148055-95-2Relevant articles and documents
Investigating molecular dynamics-guided lead optimization of EGFR inhibitors
Lavecchia, Martin J.,Puig De La Bellacasa, Raimon,Borrell, José I.,Cavasotto, Claudio N.
, p. 768 - 778 (2016)
The epidermal growth factor receptor (EGFR) is part of an extended family of proteins that together control aspects of cell growth and development, and thus a validated target for drug discovery. We explore in this work the suitability of a molecular dynamics-based end-point binding free energy protocol to estimate the relative affinities of a virtual combinatorial library designed around the EGFR model inhibitor 6{1} as a tool to guide chemical synthesis toward the most promising compounds. To investigate the validity of this approach, selected analogs including some with better and worse predicted affinities relative to 6{1} were synthesized, and their biological activity determined. To understand the binding determinants of the different analogs, hydrogen bonding and van der Waals contributions, and water molecule bridging in the EGFR-analog complexes were analyzed. The experimental validation was in good qualitative agreement with our theoretical calculations, while also a 6-dibromophenyl-substituted compound with enhanced inhibitory effect on EGFR compared to the reference ligand was obtained.
C4-C5 fused pyrazol-3-amines: When the degree of unsaturation and electronic characteristics of the fused ring controls regioselectivity in Ullmann and acylation reactions
Borrell, José I.,Bou-Petit, Elisabeth,Estrada-Tejedor, Roger,Font-Bardia, Mercè,Plans, Arnau,Puigjaner, Cristina,Ramon Y Cajal, Santiago,Rodríguez-Picazo, Nieves,Teixidó, Jordi,Torres-Coll, Antoni
, p. 5145 - 5156 (2020)
Pyrazol-3-amine is a scaffold present in a large number of compounds with a wide range of biological activities and, in many cases, the heterocycle is C4-C5 fused to a second ring. Among the different reactions used for the decoration of the pyrazole ring, Ullmann and acylation have been widely applied. However, there is some confusion in the literature regarding the regioselectivity of such reactions (substitution at N1 or N2 of the pyrazole ring) and no predictive rule has been so far established. As a part of our work on 3-amino-pyrazolo[3,4-b]pyridones 13, we have studied the regioselectivity of such reactions in different C4-C5 fused pyrazol-3-amines. As a rule of thumb, the Ullmann and acylation reactions take place, predominantly, at the NH and non-protonated nitrogen atom of the pyrazole ring respectively, of the most stable initial tautomer (1H- or 2H-pyrazole), which can be easily predicted by using DFT calculations. This journal is
