The tale of proteolysis targeting chimeras (PROTACs) for leucine-rich repeat kinase 2 (LRRK2)

Here we present the rational design and the synthetic methodologies towards proteolysis targeting chimeras (PROTACs) for the recently-emerged Parkinson's target leucine-rich repeat kinase 2 (LRRK2). Two highly potent, selective and brain-penetrating kinase inhibitors were selected and their structure was appropriately modified to assemble a cereblon-targeting-PROTAC. Biological data show strong kinase inhibition and the ability of the synthesized compounds to enter the cells. However, data regarding the degradation of the target protein are inconclusive. The reasons for the inefficient degradation of the target are further discussed

The Gewald multicomponent reaction

The Gewald reaction of sulfur, cyanoacetic acid derivatives, and oxo-component (G-3CR) yielding highly substituted 2-aminothiophene derivatives has seen diverse applications in combinatorial and medicinal chemistry. Its products are of great use in pharmaceutical industry mainly as small molecular weight inhibitors. We herein review synthetic scope and variations, usage, and structural biology of Gewald products

Cyanoacetamides (IV):Versatile One-Pot Route to 2-Quinoline-3-carboxamides

Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR) scaffolds. Herein, we describe scope of a valuable general protocol for the synthesis of arrays of 2-aminoquinoline-3-carboxamides from cyanoacetamides and 2-aminobenzaldehydes or heterocyclic derivatives via a Friedlander reaction variation. In many cases, the reactions involve a very convenient work up by simple precipitation and filtration. More than 40 new products are described. We foresee our protocol and the resulting derivatives becoming very valuable to greatly expanding the scaffold space of cyanoacetamide derivatives