Isoxazol-5(2H)-one: a new scaffold for potent human neutrophil elastase (HNE) inhibitors
| Parent link: | Journal of Enzyme Inhibition and Medicinal Chemistry Vol. 32, iss. 1.— 2017.— [P. 821-831] |
|---|---|
| Autor Corporativo: | |
| Outros autores: | , , , , , , , , , |
| Summary: | Title screen Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure-activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC50value =20 nM) and chemical stability in aqueous buffer (t1/2=8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds 2o and 2s contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups. Режим доступа: по договору с организацией-держателем ресурса |
| Idioma: | inglés |
| Publicado: |
2017
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| Subjects: | |
| Acceso en liña: | https://doi.org/10.1080/14756366.2017.1326915 |
| Formato: | Electrónico Capítulo de libro |
| KOHA link: | https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=656791 |
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| 200 | 1 | |a Isoxazol-5(2H)-one: a new scaffold for potent human neutrophil elastase (HNE) inhibitors |f C. Vergelli, I. A. Schepetkin, L. Crocetti [et al.] | |
| 203 | |a Text |c electronic | ||
| 300 | |a Title screen | ||
| 320 | |a [References: p. 830-831 (41 tit.)] | ||
| 330 | |a Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure-activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC50value =20 nM) and chemical stability in aqueous buffer (t1/2=8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds 2o and 2s contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups. | ||
| 333 | |a Режим доступа: по договору с организацией-держателем ресурса | ||
| 461 | |t Journal of Enzyme Inhibition and Medicinal Chemistry | ||
| 463 | |t Vol. 32, iss. 1 |v [P. 821-831] |d 2017 | ||
| 610 | 1 | |a электронный ресурс | |
| 610 | 1 | |a труды учёных ТПУ | |
| 610 | 1 | |a Isoxazol-5(2H)-one | |
| 610 | 1 | |a human neutrophil elastase | |
| 610 | 1 | |a HNE inhibitor | |
| 610 | 1 | |a chemical stability | |
| 610 | 1 | |a molecular docking | |
| 610 | 1 | |a изоксазолы | |
| 610 | 1 | |a нейтрофильная эластаза | |
| 610 | 1 | |a ингибиторы | |
| 610 | 1 | |a химическая стабильность | |
| 610 | 1 | |a молекулярная стыковка | |
| 701 | 1 | |a Vergelli |b C. |g Claudia | |
| 701 | 1 | |a Schepetkin (Shchepyotkin) |b I. A. |c doctor-biophysicist |c leading researcher of Tomsk Polytechnic University, candidate of medical science |f 1962- |g Igor Aleksandrovich |3 (RuTPU)RU\TPU\pers\37358 | |
| 701 | 1 | |a Crocetti |b L. |g Letizia | |
| 701 | 1 | |a Iacovone |b A. |g Antonella | |
| 701 | 1 | |a Giovannoni |b M. P. |g Maria Paola | |
| 701 | 1 | |a Guerrini |b G. |g Gabriella | |
| 701 | 1 | |a Khlebnikov |b A. I. |c Chemist |c Professor of Tomsk Polytechnic University |f 1963- |g Andrey Ivanovich |3 (RuTPU)RU\TPU\pers\33927 | |
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| 701 | 1 | |a Ciciani |b G. |g Giovanna | |
| 701 | 1 | |a Quinn |b M. T. |g Mark | |
| 712 | 0 | 2 | |a Национальный исследовательский Томский политехнический университет (ТПУ) |b Институт физики высоких технологий (ИФВТ) |b Кафедра биотехнологии и органической химии (БИОХ) |3 (RuTPU)RU\TPU\col\18693 |
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