Browse
Submit Data
Databases
API
Help

Dataset Information

12 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

5-(Indol-2-yl)pyrazolo[3,4-b]pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis.

ABSTRACT: TASK channels belong to the two-pore-domain potassium (K_2P) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization. TASK-3 is expressed in different cancer cell types and neurons. Thus, the discovery of novel TASK-3 inhibitors makes these bioactive compounds very appealing to explore new cancer and neurological therapies. TASK-3 channel blockers are very limited to date, and only a few heterofused compounds have been reported in the literature. In this article, we combined a pharmacophore hypothesis with molecular docking to address for the first time the rational design, synthesis, and evaluation of 5-(indol-2-yl)pyrazolo[3,4-b]pyridines as a novel family of human TASK-3 channel blockers. Representative compounds of the synthesized library were assessed against TASK-3 using Fluorometric imaging plate reader-Membrane Potential assay (FMP). Inhibitory properties were validated using two-electrode voltage-clamp (TEVC) methods. We identified one active hit compound (MM-3b) with our systematic pipeline, exhibiting an IC₅₀ ≈ 30 μM. Molecular docking models suggest that compound MM-3b binds to TASK-3 at the bottom of the selectivity filter in the central cavity, similar to other described TASK-3 blockers such as A1899 and PK-THPP. Our in silico and experimental studies provide a new tool to predict and design novel TASK-3 channel blockers.

SUBMITTER: Ramirez D

PROVIDER: S-EPMC8271858 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Organometallic 3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines as potential anticancer agents.

Project description:Six organometallic complexes of the general formula [M(II)Cl(?(6)-p-cymene)(L)]Cl, where M = Ru (11a, 12a, 13a) or Os (11b, 12b, 13b) and L = 3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3) have been synthesized. The latter are known as potential cyclin-dependent kinase (Cdk) inhibitors. All compounds have been comprehensively characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, UV-vis spectroscopy, ESI mass spectrometry, and X-ray crystallography (11b and 12b). The multistep synthesis of 3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3), which was reported by other researchers, has been modified by us essentially (e.g., the synthesis of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (3) via 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (2); the synthesis of 1-methoxymethyl-2,3-diaminobenzene (5) by avoiding the use of unstable 2,3-diaminobenzyl alcohol; and the activation of 1H-pyrazolo[3,4-b]pyridine-3-carboxylic acids (1, 3) through the use of an inexpensive coupling reagent, N,N'-carbonyldiimidazole (CDI)). Stabilization of the 7b tautomer of methoxymethyl-substituted L3 by coordination to a metal(II) center, as well as the NMR spectroscopic characterization of two tautomers 7b-L3 and 4b'-L3 in a metal-free state are described. Structure-activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells, as well as Cdk inhibitory activity, are also reported.

| S-EPMC3255473 | biostudies-literature

Regioselective difunctionalization of pyridines via 3,4-pyridynes.

Project description:A new regioselective 3,4-difunctionalization of 3-chloropyridines via 3,4-pyridyne intermediates is reported. Regioselective lithiation of 3-chloro-2-ethoxypyridine and a related 2-thio-derivative followed by treatment with aryl- and alkylmagnesium halides as well as magnesium thiolates at -78 °C produced 3,4-pyridynes during heating to 75 °C. Regioselective addition of the Grignard moiety in position 4 followed by an electrophilic quench in position 3 led to various 2,3,4-trisubstituted pyridines. This method was adapted into a continuous flow set-up. As an application, we have prepared a key intermediate for (±)-paroxetine.

| S-EPMC8098683 | biostudies-literature

Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening.

Project description:TASK-3 is a two-pore domain potassium (K2P) channel highly expressed in the hippocampus, cerebellum, and cortex. TASK-3 has been identified as an oncogenic potassium channel and it is overexpressed in different cancer types. For this reason, the development of new TASK-3 blockers could influence the pharmacological treatment of cancer and several neurological conditions. In the present work, we searched for novel TASK-3 blockers by using a virtual screening protocol that includes pharmacophore modeling, molecular docking, and free energy calculations. With this protocol, 19 potential TASK-3 blockers were identified. These molecules were tested in TASK-3 using patch clamp, and one blocker (DR16) was identified with an IC50 = 56.8 ± 3.9 ?M. Using DR16 as a scaffold, we designed DR16.1, a novel TASK-3 inhibitor, with an IC50 = 14.2 ± 3.4 ?M. Our finding takes on greater relevance considering that not many inhibitory TASK-3 modulators have been reported in the scientific literature until today. These two novel TASK-3 channel inhibitors (DR16 and DR16.1) are the first compounds found using a pharmacophore-based virtual screening and rational drug design protocol.

| S-EPMC6720600 | biostudies-literature

Construction of pyrazolo[3,4-b]pyridines and pyrazolo[4,3-c]pyridines by ring closure of 3-acylpyridine N-oxide tosylhydrazones.

