In this study, a series of new benzimidazole-thiadiazole hybrids were synthesized, and the synthesized compounds were screened for their antimicrobial activities against eight species of pathogenic bacteria and three fungal species. Azithromycin, voriconazole, and fluconazole were used as reference drugs in the mtt assay. Among them, compounds 5f and 5h showed potent antifungal activity against C. albicans with a MIC of 3.90 μg/mL. Further, the results of the antimicrobial assay for compounds 5a, 5b, 5f, and 5h proved to be potent against E. faecalis (ATCC 2942) on the basis of an acceptable MIC value of 3.90 μg/mL. The cytotoxic effects of compounds that are effective as a result of their antimicrobial activity on healthy mouse fibroblast cells (L929) were evaluated. According to HOMO-LUMO analysis, compound 5h (with the lower ΔE = 3.417 eV) is chemically more reactive than the other molecules, which is compatible with the highest antibacterial and antifungal activity results. A molecular docking study was performed to understand their binding modes within the sterol 14-α demethylase active site and to interpret their promising fungal inhibitory activities. Molecular dynamics (MD) simulations of the most potent compounds 5f and 5h were found to be quite stable in the active site of the 14-α demethylase (5TZ1) protein.

Inhibition ofaldose reductase (AR), α-glycosidase (α-GLY), and α-amylase (α-AMY) are some of the essential targets in diabetes mellitus (DM). Here, a series of imidazo­[1,2-a]­pyridine-based 1,3,4-thiadiazole derivatives (8a–k) were successfully synthesized and characterized using 1H NMR, 13C NMR, and HRMS spectroscopic techniques. The inhibition effects of the synthesized derivatives against AR, α-GLY, and α-AMY were evaluated using both in vitro and in silico methods. In vitro studies revealed that the derivatives (8a–k) showed significant inhibition activity. The results showed that the novel derivatives (8a–k) demonstrated potential inhibitory activity, with KI values covering the following ranges: 23.47 ± 2.40 to 139.60 ± 13.33 nM for AR and 6.09 ± 0.37 to 119.80 ± 12.31 μM for α-GLY, with IC50 values 81.14 to 153.51 μM for α-AMY. Furthermore, many of these compounds exhibited high inhibition activity, while some of them showed higher potency than the reference compounds. Molecular docking of the target compounds was carried out in the active sites of AR (PDB ID: 4JIR) and α-GLY (PDB ID: 5NN8).

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.

The aim of this research is the synthesis of benzimidazole-1,3,4-oxadiazole derivatives that could be potential anticancer leads inhibiting VEGFR2. The compounds were evaluated for their cytotoxicity against cancer cell lines PANC-1, MCF-7, and A549 using the MTT assay. Two different normal cell lines (hTERT-HPNE and CCD-19Lu) were used to calculate the selectivity indices of the compounds. Compound 4r showed the highest anticancer activities, with IC50 = 5.5, 0.3, and 0.5 μM against the PANC-1, A549, and MCF-7 cell lines, respectively. Also, compounds 4r and 4s were further evaluated for their inhibitory activity against VEGFR2. VGFRA immunolocalizations of compounds 4r and 4s were visualized by the VEGFA immunofluorescent staining method. Molecular docking studies have proven that, as in sorafenib, compounds 4r and 4s show hydrogen bond formation with Asp1046 and Cys919 and hydrophobic interactions with other active site amino acids. Molecular dynamics simulations were carried out for compounds 4r and 4s to examine the stability and behavior of the protein–ligand complex obtained from molecular docking under in silico physiological conditions. An in silico ADME investigation was undertaken to confirm the druglikeness of the synthesized compounds. Furthermore, the stable geometries of the ligands were determined through the application of density functional theory (DFT). The optimized geometries were confirmed to correspond to true minima, as no imaginary frequencies were observed in the vibration frequency survey. The rotations of the thio and benzimidazole groups with respect to the 1,3,4-oxadiazole rings are 180 deg, and the molecules are planar.

Thiadiazole and hydrazone derivatives (5a-5i) were synthesized and their chemical structures were verified and described by ¹H NMR, ¹³C NMR, and HRMS spectra. Three cancer cell lines (MCF-7, MDA, and HT-29) and one healthy cell line (L929) were used to test the cytotoxicity activity of synthesized compounds as well as their inhibitory activity against carbonic anhydrase I, II and IX isoenzymes. Compound 5d (29.74 µM) had a high inhibitory effect on hCA I and compound 5b (23.18 µM) had a high inhibitory effect on hCA II. Furthermore, compound 5i was found to be the most potent against CA IX. Compounds 5a-5i, 5b and 5i showed the highest anticancer effect against MCF-7 cell line with an IC₅₀ value of 9.19 and 23.50 µM, and compound 5d showed the highest anticancer effect against MDA cell line with an IC₅₀ value of 10.43 µM. The presence of fluoro substituent in the o-position of the phenyl ring increases the effect on hCA II, while the methoxy group in the o-position of the phenyl ring increases the activity on hCA I as well as increase the anticancer activity. Cell death induction was evaluated by Annexin V assay and it was determined that these compounds cause cell death by apoptosis. Molecular docking was performed for compounds 5b and 5d to understand their biological interactions. The physical and ADME properties of compounds 5b and 5d were evaluated using SwissADME.