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

Tassini, Sabrina, Castagnolo, Daniele, Scalacci, Nicolò, Kissova, Miroslava, Armijos-Rivera, Jorge, Giagnorio, Federica, Maga, Giovanni, Costantino, Gabriele, Crespan, Emmanuele and Radi, Marco (2016) A multicomponent pharmacophore fragment-decoration approach to identify selective LRRK2-targeting probes. MedChemComm, 7 (3). pp. 484-494. ISSN 2040-2503

Full text not available from this repository. (Request a copy)
Official URL: https://doi.org/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.

Item Type: Article
Subjects: B900 Others in Subjects allied to Medicine
C100 Biology
F100 Chemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Becky Skoyles
Date Deposited: 15 Apr 2016 10:48
Last Modified: 10 Oct 2019 18:01
URI: http://nrl.northumbria.ac.uk/id/eprint/26562

Actions (login required)

View Item View Item


Downloads per month over past year

View more statistics