Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

4-Hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: a novel inhibitor of the canonical NF-?B cascade.

ABSTRACT: The NF-?B signaling pathway is a validated oncological target. Here, we applied scaffold hopping to IMD-0354, a presumed IKK? inhibitor, and identified 4-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide (4) as a nM-inhibitor of the NF-?B pathway. However, both 4 and IMD-0354, being potent inhibitors of the canonical NF-?B pathway, were found to be inactive in human IKK? enzyme assays.

SUBMITTER: Pippione AC

PROVIDER: S-EPMC6084005 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

4-Hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: a novel inhibitor of the canonical NF-κB cascade.

Pippione Agnese C AC Federico Antonella A Ducime Alex A Sainas Stefano S Boschi Donatella D Barge Alessandro A Lupino Elisa E Piccinini Marco M Kubbutat Michael M Contreras Jean-Marie JM Morice Christophe C Al-Karadaghi Salam S Lolli Marco L ML

MedChemComm 20170825 9

The NF-κB signaling pathway is a validated oncological target. Here, we applied scaffold hopping to IMD-0354, a presumed IKKβ inhibitor, and identified 4-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide (4) as a nM-inhibitor of the NF-κB pathway. However, both 4 and IMD-0354, being potent inhibitors of the canonical NF-κB pathway, were found to be inactive in human IKKβ enzyme assays. ...[more]

PMID: 30108896

Similar Datasets

1-(5-Hydroxy-1-phenyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethanone.

Project description:The crystal structure of the title compound, C(12)H(9)F(3)N(2)O(2), contains two independent mol-ecules in the asymmetric unit. The mol-ecules are chemically identical but exhibit a significant difference in the dihedral angles between the mean planes of the phenyl and pyrazole rings, with values of of 11.62?(13) and 18.17?(11)°. Moreover, the trifluoro-methyl group in one of the mol-ecules shows rotational disorder of the F atoms, with site occupancy factors of 0.929?(6) and 0.071?(6). The hydroxyl group in each of the mol-ecules shows a strong intra-molecular hydrogen bond with the carbonyl O atom, forming a six-membered ring and forcing the formyl group and pyrazole ring to be coplanarshowing C-C-C-O torsion angles of ?0.3(5)o and 0.°. Weak inter-molecular C-H?O and C-H?F inter-actions contribute to the stabilization of the crystal packing.

| S-EPMC2980148 | biostudies-literature

Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors.

Project description:At present, inhibitors of ?/?-hydrolase domain?6 (ABHD6) are viewed as a promising approach to treat inflammation and metabolic disorders. This article describes the development of 1,2,5-thiadiazole carbamates as ABHD6 inhibitors. Altogether, 34 compounds were synthesized, and their inhibitory activity was tested using lysates of HEK293 cells transiently expressing human ABHD6 (hABHD6). Among the compound series, 4-morpholino-1,2,5-thiadiazol-3-yl cyclooctyl(methyl)carbamate (JZP-430) potently and irreversibly inhibited hABHD6 (IC50 =44 nM) and showed ?230-fold selectivity over fatty acid amide hydrolase (FAAH) and lysosomal acid lipase (LAL), the main off-targets of related compounds. Additionally, activity-based protein profiling indicated that JZP-430 displays good selectivity among the serine hydrolases of the mouse brain membrane proteome. JZP-430 has been identified as a highly selective, irreversible inhibitor of hABHD6, which may provide a novel approach in the treatment of obesity and type?II diabetes.

| S-EPMC4471478 | biostudies-literature

Synthesis of 3,5-Bis(trifluoromethyl)phenyl-Substituted Pyrazole Derivatives as Potent Growth Inhibitors of Drug-Resistant Bacteria.

Project description:Enterococci and methicillin-resistant S. aureus (MRSA) are among the menacing bacterial pathogens. Novel antibiotics are urgently needed to tackle these antibiotic-resistant bacterial infections. This article reports the design, synthesis, and antimicrobial studies of 30 novel pyrazole derivatives. Most of the synthesized compounds are potent growth inhibitors of planktonic Gram-positive bacteria with minimum inhibitory concertation (MIC) values as low as 0.25 µg/mL. Further studies led to the discovery of several lead compounds, which are bactericidal and potent against MRSA persisters. Compounds 11, 28, and 29 are potent against S. aureus biofilms with minimum biofilm eradication concentration (MBEC) values as low as 1 µg/mL.

| S-EPMC8398255 | biostudies-literature

3-Phenyl-sulfanyl-4-phenyl-sulfonyl-1,2,5-oxadiazole 2-oxide.

Project description:In the title compound, C(14)H(10)N(2)O(4)S(2),the furoxan heterocyclic ring and the two S atoms are almost co-planar, with a mean deviation of 0.036?Å. The bond lengths in the penta-gonal ring show electron delocalization and the furoxan N-O bond length is quite short [1.211?(3)?Å]. The dihedral angles between the central ring and pendant phenyl rings are 78.05?(14) and 84.28?(2)°.

| S-EPMC3011692 | biostudies-literature

(Z)-4-Amino-1,2,5-oxadiazole-3-carboxamide oxime.

