Imidazole-Derived Alkyl and Aryl Ethers: Synthesis, Characterization, In Vitro Anticancer and Antioxidant Activities, Carbonic Anhydrase I–II Inhibition Properties, and In Silico Studies

TL;DR

This study synthesizes and tests imidazole-based compounds for anticancer, antioxidant, and enzyme inhibition properties, showing some are more effective than standard drugs in certain cancer cell lines.

Contribution

The paper introduces nine new imidazole ether derivatives with promising anticancer and enzyme inhibition profiles, supported by in vitro and in silico analyses.

Findings

Compounds 17 and 19–24 inhibited hCA I and II with IC50 values between 4.13–15.67 nM and 5.65–14.84 nM, respectively.

Compound 3b was more toxic than cisplatin on glioma cells (IC50: 10.721 μM) and compound 3a on colon cancer cells (IC50: 20.88 μM).

Flow cytometry showed compounds 3a and 3b induced apoptosis and G0/G1 cell cycle arrest in cancer cells.

Abstract

Imidazole derivatives
display extensive applications in pharmaceutical
chemistry and have been investigated as bioactive compounds for medicinal
chemistry. In this study, besides the starting materials (3a–c and 4a–c),
synthesis, characterization, and biological activity studies were
conducted on a total of 18 compounds, nine of which are known and
the other nine are original. The compounds investigated in the study
are a series of alkyl (7–15) and
aryl (16–24) ether derivatives bearing
substituted phenyl and imidazole rings, which were characterized using
various methods including 1H NMR, 13C NMR, FT-IR
analysis, elemental analysis, and mass spectroscopy. Computer-aided
drug design studies have been carried out to predict the biological
activities of compounds. Besides DFT calculations, the binding affinities
of the compounds to EGFR, VEGFR2, FGFR1, HSP90, hCA I, and hCA II
were investigated. Additionally, drug-likeness and ADME analyses were
performed on the compounds. Anticancer, antioxidant, and enzyme inhibition
activity tests were performed in biological activity studies on the
synthesized compounds. Among the synthesized compounds, compounds 17 and 19–24 generally exhibited
inhibition profiles against the widespread cytosolic hCA I isozyme
with IC50 values ranging from 4.13 to 15.67 nM and cytosolic
hCA II isozyme with IC50 values ranging from 5.65 to 14.84
nM. L929 (mouse fibroblast cell line) was used as the control healthy
cell line, and MCF7 (breast cancer), C6 (rat glioblastoma), and HT-29
(colon cancer) cells were used in cell culture studies as cancer cell
lines. Before the study on cancer cells, all compounds were examined
on healthy cells, and their cytotoxicity was determined. As a result
of these data, studies continued with six compounds determined to
be nontoxic. On cancerous cells, it was determined that compounds 3a, 3b, 4a, 4b, 4c, and 7 had cytotoxic effects
on both colon cancer and brain tumors. It was found that compound 3b had a more toxic effect than cisplatin on the glioma cell
line with an IC50 value of 10.721 ± 0.38 μM,
and compound 3a had a more toxic effect on the colon
cancer cell line with an IC50 value of 20.88 ± 1.02
μM. However, it was determined that the same compounds did not
have a statistically significant effect on breast cancer. Flow cytometry
studies also showed that when the IC50 dose of compound 3b was applied to the C6 cell line, the cells tended to early
and late apoptosis. Additionally, it has been shown by flow cytometry
that the cell cycle stops in the G0/G1 phase. A similar effect was
observed in the colon cancer cell line with compound 3a. Compound 3b caused early and late apoptosis of the
colon cancer cell line with the applied IC50 dose and stopped
the cell cycle in the G0/G1 phase. Finally, the FRAP method studied
all synthesized compounds’ antioxidant effects. According to
the measured antioxidant power results, it was determined that no
compound had a more effective reducing power than vitamin E.

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