenes were found in trace amounts. In contrast, HEOLv was primarily composed of sesquiterpenes (63.2%), including germacrene D (25.7%) and β-caryophyllene (9.5%). HEOLv also contained oxygenated monoterpenes, including terpinen-4-ol (2.6%), while monoterpene hydrocarbons were found in trace amounts. Both HEOFl and HEOLv inhibited neutrophil Ca2+ mobilization, chemotaxis, and reactive oxygen species (ROS) production, with HEOLv being much more active than HEOFl. Furthermore, the pure sesquiterpenes germacrene D, β-caryophyllene, and α-humulene also inhibited these neutrophil responses, suggesting that these compounds represented the active components of HEOLv. Although reverse pharmacophore mapping suggested that potential protein targets of germacrene D, β-caryophyllene, bicyclogermacrene, and α-humulene could be PIM1 and mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAK2), a kinase binding affinity assay did not support this finding, implying that other biological targets are involved. Our results provide a cellular and molecular basis to explain at least part of the beneficial immunotherapeutic properties of the H. perforatum essential oils.

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Section: Methodsmentioning

confidence: 99%

Chemical Composition and Immunomodulatory Activity of Hypericum perforatum Essential Oils

Schepetkin

Özek

et al. 2020

Biomolecules

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“…Starting from Scheme 1 , fragment 2 was inserted at the N-1 position of four different bi-heterocycles that were previously investigated by our research group as N(1)-CO- aryl(alkyl) derivatives: indoles (Crocetti et al, 2016 ), indazoles (Crocetti et al, 2011 , 2013 ), 7-azaindoles (Crocetti et al, 2018 ; Giovannoni et al, 2019 ) and 7-azaindazoles (data not shown). Indole derivatives 3a-c were obtained starting from the precursors 1a-c ( 1a : Shahidul et al, 2006 ; 1b : DeGraw and Goodman, 1964 ; 1c : Yuen et al, 2013 ) by treatment with 4-(chlorosulfonyl)phenyl pivalate 2 and sodium hydride in anhydrous tetrahydrofuran (THF) at room temperature.…”

Section: Resultsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

“…Sivelestat acts as acyl-enzyme inhibitor (IC 50 = 44 nM) (Ohbayashi, 2005 ), as demonstrated by electrospray ionization mass spectrometry (ESI), which highlighted the formation of a HNE-Sivelestat complex after 0–10 min incubation of the drug with HNE ( Figure 2 ) (Nakayama et al, 2002 ). We have been working for some time on the design and synthesis of HNE inhibitors with different nitrogen monocyclic and bicyclic scaffolds (Crocetti et al, 2011 , 2013 , 2016 , 2017 , 2018 ; Giovannoni et al, 2016 , 2018 , 2019 ; Vergelli et al, 2017 ). Figure 3 illustrates the compounds already investigated ( A-F ) and the range of activity for each series.…”

Section: Introductionmentioning

confidence: 99%

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Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors

et al. 2020

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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.

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“…Nevertheless, only two HNE inhibitors are commercially available: Sivelestat (Elaspol® 100), which is in use for the treatment of ALI and ARDS only marketed in Korea and Japan (Iwata et al, ), and Prolastin (purified α1‐AT), which is use for the treatment of α1‐antitrypsin deficiency (Bayer Corporation, ). In order to develop new compounds that modulate the HNE proteolytic activity, our research group has investigated several molecular scaffolds, such as indazoles (Crocetti et al, , ), indoles (Crocetti et al, ), azaindoles (Crocetti et al, ; Giovannoni et al, ), cinnolinones (Giovannoni et al, ), and thiazolones (Crocetti et al, ). Most recently, we focused on the synthesis isoxazol‐5(2 H )‐one derivatives (Giovannoni et al, ; Vergelli et al, ).…”

Section: Introductionmentioning

confidence: 99%

New 3‐unsubstituted isoxazolones as potent human neutrophil elastase inhibitors: Synthesis and molecular dynamic simulation

Giovannoni

Crocetti

Cantini

et al. 2019

Drug Development Research

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Human neutrophil elastase (HNE) is a proteolytic enzyme belonging to the serine protease family and is involved in a variety of pathologies. Thus, compounds able to inhibit HNE represent promising therapeutics for the treatment of inflammatory diseases. Here, we report the further elaboration of our previously reported 3-methylisoxazolone derivatives, synthesizing a new series of 3-nor-derivatives bearing different substituents at the 4-phenyl ring. The most potent compounds 3a, 3g, and 3h, had IC 50 values of 16, 11, and 18 nM, respectively. Molecular modeling studies and molecular dynamic (MD) simulations demonstrated no substantial differences between the 3-methylisoxazole derivatives previously tested and the corresponding 3-unsubstituted derivatives in the snapshot conformations sampled during the MD simulations, which is consistent with their similar levels of HNE inhibitory activity.Thus, we conclude that the isoxazolone scaffold is a good scaffold for developing HNE inhibitors, as it tolerates several modifications when adhering to basic scaffold requirements, and the resulting derivatives are quite potent HNE inhibitors. K E Y W O R D Shuman neutrophil elastase inhibitors, molecular and crystal structures, molecular modeling

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Further modifications of 1H‐pyrrolo[2,3‐b]pyridine derivatives as inhibitors of human neutrophil elastase

Cited by 8 publications

References 32 publications

Chemical Composition and Immunomodulatory Activity of Hypericum perforatum Essential Oils

Chemical Composition and Immunomodulatory Activity of Hypericum perforatum Essential Oils

Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors

New 3‐unsubstituted isoxazolones as potent human neutrophil elastase inhibitors: Synthesis and molecular dynamic simulation

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