Synthesis of pyrazolo[1,5-c]quinazolines from four easily available precursors is presented through a one-pot tricyclic Pd(ii)/Ag(i) relay catalysis. The bimetallic relay cascade forges five new chemical bonds by concatenating six discrete chemical steps. The relay catalysis enables four-component assembly of pyrazolo[1,5-c]quinazolines that selectively inhibit EGFR, exhibit apoptosis through the ROS-induced mitochondrial-mediated pathway, and arrest the cell cycle at the G1 phase.

G9a is a lysine methyltransferase able to di-methylate lysine 9 of histone H3, promoting the repression of genes involved in learning and memory. Novel strategies based on synthesizing epigenetic drugs could regulate gene expression through histone post-translational modifications and effectively treat neurodegenerative diseases, like Alzheimer's disease (AD). Here, potential G9a inhibitors were identified using a structure-based virtual screening against G9a, followed by in vitro and in vivo screenings. First, screening methods with the AD transgenic Caenorhabditis elegans strain CL2006, showed that the toxicity/ function range was safe and recovered age-dependent paralysis. Likewise, we demonstrated that the best candidates direct target G9a by reducing H3 K9me2 in the CL2006 strain. Further characterization of these compounds involved the assessment of the blood-brain barrier-permeability and impact on amyloidβ aggregation, showing promising results. Thus, we present a G9a inhibitor candidate, F, with a novel and potent structure, providing both leads in G9a inhibitor design and demonstrating their participation in reducing AD pathology.

Alzheimer’s Disease (AD) is one of the significant diseases of the aging population and affects Central Nervous System dominantly. Blood-brain-barrier permeation is a substantial complication in developing CNS drugs, and it is considered challenging with minimal success rates. Although Glycogen synthase kinase-3β (GSK-3β) is an attractive disease-modifying target for AD, there is no single GSK-3β inhibitor in clinical trials for AD. Here we performed structure-based virtual screening on the Chembridge CNS-Set library compounds. 10 hits were identified based on interaction, binding energy, and dock score. These 10 chosen compounds showed a potential ADME profile and were then investigated for in vitro kinase inhibitory activity against GSK-3β and other AD-related kinases. Among these, the molecule 7114202 showed 48% GSK-3β inhibition while showing selectivity over other AD-related kinases. Molecular dynamic simulations of apoenzyme, co-crystallized molecule, and 7114202 validated the Lys85, Val135, Leu188, Asp200 located in the active site of enzyme plays a significant role for GSK-3β complex formation with inhibitors, and they are responsible for activity and selectivity. The in vitro studies also revealed a potent and selective Casein Kinase 1ε (CK1ε) inhibitor 7774767 with IC50 5.10 µM.

No abstract