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

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3897
Author(s):  
David Ramírez ◽  
Melissa Mejia-Gutierrez ◽  
Braulio Insuasty ◽  
Susanne Rinné ◽  
Aytug K. Kiper ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Rational Design ◽  
Experimental Studies ◽  
Input Resistance ◽  
Cell Types ◽  
Imaging Plate ◽  
Channel Blockers ◽  
Design Synthesis ◽  
New Family ◽  
Channel Inhibition

TASK channels belong to the two-pore-domain potassium (K2P) 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.

Structure-based rational design, synthesis, crystal structure, DFT and molecular docking of 1,4-benzene dicarboxamide isomers with application as hardeners

2019 ◽  
Vol 43 (21) ◽  
pp. 7972-7983
Author(s):  
Meenu Teotia ◽  
Nazia Tarannum ◽  
Mohit Chauhan ◽  
Rakesh Kumar Soni
Keyword(s):  
Crystal Structure ◽  
Molecular Docking ◽  
Dft Calculations ◽  
Epoxy Resins ◽  
Rational Design ◽  
Antimicrobial Properties ◽  
Molecular Structures ◽  
Design Synthesis ◽  
Curing Agents

Molecular structures of two isomers have been investigated by SXRD analysis and DFT calculations and the isomers are assessed for their antimicrobial properties and as curing agents for epoxy resins.

scholarly journals Rational Design, Synthesis, and In-Silico Evaluation of Homologous Local Anesthetic Compounds as TASK-1 Channel Blockers

2020 ◽  
Vol 3 (1) ◽  
pp. 67
Author(s):  
Lorena Camargo-Ayala ◽  
Luis Prent-Peñaloza ◽  
Mauricio Bedoya ◽  
Margarita Gutiérrez ◽  
Wendy González
Keyword(s):  
Local Anesthetic ◽  
In Silico ◽  
Rational Design ◽  
Channel Blockers ◽  
Design Synthesis

Advances in different technological and scientific fields have led to the development of tools that allow the design of drugs in a rational way, using defined therapeutic targets, and through simulations that offer a molecular view of the ligand–receptor interactions, giving precise information for the design and synthesis of new compounds. Ion channels are of great relevance as therapeutic targets since they play roles in different pathologies. Several ion channels are expressed in the atria and constitute a therapeutic target for the treatment of atrial fibrillation (AF), the most common type of arrhythmia and an important risk factor for an increase in cerebrovascular illness. The action potential (AP) of a cardiomyocyte is initiated by the depolarization of the membrane through the inflow of sodium (Na+). The repolarization currents are realized by different potassium (K+) channels. Background currents of TASK-1 channels can also contribute to AP, and TASK-1 channel blockers could become innovative strategies against AF. The compounds used in this study were based on local anesthetic (LAs)-type compounds that have been shown to be TASK-1 channel blockers, such as lidocaine, ropivacaine, and bupivacaine, and that have antiarrhythmic capacity, becoming potentially effective drugs for the treatment of AF. The main objective of this study was, based on the common characteristics of LAs, to propose the synthesis of analogues of LAs and evaluate them in silico as TASK-1 channel blockers.

scholarly journals Rational Design, Synthesis, In Vitro, and In Silico Studies of Dihydropyrimidinone Derivatives as β-Glucuronidase Inhibitors

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Somaye Karimian ◽  
Yasaman Moghdani ◽  
Mahsima Khoshneviszadeh ◽  
Somayeh Pirhadi ◽  
Aida Iraji ◽  
...  
Keyword(s):  
Molecular Docking ◽  
13C Nmr ◽  
Rational Design ◽  
Spectroscopic Techniques ◽  
Design Synthesis ◽  
Structure Activity ◽  
Ic50 Value ◽  
In Silico Studies ◽  
Molecular Docking And Dynamics

In the current study, a series of dihydropyrimidinone derivatives were rationally designed as β-glucuronidase inhibitors. These designed compounds were successfully synthesized and characterized through various spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, and EI-MS. A structure-activity relationship (SAR) of synthesized derivatives to inhibit β-glucuronidase was also established. In vitro biological evaluations revealed that 4i as the most potent compound in this series has an IC50 value of 31.52 ± 2.54 μM compared to the standard D-saccharic acid 1,4-lactone (IC50 = 41.32 ± 1.82 µM). Also, molecular docking and dynamics studies of the most potent compound are performed to evaluate interactions between the active compound and binding site.

scholarly journals Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3180 ◽  
Author(s):  
Zhan-Fang Fan ◽  
Sai-Tim Ho ◽  
Rui Wen ◽  
Ya Fu ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Natural Products ◽  
Molecular Docking ◽  
Rational Design ◽  
Binding Mode ◽  
Design Synthesis ◽  
Telomerase Inhibitors ◽  
Ic50 Value ◽  
Human Telomerase ◽  
Dynamics Analyses

Based on the structural scaffolds of natural products, two series of flavonoid derivatives, for a total of twelve compounds, were designed and synthesized as potential human telomerase inhibitors. Using a modified TRAP-PCR assay, compound 5c exhibited the most potent inhibitory activity against human telomerase with an IC50 value of less than 50 μM. In vitro, the results demonstrated that compound 5c had potent anticancer activity against five classes of tumor cell lines. The molecular docking and molecular dynamics analyses binding to the human telomerase holoenzyme were performed to elucidate the binding mode of active compound 5c. This finding helps the rational design of more potent telomerase inhibitors based on the structural scaffolds of natural products.

Pyridine‐derived VEGFR‐2 inhibitors: Rational design, synthesis, anticancer evaluations, in silico ADMET profile, and molecular docking

2021 ◽  
Author(s):  
Nashwa M. Saleh ◽  
Adel A.‐H. Abdel‐Rahman ◽  
Asmaa M. Omar ◽  
Mohamed M. Khalifa ◽  
Khaled El‐Adl
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Rational Design ◽  
Design Synthesis ◽  
In Silico Admet

Design, Synthesis and Docking Studies of Some Novel Fluoroquinolone Compounds with Antibacterial Activity

2018 ◽  
Vol 69 (4) ◽  
pp. 815-822 ◽  
Author(s):  
Lucia Pintilie ◽  
Amalia Stefaniu ◽  
Alina Ioana Nicu ◽  
Maria Maganu ◽  
Miron Teodor Caproiu
Keyword(s):  
Antimicrobial Activity ◽  
Antibacterial Activity ◽  
Molecular Docking ◽  
Drug Discovery ◽  
Elemental Analysis ◽  
Docking Studies ◽  
Receptor Protein ◽  
Chemical Methods ◽  
Design Synthesis ◽  
Gram Negative

A new series of fluoroquinolone compounds have been obtained by Gould-Jacobs method. The compounds have been characterized by physic-chemical methods (elemental analysis, FTIR, NMR, UV-Vis) and by antimicrobial activity against Gram-positive and Gram-negative microorganisms. For the synthesized compounds have been performed calculations of characteristics and molecular properties, using Spartan�14 Software from Wavefunction, Inc. Irvine, CA. and molecular docking studies using CLC Drug Discovery Workbench 2.4 software, to identify and visualize the most likely interaction ligand (fluoroquinolone) with the receptor protein.

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