Project description:3-Acylpyridine N-oxide tosylhydrazones give good overall yields of a mixture of pyrazolo[3,4-b]pyridines and pyrazolo[4,3-c]pyridines when treated with an electrophilic additive and an amine base. (Z)-Hydrazones cyclize readily, while (E)-hydrazones fail to react under the reported conditions. The reaction takes place at room temperature, and moderate regiocontrol over the cyclization can be achieved by varying the electrophile/solvent combination.

| S-EPMC3278155 | biostudies-literature

Four-component strategy for selective synthesis of azepino[5,4,3-cd]indoles and pyrazolo[3,4-b]pyridines.

Project description:A novel four-component strategy for the selective synthesis of fused azepino[5,4,3-cd]indoles and pyrazolo [3,4-b]pyridines has been established. The bond-forming efficiency, accessibility of starting materials and substrate scope provide invaluable access to tetra-, and bis-heterocyclic scaffolds.

| S-EPMC4060249 | biostudies-literature

3,4-Bis[1-(prop-2-yn-yl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione.

Project description:In the title mol-ecule, C26H17N3O2, both indole ring systems are essentially planar, with maximum deviations of 0.019?(2) and 0.033?(1)?Å for the N atoms, and form dihedral angles of 34.40?(9) and 45.06?(8)° with the essentially planar pyrrole ring [maximum deviation = 0.020?(2)?Å]. The dihedral angle between the two indole ring systems is 58.78?(6)°. In the crystal, mol-ecules are connected by pairs of N-H?O hydrogen bonds, forming inversion dimers and generating R 2 (2)(8) rings. Weak ?-? stacking inter-actions, with a centroid-centroid distance of 3.983?(2)?Å, are also observed.

| S-EPMC3685074 | biostudies-literature

Isoprop-yl (3,4-dimethyl-5,5-dioxo-4H-pyrazolo-[4,3-c][1,2]benzothia-zin-2-yl)acetate.

Project description:In the title mol-ecule, C(16)H(19)N(3)O(4)S, the heterocyclic thia-zine ring adopts a half-chair conformation, with the S and N atoms displaced by 0.547?(2) and -0.254?(3)?Å, respectively, from the plane formed by the remaining atoms. In the crystal, weak C-H?N and C-H?O hydrogen bonds link the mol-ecules.

| S-EPMC2983407 | biostudies-literature

5-(Pyridin-4-ylmeth-yl)-1H-pyrazolo-[3,4-d]pyrimidin-4(5H)-one.

Project description:In the title compound, C(11)H(9)N(5)O, the pyrazolo-pyrimidin-4-one ring system is almost planar, with a maximum deviation of 0.0546?(13)?Å for the O atom. The crystal packing is stabilized by inter-molecular N-H?N, C-H?O and C-H?N hydrogen bonds. In addition, ?-? stacking is found between the pyridine ring and the pyrazolo-pyrimidin-4-one ring systems, with centroid-centroid distances in the range 3.9627?(12)-4.6781?(12)?Å.

| S-EPMC3212314 | biostudies-literature

Development of 1H-Pyrazolo[3,4-b]pyridines as Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators.

Project description:The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling in association with the N-methyl-d-aspartate receptor (NMDAR). We describe the synthesis of 1H-pyrazolo[3,4-b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs) without inherent agonist activity. A facile and convergent synthetic route provided access to a structurally diverse set of analogues that contain neither the aryl-acetylene-aryl nor aryl-methyleneoxy-aryl elements, the predominant structural motifs described in the literature. Binding studies suggest that members of our new chemotype do not engage the receptor at the MPEP and CPPHA mGluR5 allosteric sites. SAR studies culminated in the first non-MPEP site PAM, 1H-pyrazolo[3,4-b]pyridine 31 (BMT-145027), to improve cognition in a preclinical rodent model of learning and memory.

| S-EPMC5150689 | biostudies-literature

5,6-Dimethyl-4-(thio-phen-2-yl)-1H-pyrazolo-[3,4-b]pyridin-3-amine.

Project description:In the title mol-ecule, C(12)H(12)N(4)S, the thio-phene ring is disordered over two orientations with a refined site-occupancy ratio of 0.777?(4):0.223?(4). The pyrazolo-pyridine ring system is essentially planar with an r.m.s. deviation of 0.0069?(3)?Å and makes dihedral angles of 82.8?(2) and 72.6?(5)°, respectively, with the major and minor components of the thio-phene ring. In the crystal, mol-ecules are linked into a chain along the a axis by a pair of N-H?N(pyrazole) hydrogen bonds and a pair of N-H?N(pyridine) hydrogen bonds, both having a centrosymmetric R(2) (2)(8) graph-set motif. A C-H?? inter-action is also present.

| S-EPMC3295413 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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