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 (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.

Identification of Druggable Binding Sites and Small Molecules as Modulators of TMC1

“…TMC1 is a nonselective cation channel which primarily passes Ca 2+ and K + into hair cells in response to mechanical stimulation. Unlike other cation channels, TMC1 lacks a conventional cylindrical pore selectivity filter 81 , and instead features a long-curved pore cavity that may be partially exposed to the plasma membrane 54,88,89 . Consequently, it is significantly permeable to bulky organic molecules such as FM1-43 56,57,57 , AGs 17 and others.…”

“…These methods enable a deeper understanding of the key structural factors and moieties required for hit-to-lead optimization with improved biological activities. Previously, we have successfully utilized these methods to design blockers for several ion channels as well as to design other small molecules of biological relevance [93][94][95][96] .…”

Evaluation of Interaction of Some Quinolone Derivatives on RSK-4 Using a Theoretical Model

“…The interaction of quinone derivatives with RSK-4 was evaluated using 6rv2 [38] protein and LJH685 (2,6-Difluoro-4-[4-[4-(4-methylpiperazin-1-yl)phenyl]pyridin-3-yl]phenol) [39] as theoretical tools. Besides, to evaluate the types of binding energy involved in the interaction of quinolone derivatives with the 6rv2 [40] protein surface, the Docking Server software was used. [41] Pharmacokinetics parameter Pharmacokinetic parameters were determined using the Swiss ADME software.…”

Síntesis asistida por ultrasonido de Pirazolo[3,4-b]Piridinas policíclicas fusionadas

“…Dentro de estos andamios moleculares, los derivados azólicos, específicamente los 5-amino-pirazoles, son considerados núcleos únicos que combinan propiedades estructurales, eléctricas y electrónicas, así como una relación estructura-actividad (Dwivedi et al, 2018), las cuales permiten explorar transformaciones químicas para incorporar diversidad molecular y también aplicaciones como bloques de construcción versátiles en la síntesis de sistemas heterocíclicos fusionados (Arias-Gómez et al, 2021;Shaabani et al, 2019;Murlykina et al, 2018;Polo et al, 2017). A partir de 5-amino-pirazoles, se puede acceder a heterociclos fusionados de tipo pirazolopiridínico (PPd) (Ramírez, et al, 2021) a través de diferentes estrategias sintéticas, que incluyen reacciones convencionales (Zhai, et al, 2019;Baradarani et al, 2018), multicomponentes one-pot (Arlan et al, 2020;Afsar et al, 2018;Ezzati, et al, 2018;Hill et al, 2016), ciclocondensación (Hu et al, 2018) o protocolos tándem (Aggarwal and Kumar 2018). Los sistemas PPd están conformados por cinco isómeros (los [3,4-b], [3,4-c], [4,3-c], [4,3-b] y [1,5-a]), entre los que resaltan las pirazolo [3,4-b]piridinas-PPd, sistemas bicíclicos de variado potencial biológico (Donaire-Arias et al, 2022;Vidali et al, 2022;Ramírez et al, 2021;Eagon et al, 2020;Zhai et al, 2019;Mekky and Sanad, 2019;Patnaik et al, 2019;Quiroga et al, 2017;Hill et al, 2016) combinado con un amplio alcance sintético (Gouda et al, 2020;Aly et al, 2019) (Figura 1).…”