Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 4 (23), 20381-20393

Design, Synthesis, and Anticancer Activity of Novel Trimethoxyphenyl-Derived Chalcone-Benzimidazolium Salts


Design, Synthesis, and Anticancer Activity of Novel Trimethoxyphenyl-Derived Chalcone-Benzimidazolium Salts

Jun-Li Yang et al. ACS Omega.


A series of novel trimethoxyphenyl-derived chalcone-benzimidazolium salts were synthesized. The biological properties of the compounds were screened in vitro against five different human tumor cell lines. The results suggest that the 5,6-dimethyl-benzimidazole or 2-methyl-benzimidazole ring as well as the 2-naphthylmethyl, 4-methylbenzyl, or 2-naphthylacyl substituent at position-3 of the benzimidazole ring was important to the cytotoxic activity. Notably, (E)-5,6-dimethyl-3-(naphthalen-2-ylmethyl)-1-(3-(4-(3-(3,4,5-trimethoxyphenyl)acryloyl)phenoxy)propyl)-1H-benzo[d]imidazol-3-ium bromide (7f) was more selective to HL-60, MCF-7, and SW-480 cell lines with IC50 values 8.0-, 11.1-, and 5.8-fold lower than DDP. Studies of the antitumor mechanism of action showed that compound 7f could induce cell-cycle G1 phase arrest and apoptosis in SMMC-7721 cells.

Conflict of interest statement

The authors declare no competing financial interest.


Figure 1
Figure 1
Representative structures of chalcone, imidazolium salts, and trimethoxyphenyl-derived compounds.
Scheme 1
Scheme 1. Syntheses of Hybrid Compounds 6ac, 7aj, 8aj, and 9aj
Figure 2
Figure 2
X-ray crystal structure of compound 8d.
Scheme 2
Scheme 2. Structure Analysis of Trimethoxyphenyl-Derived Chalcone-Benzimidazolium Salts
Figure 3
Figure 3
Compound 7f caused significant apoptosis of SMMC-7721 cells. (A) Cells were treated with 5 and 10 μM compound 7f for 48 h. Cell apoptosis was determined by the annexin V–FITC/PI double-staining assay. (B) Quantification of cell apoptosis.
Figure 4
Figure 4
Effects of compound 7f on SMMC-7721 cell-cycle progression. (A) Cells were treated with 2.5 and 5 μM of compound 7f for 24 h. Cell cycle was determined by PI staining and cell cytometry. (B) Percentage of cells in different phases was quantified. At least three independent experiments were performed, and data from one representative experiment is shown. Data represents the mean ± standard deviation (S.D.) of three independent experiments.
Figure 5
Figure 5
Model of compound 7f docked into PI3Kγ.

Similar articles

See all similar articles


    1. Zhuang C.; Zhang W.; Sheng C.; Zhang W.; Xing C.; Miao Z. Chalcone: A Privileged Structure in Medicinal Chemistry. Chem. Rev. 2017, 117, 7762–7810. 10.1021/acs.chemrev.7b00020. - DOI - PMC - PubMed
    1. Hsieh C.-J.; Xu K.; Lee I.; Graham T.-J.-A.; Tu Z.; Dhavale D.; Kotzbauer P.; Mach R.-H. Chalcones and Five-Membered Heterocyclic Isosteres Bind to Alpha Synuclein Fibrils in Vitro. ACS Omega 2018, 3, 4486–4493. 10.1021/acsomega.7b01897. - DOI - PMC - PubMed
    1. Israf D.-A.; Khaizurin T.-A.; Syahida A.; Lajis N.-H.; Khozirah S. Cardamonin Inhibits COX and iNOS Expression via Inhibition of p65NF-kB Nuclear Translocation and Ik-B Phosphorylation in RAW 264.7 Macrophage Cells. Mol. Immunol. 2007, 44, 673–679. 10.1016/j.molimm.2006.04.025. - DOI - PubMed
    1. Yamamoto T.; Yoshimura M.; Yamaguchi F.; Kouchi T.; Tsuji R.; Saito M.; Obata A.; Kikuchi M. Anti-allergic Activity of Naringenin Chalcone from a Tomato Skin Extract. Biosci. Biotechnol. Biochem. 2004, 68, 1706–1711. 10.1271/bbb.68.1706. - DOI - PubMed
    1. Cho S.; Kim S.; Jin Z.; Yang H.; Han D.; Baek N.-I.; Jo J.; Cho C.-W.; Park J.-H.; Shimizu M.; Jin Y.-H. Isoliquiritigenin, a Chalcone Compound, Is a Positive Allosteric Modulator of GABAA Receptors and Shows Hypnotic Effects. Biochem. Biophys. Res. Commun. 2011, 413, 637–642. 10.1016/j.bbrc.2011.09.026. - DOI - PubMed

LinkOut - more resources