Project description:The asymmetric unit of the title compound, C(3)H(5)N(5)O(2), contains three crystallograpically independent mol-ecules. In the crystal structure, inter-molecular N-H?N, N-H?O, O-H?N and O-H?O hydrogen bonds link the mol-ecules into a three-dimensional network.

| S-EPMC2971256 | biostudies-other

N-[(S)-1-(3,5-Dimethyl-2-hydroxy-phenyl)-ethyl]-N-[(R)-2-hydr-oxy-1-phenyl-ethyl]ammonium chloride.

Project description:In the title compound, C(18)H(24)NO(2) (+)·Cl(-), the absolute configuration of the new stereogenic centre (the C atom with a CH(2)OH substituent) was unambiguously determined to have an R configuration. The dihedral angle between the two aromatic rings is 30.82?(2)°. Inter-molecular N-H?Cl and O-H?Cl hydrogen bonds and intra-molecular N-H?O hydrogen bonds stabilize the crystal structure.

| S-EPMC2915299 | biostudies-literature

Carbonyl reductase identification and development of whole-cell biotransformation for highly efficient synthesis of (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol.

Project description:BACKGROUND:(R)-[3,5-bis(trifluoromethyl)phenyl] ethanol [(R)-3,5-BTPE] is a valuable chiral intermediate for Aprepitant (Emend) and Fosaprepitant (Ivemend). Biocatalyzed asymmetric reduction is a preferred approach to synthesize highly optically active (R)-3,5-BTPE. However, the product concentration and productivity of reported (R)-3,5-BTPE synthetic processes remain unsatisfied. RESULTS:A NADPH-dependent carbonyl reductase from Lactobacillus kefir (LkCR) was discovered by genome mining for reduction of 3,5-bis(trifluoromethyl) acetophenone (3,5-BTAP) into (R)-3,5-BTPE with excellent enantioselectivity. In order to synthesize (R)-3,5-BTPE efficiently, LkCR was coexpressed with glucose dehydrogenase from Bacillus subtilis (BsGDH) for NADPH regeneration in Escherichia coli BL21 (DE3) cells, and the optimal recombinant strain produced 250.3 g/L (R)-3,5-BTPE with 99.9% ee but an unsatisfied productivity of 5.21 g/(L h). Then, four different linker peptides were used for the fusion expression of LkCR and BsGDH in E. coli to regulate catalytic efficiency of the enzymes and improved NADPH-recycling efficiency. Using the best strain (E. coli/pET-BsGDH-ER/K(10 nm)-LkCR), up to 297.3 g/L (R)-3,5-BTPE with enantiopurity >99.9% ee was produced via reduction of as much as 1.2 M of substrate with a 96.7% yield and productivity of 29.7 g/(L h). CONCLUSIONS:Recombinant E. coli/pET-BsGDH-ER/K(10 nm)-LkCR was developed for the bioreduction of 3,5-BTAP to (R)-3,5-BTPE, offered the best results in terms of high product concentration and productivity, demonstrating its great potential in industrial manufacturing of (R)-3,5-BTPE.

| S-EPMC5106766 | biostudies-literature

3,5-Dibromo-2-hydroxy-benzaldehyde.

Project description:The title compound, C(7)H(4)Br(2)O(2), exhibits a layer packing structure via weak ?-? stacking inter-actions [centroid-centroid distances between adjacent aromatic rings are 4.040?(8) and 3.776?(7)?Å]. Mol-ecules in each layer are linked by inter-molecular O-H?O hydrogen bonding and Br?Br inter-actions [3.772?(4)?Å]. There are two mol-ecules in the asymmetric unit.

| S-EPMC2961300 | biostudies-literature

3,5-Dichloro-2-hydroxy-benzaldehyde.

Project description:The title compound, C(7)H(4)Cl(2)O(2), exhibits a layer crystal structure; mol-ecules within each layer are linked by weak C-H?O inter-molecular hydrogen bonds. There is also an intramolecular O-H?O hydrogen bond.

| S-EPMC2961496 | biostudies-literature

Trifluoromethyl-substituted 3,5-bis(arylidene)-4-piperidones as potential anti-hepatoma and anti-inflammation agents by inhibiting NF-кB activation.

Project description:Some methoxy-, hydroxyl-, pyridyl-, or fluoro-substituted 3,5-bis(arylidene)-4-piperidones (BAPs) could reduce inflammation and promote hepatoma cell apoptosis by inhibiting activation of NF-κB, especially after introduction of trifluoromethyl. Herein, a series of trifluoromethyl-substituted BAPs (4-30) were synthesised and the biological activities were evaluated. We successfully found the most potential 16, which contains three trifluoromethyl substituents and exhibits the best anti-tumour and anti-inflammatory activities. Preliminary mechanism research revealed that 16 could promote HepG2 cell apoptosis in a dose-dependent manner by down-regulating the expression of Bcl-2 and up-regulating the expression of Bax, C-caspase-3. Meanwhile, 16 inhibited activation of NF-κB by directly inhibiting the phosphorylation of p65 and IκBα induced by LPS, together with indirectly inhibiting MAPK pathway, thereby exhibiting both anti-hepatoma and anti-inflammatory activities. Molecular docking confirmed that 16 could bind to the active sites of Bcl-2, p65, and p38 reasonably. The above results suggested that 16 has enormous potential to be developed as a multifunctional agent for the clinical treatment of liver cancers and inflammatory diseases.

| S-EPMC8297402 | biostudies-literature