A multicomponent pharmacophore fragment-decoration approach to identify selective LRRK2-targeting probesThe authors declare no competing interest.Electronic supplementary information (ESI) available: Experimental procedures and analytical data for compounds 9 and 10, in vitro LRRK2 inhibition assays, inhibition mechanism and kinase panel data. See DOI: 10.1039/c5md00462d

• Main Authors: Tassini, Sabrina, Castagnolo, Daniele, Scalacci, Nicolò, Kissova, Miroslava, Armijos-Rivera, Jorge I, Giagnorio, Federica, Maga, Giovanni, Costantino, Gabriele, Crespan, Emmanuele, Radi, Marco
• Format: Journal Article
• Published: 16.03.2016
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c5md00462d

Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. Based on the structure of recently identified inhibitors, we decided to develop a new multicomponent approach to explore the biologically relevant space around their key pharmacophore fragment. The combination of organo/metal catalysis and microwave-assisted technology, allowed us to quickly generate highly functionalized heteroaryl-hydrazone derivatives for biological investigation. Enzymatic studies on the synthesized compounds allowed the identification of promising compounds endowed with a good LRRK2 specificity index (wt/G2019S activity ratio), low affinity towards a small panel of selected kinases and a mixed-type inhibition against the pathogenic G2019S mutant. These results show how a diversity-oriented approach based on a privileged pharmacophore fragment may play a key role in the identification of novel biologically relevant chemical probes. Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents.