Synthesis, Docking Study and Kinase Inhibitory Activity of a Number of New Substituted Pyrazolo[3,4-<i>c</i>]pyridines

Abstract

A series of new pyrazolo[3,4-c]pyridines bearing various 1, 3, 5 or 1, 3, 7 pattern substitutions, were designed and synthesized. Some of them showed interesting inhibitory activity mainly against glycogen synthase kinase 3 (GSK3)α/β as well as against cdc2-like kinases 1 (CLK1) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), with good selectivity and remarkable structure-activity relationships (SARs), without being cytotoxic. Molecular simulations in correlation with biological data revealed the importance of the existence of N1-H as well as the absence of a bulky 7-substituent.Key words pyrazolopyridine; kinase inhibition; glycogen synthase kinase 3 (GSK3)α/β; purine analogue; molecular simulation Neurodegenerative diseases are among the most challenging diseases with poorly known mechanism and lack of complete cure. Alzheimer's disease (AD) in particular, is the most prevalent cause of dementia, very devastating for the patients and their families, provided that current treatments offer only modest symptomatic relief. This severe mental disorder is mostly aging-associated and represents a global health problem, since it currently affects more than 30 million people worldwide, and its incidence is predicted to rise significantly, due to the increasing average life span. 1) In an effort to explain the pathogenesis of AD, many hypotheses have been explored, among them neurotransmitter modulation, chronic inflammation, metal-induced oxidative stress, elevated cholesterol, and glycogen synthase kinase 3 (GSK-3) implication are of major importance.2) GSK-3 is a ubiquitous serine/threonine kinase, which was first described as the major regulator of glycogen metabolism. It was revealed that GSK-3 plays central roles in important cell signaling pathways, and its malfunction is associated with neurodegeneration and the pathogenesis of several diseases, including diabetes type II, immune and bipolar disorders, chronic inflammation, heart failure and cancer.3) In AD, GSK-3 promotes neuronal death and is a linker between the two histopathological hallmarks: the deposition of extracellular senile plaques composed of amyloid-beta (Aβ) peptide, and the accumulation of hyperphosphorylated microtubule-binding tau protein, leading to tau aggregation and the formation of intracellular neurofibrillary tangles. 4)On the other hand, substantial evidence exists to support the involvement of additional phylogenetically and physiologically relevant protein kinases in neurodegenerative disorders, and, most notably, cyclin dependent kinase 5 (CDK5), 5) dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK 1A), 6) casein kinase 1 (CK1) 7) and cdc2-like kinases CLK1 and CLK2 8) are also investigated as potential targets for the development of novel AD therapeutics. Consequently, the exploitation of small molecule inhibitors for potential inhibitory activity against a set of the above mentioned protein kinases could offer interesting information and assist in the understanding of AD and related tau...

Dual A1/A3 Adenosine Receptor Antagonists: Binding Kinetics and Structure−Activity Relationship Studies Using Mutagenesis and Alchemical Binding Free Energy Calculations

“…The 52 compounds tested were available from an in-house library of the Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens. The compounds shown in Figure were synthesized as described previously in refs and for examining them in detail against A 1 R and A 3 R. The citations for the other series of compounds tested can be found in the Supporting Information. All compounds used for the in vitro testing were >95% pure by elemental analysis.…”

SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors

“…Further analysis of the utility of SIRT2i_Predictor was performed by analyzing our small in-house database of compounds ( Supplementary Materials, Table S12 ) [ 53 , 54 ]. Unfortunately, predicted probabilities for binary models for all in-house compounds were outside the defined applicability domain or predicted to be inactive.…”

Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies

“…On the other hand, pyrazolopyridine derivatives are another interesting scaffold and have appeared in many medicinal chemistry programs due to their great variety of biological activities. These derivatives possess antimicrobial [ 26 , 27 ], antioxidant [ 28 ], anxiolytic [ 29 ], anticancer [ 30 , 31 ], antiproliferative [ 32 ], cytotoxic [ 33 ], antileishmanial [ 34 , 35 ], and antimalarial [ 36 ] properties, as well as phosphodiesterrase (PDE4) [ 37 ], kinase [ 38 ], and angiogenesis [ 39 ] inhibitory activities.…”