Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Utilization of the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide scaffold in the design of potential inhibitors of human neutrophil proteinase 3.

ABSTRACT: The S' subsites of human neutrophil proteinase 3 (Pr 3) were probed by constructing diverse libraries of compounds based on the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide using combinational and click chemistry methods. The multiple points of diversity embodied in the heterocyclic scaffold render it well-suited to the exploration of the S' subsites of Pr 3. Molecular modeling studies suggest that further exploration of the S' subsites of Pr 3 using the aforementioned heterocyclic scaffold may lead to the identification of highly selective, reversible competitive inhibitors of Pr 3.

SUBMITTER: Dou D

PROVIDER: S-EPMC2853038 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Utilization of the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide scaffold in the design of potential inhibitors of human neutrophil proteinase 3.

Dou Dengfeng D He Guijia G Li Yi Y Lai Zhong Z Wei Liuqing L Alliston Kevin R KR Lushington Gerald H GH Eichhorn David M DM Groutas William C WC

Bioorganic & medicinal chemistry 20091229 3

The S' subsites of human neutrophil proteinase 3 (Pr 3) were probed by constructing diverse libraries of compounds based on the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide using combinational and click chemistry methods. The multiple points of diversity embodied in the heterocyclic scaffold render it well-suited to the exploration of the S' subsites of Pr 3. Molecular modeling studies suggest that further exploration of the S' subsites of Pr 3 using the aforementioned heterocyclic scaffold may lea ...[more]

PMID: 20061159

Similar Datasets

Isoxazol-5(2H)-one: a new scaffold for potent human neutrophil elastase (HNE) inhibitors.

Project description: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 (IC50 value =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.

| S-EPMC5927774 | biostudies-literature

X-ray snapshot of the mechanism of inactivation of human neutrophil elastase by 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives.

Project description:The mechanism of action of a general class of mechanism-based inhibitors of serine proteases, including human neutrophil elastase (HNE), has been elucidated by determining the X-ray crystal structure of an enzyme-inhibitor complex. The captured intermediate indicates that processing of inhibitor by the enzyme generates an N-sulfonyl imine functionality that is tethered to Ser195, in accordance with the postulated mechanism of action of this class of inhibitors. The identity of the HNE-N-sulfonyl imine species was further corroborated using electrospray ionization mass spectrometry.

| S-EPMC3623276 | biostudies-literature

2-Methyl-1,2-benzisothia-zol-3(2H)-one 1,1-dioxide.

Project description:All atoms of the title mol-ecule, C(8)H(7)NO(3)S, except the two oxide O atoms and two H atoms of the methyl group, lie on a crystallographic mirror plane. The crystal structure is stabilized by weak inter- and intra-molecular C-H⋯O hydrogen bonds.

| S-EPMC2960984 | biostudies-literature

Biological activities of 4H-thiochromen-4-one 1,1-dioxide derivatives against tropical disease parasites: A target-based drug design approach.

Project description:A promising strategy for developing novel therapies against tropical diseases, including malaria, leishmaniasis, and trypanosomiasis, is to detect biological targets such as trypanothione reductase, a vital parasite enzyme that regulates oxidative stress. This enzyme is highly selective and conserved in the Trypanosotidae family and has an ortholog in the Plasmodium genus. Previous studies have established that an isosteric replacement of naphthoquinone's carbonyl group with a sulfone group leads to compounds with high bioactivity and selectivity (half-maximal inhibitory concentration = 3 μM against intracellular amastigotes of L. panamensis, selectivity index = 153 over monocytes U-937). In this study, we analyzed the reactive oxygen species (ROS) levels of parasites through indirect measurements of the tryparedoxin system after treatment with these isosteric compounds. This strategy proved that a significant increase in the ROS levels and strong mitochondrial perturbation led to the death of parasites due to cell homeostatic imbalance, confirming the compounds' effectiveness in disrupting this important metabolic pathway. To improve understanding of the parasite-molecule interaction, 27 new compounds were synthesized and assessed against parasites of the three principal tropical diseases (malaria, leishmaniasis, and trypanosomiasis), displaying an EC50 below 10 μM and good correlation with in-silico studies, indicating that the 4H-thiochromen-4-one 1,1-dioxide core is a special allosteric modulator. It can interact in the binding pocket through key amino acids like Ser-14, Leu-17, Trp-21, Ser-109, Tyr-110, and Met-113, leading to interhelical disruption.

| S-EPMC10362183 | biostudies-literature

2-(Prop-2-en-yl)-1,2-benzisothia-zol-3(2H)-one 1,1-dioxide.

Project description:In the title compound, C(10)H(9)NO(3)S, the benzisothia-zole group is almost planar (with a maximum deviation of 1.61?Å). The crystal structure is stabilized by weak inter-molecular C-H?O hydrogen bonds, forming a chain of mol-ecules along b.

| S-EPMC2969636 | biostudies-literature

2-n-Butyl-1,2-benzisothia-zol-3(2H)-one 1,1-dioxide.

Project description:The crystal packing of the title compound, C(11)H(13)NO(3)S, exhibits weak inter-molecular C-H?O hydrogen bonding, which links mol-ecules related by translation along the b axis into chains, and ?-? inter-actions [centroid-centroid distance of 3.778?(2)?Å between benzene rings].

| S-EPMC2961223 | biostudies-other

2-[(Methyl-sulfan-yl)meth-yl]-1,2-benz-isothia-zol-3(2H)-one 1,1-dioxide.

Project description:In the title mol-ecule, C(9)H(9)NO(3)S(2), the essentially planar benzisothia-zole ring system and the C-S-C atoms of the methyl-sulfanyl side chain form an angle of 64.45?(7)°. The structure is devoid of any classical hydrogen bonding. However, weak non-classical inter- and intra-molecular hydrogen bonds of the type C-H?O are present.

| S-EPMC2959482 | biostudies-literature

2-[(E)-3-Phenyl-prop-2-en-yl]-1,2-benzisothia-zol-3(2H)-one 1,1-dioxide.

Project description:In the crystal structure of the title compound, C(16)H(13)NO(3)S, the benzisothia-zole group is almost planar (r.m.s. deviation for all non-H atoms excluding the two O atoms bonded to S = 0.009 Å). The dihedral angle between the fused ring and the terminal ring is 13.8 (1)°. In the crystal, mol-ecules are linked through inter-molecular C-H⋯O contacts forming a chain of mol-ecules along b.

| S-EPMC2977698 | biostudies-literature

2,5-Dihexyl-thio-phene 1,1-dioxide.

Project description:In the title mol-ecule, C16H28O2S, the two n-hexyl groups are in all-trans conformations. Their C atoms are situated close to the plane of the thio-phene ring with a maximum deviation of 0.718?(6)?Å for one of the terminal methyl groups. In the crystal, a short C-H?O contact is observed between thio-phene 1,1-dioxide groups.

| S-EPMC3589018 | biostudies-literature

2,5-Dichloro-thio-phene 1,1-dioxide.

Project description:The complete mol-ecule of the title compound, C(4)H(2)Cl(2)O(2)S, is generated by crystallographic twofold symmetry, with the S atom lying on the rotation axis. In the crystal, the molecules are linked by C-H?O hydrogen bonds..

| S-EPMC2972006 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data