TY - JOUR

T1 - Non-chelating p-phenylidene-linked bis-imidazoline analogs of known influenza virus endonuclease inhibitors

T2 - Synthesis and anti-influenza activity

AU - Dar'in, Dmitry

AU - Zarubaev, Vladimir

AU - Galochkina, Anastasia

AU - Gureev, Maxim

AU - Krasavin, Mikhail

PY - 2019/1/1

Y1 - 2019/1/1

N2 - A novel chemotype topologically similar to known influenza virus PA endonuclease inhibitors has been designed. It was aimed to reproduce the extended topology of the known metal-chelating ligands with a p-phenylidene-linked bis-imidazoline scaffold. It was envisioned that aromatic groups introduced to this scaffolds via metal-catalyzed N-arylation (Buchwald-Hartwig or Chan-Evans-Lam) would contribute to lipophilic binding to the target and one of the imidazoline nitrogen atoms would ensure non-chelating coordination to the prosthetic divalent metal ion. The compounds displayed appreciable anti-influenza activity in vitro and substantial concentration window from the general cytotoxicity range. Docking analysis of low-energy poses of the most active compound (as well as their comparison to the binding of an inactive compound) revealed that these compounds reproduced similar binding components to a known PA endonuclease inhibitor and displayed similar binding pose and desired monodentate metal coordination, as was initially envisioned. These findings warrant further investigation of the mechanism of action of the newly discovered series.

AB - A novel chemotype topologically similar to known influenza virus PA endonuclease inhibitors has been designed. It was aimed to reproduce the extended topology of the known metal-chelating ligands with a p-phenylidene-linked bis-imidazoline scaffold. It was envisioned that aromatic groups introduced to this scaffolds via metal-catalyzed N-arylation (Buchwald-Hartwig or Chan-Evans-Lam) would contribute to lipophilic binding to the target and one of the imidazoline nitrogen atoms would ensure non-chelating coordination to the prosthetic divalent metal ion. The compounds displayed appreciable anti-influenza activity in vitro and substantial concentration window from the general cytotoxicity range. Docking analysis of low-energy poses of the most active compound (as well as their comparison to the binding of an inactive compound) revealed that these compounds reproduced similar binding components to a known PA endonuclease inhibitor and displayed similar binding pose and desired monodentate metal coordination, as was initially envisioned. These findings warrant further investigation of the mechanism of action of the newly discovered series.

KW - Bis-imidazoline

KW - In silico modeling

KW - Influenza virus

KW - Metal-catalyzed N-Arylation

KW - N-aryl imidazoline

KW - PROTEIN

KW - IDENTIFICATION

UR - http://www.scopus.com/inward/record.url?scp=85055737429&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2018.10.063

DO - 10.1016/j.ejmech.2018.10.063

M3 - Article

AN - SCOPUS:85055737429

VL - 161

SP - 526

EP - 532

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -