| 000 | 03855nlm1a2200565 4500 | ||
|---|---|---|---|
| 001 | 659744 | ||
| 005 | 20231030041640.0 | ||
| 035 | _a(RuTPU)RU\TPU\network\28532 | ||
| 035 | _aRU\TPU\network\14529 | ||
| 090 | _a659744 | ||
| 100 | _a20190327a2018 k y0engy50 ba | ||
| 101 | 0 | _aeng | |
| 102 | _aNL | ||
| 135 | _adrcn ---uucaa | ||
| 181 | 0 | _ai | |
| 182 | 0 | _ab | |
| 200 | 1 |
_a1H-pyrrolo[2,3-b]pyridine: A new scaffold for human neutrophil elastase (HNE) inhibitors _fL. Crocetti, M. P. Giovannoni, I. A. Shchepyotkin [et al.] |
|
| 203 |
_aText _celectronic |
||
| 300 | _aTitle screen | ||
| 320 | _a[References: 38 tit.] | ||
| 330 | _aHuman neutrophil elastase (HNE) is a potent serine protease belonging to the chymotrypsin family. It is an important target for the development of novel and selective inhibitors for the treatment of inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis and biological evaluation of a new series of HNE inhibitors with a pyrrolo[2,3-b]pyridine scaffold, which is an isomer of our previously reported indazoles, in order to assess how a shift of the nitrogen from position 2 to position 7 influences activity. The majority of new compounds were effective HNE inhibitors and had IC50 values in the micromolar/submicromolar range, with some compounds active in low nanomolar levels. For example, 2a and 2b inhibited HNE with IC50 values of 15 and 14?nM, respectively. Molecular modeling of compounds differing in the position of heteroatom(s) in the bicyclic moiety and in the oxadiazole ring demonstrated that the calculated geometries of enzyme-inhibitor complexes were in agreement with the observed biological activities. Docking experiments showed that orientation of the active pyrrolo[2,3-b]pyridines in the HNE catalytic triad Ser195-His57-Asp102 correlated with effectiveness of the inhibitor interaction with the enzyme. Thus, the pyrrolo[2,3-b]pyridine scaffold represents a novel scaffold for the development of potent HNE inhibitors. | ||
| 333 | _aРежим доступа: по договору с организацией-держателем ресурса | ||
| 461 | _tBioorganic & Medicinal Chemistry | ||
| 463 |
_tVol. 26, Iss. 21 _v[P. 5583-5595] _d2018 |
||
| 610 | 1 | _aэлектронный ресурс | |
| 610 | 1 | _aтруды учёных ТПУ | |
| 610 | 1 | _ahuman neutrophil elastase | |
| 610 | 1 | _ainhibitor | |
| 610 | 1 | _apyrrolo[2,3-b]pyridine | |
| 610 | 1 | _amolecular docking | |
| 610 | 1 | _aнейтрофильная фаза | |
| 610 | 1 | _aингибиторы | |
| 610 | 1 | _aпирролы | |
| 610 | 1 | _aпиридин | |
| 610 | 1 | _aпиридины | |
| 610 | 1 | _aмолекулярная стыковка | |
| 701 | 1 |
_aCrocetti _bL. _gLetizia |
|
| 701 | 1 |
_aGiovannoni _bM. P. _gMaria Paola |
|
| 701 | 1 |
_aShchepyotkin _bI. A. _cdoctor-biophysicist _cleading researcher of Tomsk Polytechnic University, candidate of medical science _f1962- _gIgor Aleksandrovich _2stltpush _3(RuTPU)RU\TPU\pers\37358 |
|
| 701 | 1 |
_aQuinn _bM. _gMark |
|
| 701 | 1 |
_aKhlebnikov _bA. I. _cChemist _cProfessor of Tomsk Polytechnic University _f1963- _gAndrey Ivanovich _2stltpush _3(RuTPU)RU\TPU\pers\33927 |
|
| 701 | 1 |
_aCantini _bN. _gNiccolo |
|
| 701 | 1 |
_aGuerrini _bG. _gGabriella |
|
| 701 | 1 |
_aIacovone _bA. _gAntonella |
|
| 701 | 1 |
_aTeodori _bE. _gElisabetta |
|
| 701 | 1 |
_aVergelli _bC. _gClaudia |
|
| 712 | 0 | 2 |
_aНациональный исследовательский Томский политехнический университет _bИнженерная школа новых производственных технологий _bНаучно-образовательный центр Н. М. Кижнера _h7872 _2stltpush _3(RuTPU)RU\TPU\col\23556 |
| 801 | 2 |
_aRU _b63413507 _c20201103 _gRCR |
|
| 856 | 4 | _uhttps://doi.org/10.1016/j.bmc.2018.09.034 | |
| 942 | _cCF | ||