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.

A multicomponent pharmacophore fragment-decoration approach to identify selective LRRK2-targeting probes / Tassini, Sabrina; Castagnolo, Daniele; Scalacci, Nicolò; Kissova, Miroslava; Armijos Rivera, Jorge I.; Giagnorio, Federica; Maga, Giovanni; Costantino, Gabriele; Crespan, Emmanuele; Radi, Marco. - In: MEDCHEMCOMM. - ISSN 2040-2503. - 7:3(2016), pp. 484-494. [10.1039/c5md00462d]

A multicomponent pharmacophore fragment-decoration approach to identify selective LRRK2-targeting probes

TASSINI, Sabrina;GIAGNORIO, FEDERICA;COSTANTINO, Gabriele;RADI, Marco
2016-01-01

Abstract

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.
2016
A multicomponent pharmacophore fragment-decoration approach to identify selective LRRK2-targeting probes / Tassini, Sabrina; Castagnolo, Daniele; Scalacci, Nicolò; Kissova, Miroslava; Armijos Rivera, Jorge I.; Giagnorio, Federica; Maga, Giovanni; Costantino, Gabriele; Crespan, Emmanuele; Radi, Marco. - In: MEDCHEMCOMM. - ISSN 2040-2503. - 7:3(2016), pp. 484-494. [10.1039/c5md00462d]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2809179
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