5-Arylideneimidazolones as a potential solution for multi-drug resistance in cancer cells

Abstract

One of a serious threats in treatment of cancer diseases is multi-drug resistance (MDR). MDR of cancer cells is a significant problem of chemotherapy failure and is growing rapidly. Thus, searching for compounds able to block at least one mechanism of cancer MDR is an important goal of medicinal chemistry. Such activity was described previously for imidazolone derivatives. Therefore, the aim of our research is searching for compounds able to inhibit MDR in cancer cells in the group of 5-arylideneimidazolone derivatives. Hence, we designed and synthesized 18 new compounds. To assess their activity, rhodamine 123 accumulation assay was conducted using sensitive and Pgp overexpressing MDR mouse T-lymphoma cell lines. Additionally, lipophilicity was examined using RP-TLC method. As results, imidazolones containing various aromatic moieties at position 5 and amine fragment at position 2 or at position 2 and 3 were synthesized within 3- or 4-step synthesis pathways, including: (i) Knoevenagel condensation, (ii) S-methylation, (iii) reaction with amine with or without (iv) Dimroth rearrangement. Final products were converted into hydrochlorides to be tested in the biological assays. Results pointed out 2 compounds as highly cytotoxic for MDR cancer cells, while weakly for the reference ones. In rhodamine123 accumulation assay, other two compounds displayed activity in the range of the strong reference Pgp-inhibitor, tariquidar. The lipophilicity test results showed a “drug-like” lipophilicity for this series (RM0 = 1.48-3.35). Basing on obtained results, 5-arylideneimidazolones might be a promising tool to inhibit MDR in cancer cells. This work was supported by grants: 0169/DIA/2017/46, N42/DBS/000070 and N42/DBS/000027.