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

Autor:	Gabriele Costantino, Miroslava Kissova, Jorge I. Armijos-Rivera, Daniele Castagnolo, Marco Radi, Nicolò Scalacci, Federica Giagnorio, Giovanni Maga, Sabrina Tassini, Emmanuele Crespan
Rok vydání:	2016
Předmět:	Pharmacology 010405 organic chemistry Chemistry Organic Chemistry Pharmaceutical Science 010402 general chemistry 01 natural sciences Biochemistry Combinatorial chemistry 0104 chemical sciences Rapid identification Low affinity Fragment (logic) Drug Discovery Molecular Medicine Pharmacophore
Zdroj:	MedChemComm. 7:484-494
ISSN:	2040-2511 2040-2503
DOI:	10.1039/c5md00462d
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::66b4e1698315a6d4979ef8c31c09a1d6 https://doi.org/10.1039/c5md00462d Zobrazit plný text záznamu