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 IC50 values of 16, 11, and 18 nM, respectively. Molecular modelling 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.

New 3-unsubstituted Isoxazolones as Potent Human Neutrophil Elastase Inhibitors: Synthesis and Molecular Dynamic Simulation / Maria Paola Giovannoni, Letizia Crocetti, Niccolò Cantini, Gabriella Guerrini, Claudia Vergelli, Antonella Iacovone, Elisabetta Teodori, Igor A. Schepetkin, Mark T. Quinn, Samuele Ciattini,Patrizia Rossi, Paola Paoli. - In: DRUG DEVELOPMENT RESEARCH. - ISSN 1098-2299. - ELETTRONICO. - 81:(2020), pp. 338-349. [10.1002/ddr.21625]

New 3-unsubstituted Isoxazolones as Potent Human Neutrophil Elastase Inhibitors: Synthesis and Molecular Dynamic Simulation

Maria Paola Giovannoni;Letizia Crocetti
;
Niccolò Cantini;Gabriella Guerrini;Claudia Vergelli;Elisabetta Teodori;Samuele Ciattini;Patrizia Rossi;Paola Paoli
2020

Abstract

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 IC50 values of 16, 11, and 18 nM, respectively. Molecular modelling 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.
2020
81
338
349
Maria Paola Giovannoni, Letizia Crocetti, Niccolò Cantini, Gabriella Guerrini, Claudia Vergelli, Antonella Iacovone, Elisabetta Teodori, Igor A. Schep...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1179241
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