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Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase.

ABSTRACT: Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC?? values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors.

SUBMITTER: Crocetti L 

PROVIDER: S-EPMC6777343 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase.

Crocetti Letizia L   Giovannoni Maria Paola MP   Schepetkin Igor A IA   Quinn Mark T MT   Khlebnikov Andrei I AI   Cilibrizzi Agostino A   Piaz Vittorio Dal VD   Graziano Alessia A   Vergelli Claudia C  

Bioorganic & medicinal chemistry 20110707 15

Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC₅₀ values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the b  ...[more]

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