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Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance
Author(s) -
Kaczor Aneta,
Szemerédi Nikoletta,
KucwajBrysz Katarzyna,
Dąbrowska Monika,
Starek Małgorzata,
Latacz Gniewomir,
Spengler Gabriella,
Handzlik Jadwiga
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100252
Subject(s) - multiple drug resistance , pharmacophore , rhodamine 123 , chemistry , in silico , cytotoxicity , pharmacology , mechanism of action , p glycoprotein , stereochemistry , biology , biochemistry , in vitro , antibiotics , gene
ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5‐arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug‐resistant (MDR) ABCB1‐overexpressing T‐lymphoma cancer cells using cytotoxicity assays. The ABCB1‐modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp‐Glo™ Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP‐TLC). Pharmacophore‐based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents ( p ‐fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T‐lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1‐modulating action; in particular, two 5‐benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar.