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New 3‐unsubstituted isoxazolones as potent human neutrophil elastase inhibitors: Synthesis and molecular dynamic simulation
Author(s) -
Giovani Maria Paola,
Crocetti Letizia,
Cantini Niccolò,
Guerrini Gabriella,
Vergelli Claudia,
Iacovone Antonella,
Teodori Elisabetta,
Schepetkin Igor A.,
Quinn Mark T.,
Ciattini Samuele,
Rossi Patrizia,
Paoli Paola
Publication year - 2020
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21625
Subject(s) - chemistry , elastase , serine protease , serine , molecular model , enzyme , neutrophil elastase , stereochemistry , ic50 , combinatorial chemistry , protease , enzyme inhibitor , docking (animal) , in vitro , biochemistry , inflammation , biology , immunology , medicine , nursing
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.