Search for ABCB1 Modulators Among 2-Amine-5-Arylideneimidazolones as a New Perspective to Overcome Cancer Multidrug Resistance

Abstract

Multidrug resistance (MDR) is a severe problem in the treatment of cancer with overexpression of glycoprotein P (Pgp, ABCB1) as a reason for chemotherapy failure. A series of 14 novel 5-arylideneimidazolone derivatives containing the morpholine moiety, with respect to two different topologies (groups A and B), were designed and obtained in a three- or four-step synthesis, involving the Dimroth rearrangement. The new compounds were tested for their inhibition of the ABCB1 efflux pump in both sensitive (parental (PAR)) and ABCB1-overexpressing (MDR) T-lymphoma cancer cells in a rhodamine 123 accumulation assay. Their cytotoxic and antiproliferative effects were investigated by a thiazolyl blue tetrazolium bromide (MTT) assay. For active compounds, an insight into the mechanisms of action using either the luminescent Pgp-Glo™ Assay in vitro or docking studies to human Pgp was performed. The safety profile in vitro was examined. Structure–activity relationship (SAR) analysis was discussed. The most active compounds, representing both 2-substituted- (11) and Dimroth-rearranged 3-substituted (18) imidazolone topologies, displayed 1.38–1.46 fold stronger efflux pump inhibiting effects than reference verapamil and were significantly safer than doxorubicin in cell-based toxicity assays in the HEK-293 cell line. Results of mechanistic studies indicate that active imidazolones are substrates with increasing Pgp ATPase activity, and their dye-efflux inhibition via competitive action on the Pgp verapamil binding site was predicted in silico.

Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance

“…The specific activity in the ethidium bromide assay was found for the amine-free hydantoins with benzyloxybenzylidene moiety at position 5 (3, Figure 2) [23]. In particular, imidazolones with an amine group at position 2 or 2 and 3, demonstrated the potential ABCB1 modulating activity (4 and 5, Figure 2) stronger than verapamil [24]. Previous studies have provided useful conclusions coming from performed SAR analysis.…”

“…Taking into account both, the need to find effective and pharmacologically safe ABCB1 modulators that finally would get pharmaceutical market and the growing interest of modern medicinal chemistry in multi-target drugs, it is especially promising to search for new anticancer agents, selective towards MDR cancer cells, with simultaneous MDR-reversal properties. Our previous studies indicated that some of imidazolone and hydantoin derivatives were able to modulate the efflux pump ABCB1 [22][23][24]. The specific activity in the ethidium bromide assay was found for the amine-free hydantoins with benzyloxybenzylidene moiety at position 5 (3, Figure 2) [23].…”

“…Thus, the following traits for imidazolones able to modulate ABCB1 have been postulated: (i) the aromatic moiety; (ii) the positive ionizable center; (iii) the hydrophilic moiety, (iv) the alkyl linker and (v) the hydrogen bond acceptor [22]. However, the anticancer cytotoxicity of those series was usually negligible or moderate in the best case [22][23][24]. Although our previous search for the imidazolone-derived ABCB1 modulators was comprehensive, two important aspects have been missed so far, i.e.…”

Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria

“…The routes for the synthesis of imidazolone ( 7 – 21 ) and thiazolone ( 22 , 23 ) derivatives are depicted in Scheme 1 , while the synthesis of compounds 7 – 10 , 12 – 17, 19 – 21, 24 – 30, 32 – 38 has been described elsewhere [ 27 , 28 ]. In the first step, Knoevenagel condensation was performed, in which imidazolidinone or thiazolidinone reacted with an appropriate aromatic aldehyde to access the intermediates, namely 5-arylideneimidazolidinones ( 24 – 30 , Scheme 1 ) or 5-arylidenethiazolidinone ( 31 , Scheme 1 ).…”

“…The UPLC/MS purity of compounds 7 – 23 was determined (%). The synthesis of intermediates 24 – 30, 32 – 38 and products 7 – 10, 12 – 17, 19 – 21 was described earlier [ 27 , 28 ].…”