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

Imidazole derivatives display extensive applicationsin pharmaceutical chemistry and have been investigated asbioactive compounds for medicinal chemistry. In this study,besides the starting materials (3a−c and 4a−c), synthesis,characterization, and biological activity studies were conductedon a total of 18 compounds, nine of which are known and the othernine are original. The compounds investigated in the study are aseries of alkyl (7−15) and aryl (16−24) ether derivatives bearingsubstituted phenyl and imidazole rings, which were characterizedusing various methods including 1H NMR, 13C NMR, FT-IRanalysis, elemental analysis, and mass spectroscopy. Computer-aided drug design studies have been carried out to predict the biological activities of compounds. Besides DFT calculations, thebinding 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 wereperformed 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 15.67nM and cytosolic hCA II isozyme with IC50 values ranging from 5.65 to 14.84 nM. L929 (mouse fibroblast cell line) was used as thecontrol healthy cell line, and MCF7 (breast cancer), C6 (rat glioblastoma), and HT-29 (colon cancer) cells were used in cell culturestudies as cancer cell lines. Before the study on cancer cells, all compounds were examined on healthy cells, and their cytotoxicity wasdetermined. As a result of these data, studies continued with six compounds determined to be nontoxic. On cancerous cells, it wasdetermined that compounds 3a, 3b, 4a, 4b, 4c, and 7 had cytotoxic effects on both colon cancer and brain tumors. It was found thatcompound 3b had a more toxic effect than cisplatin on the glioma cell line with an IC50 value of 10.721 ± 0.38 μM, and compound3a 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 thesame compounds did not have a statistically significant effect on breast cancer. Flow cytometry studies also showed that when theIC50 dose of compound 3b was applied to the C6 cell line, the cells tended to early and late apoptosis. Additionally, it has beenshown by flow cytometry that the cell cycle stops in the G0/G1 phase. A similar effect was observed in the colon cancer cell line withcompound 3a. Compound 3b caused early and late apoptosis of the colon cancer cell line with the applied IC50 dose and stopped thecell cycle in the G0/G1 phase. Finally, the FRAP method studied all synthesized compounds’ antioxidant effects. According to themeasured antioxidant power results, it was determined that no compound had a more effective reducing power than vitamin E.