Synthesis and analytical characterization of new thiazol-2-(3H)-ones as human neutrophil elastase (HNE) inhibitors

Crocetti, Letizia; Bartolucci, Gianluca; Cilibrizzi, Agostino; Giovannoni, Maria Paola; Guerrini, Gabriella; Iacovone, Antonella; Menicatti, Marta; Schepetkin, Igor A.; Khlebnikov, Аndrei I.; Quinn, Mark T.; Vergelli, Claudia

doi:10.1186/s13065-017-0358-1

Cited by 14 publications

(3 citation statements)

References 28 publications

(43 reference statements)

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“…Cinnoline derivatives are reversible competitive inhibitors of human NE that seem to have potential, but further studies are required 88 . The design and synthesis of small molecules based on different bicyclic scaffold allowed the isolation of isoxazol-5(2 H )-one scaffold, as good and reversible competitive inhibitor of NE 80 , while thiazol-2-(3 H )-one nucleus was not a good scaffold for NE inhibitor 89 .…”

Section: Exogenous and Therapeutic Neutrophil Serine Protease Inhibitmentioning

confidence: 99%

Neutrophil Elastase Inhibitors and Chronic Kidney Disease

Bronze-da-Rocha¹,

Santos-Silva²

2018

Int. J. Biol. Sci.

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End-stage renal disease (ESRD), the last stage of chronic kidney disease (CKD), is characterized by chronic inflammation and oxidative stress. Neutrophils are the front line cells that mediate an inflammatory response against microorganisms as they can migrate, produce reactive oxygen species (ROS), secrete neutrophil serine proteases (NSPs), and release neutrophil extracellular traps (NETs). Serine proteases inhibitors regulate the activity of serine proteases and reduce neutrophil accumulation at inflammatory sites. This review intends to relate the role of neutrophil elastase in CKD and the effects of neutrophil elastase inhibitors in predicting or preventing inflammation.

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Section: Exogenous and Therapeutic Neutrophil Serine Protease Inhibitmentioning

confidence: 99%

Neutrophil Elastase Inhibitors and Chronic Kidney Disease

Bronze-da-Rocha¹,

Santos-Silva²

2018

Int. J. Biol. Sci.

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“…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%

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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Synthesis and analytical characterization of new thiazol-2-(3H)-ones as human neutrophil elastase (HNE) inhibitors

Cited by 14 publications

References 28 publications

Neutrophil Elastase Inhibitors and Chronic Kidney Disease

Neutrophil Elastase Inhibitors and Chronic Kidney Disease

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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