Computer-aided search for 5-arylideneimidazolone anticancer agents able to overcome ABCB1-based multidrug resistance

ChemMedChem. 2021 Apr 30. doi: 10.1002/cmdc.202100252. Online ahead of print.


ABCB1 modulation is an interesting strategy in search for new anticancer agents overcoming multidrug resistance (MDR). Hence, 17 new 5-arylideneimidazolones containing amine moiety, as potential ABCB1 inhibitors was designed, synthesized, and investigated. The series was tested in both, parental (PAR) and multidrug resistant (MDR) overproducing ABCB1, T-lymphoma cancer cells using cytotoxicity assay. The ABCB1 modulating activity was examined in the rhodamine 123 accumulation test, followed by Pgp-Glo™ Assay to determine an influence of most active compounds on ATPase. Lipophilic properties were assessed both, in silico and experimentally (RP-TLC). Pharmacophore-based molecular modelling towards ABCB1 modulating was performed. The studies allowed to find 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, especially, two 5-benzyloxybenzylidene derivatives displayed activity nearly as strong as tariquidar.

PMID:33929088 | DOI:10.1002/cmdc.202100252