Novel Thiosemicarbazone Derivatives: In Vitro and In Silico Evaluation as Potential MAO-B Inhibitors

MAO-B inhibitors are frequently used in the treatment of neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Due to the limited number of compounds available in this field, there is a need to develop new compounds. In the recent works, it was shown that various thiosemicarbazone derivatives show hMAO inhibitory activity in the range of micromolar concentration. It is thought that benzofuran and benzothiophene structures may mimic structures such as indane and indanone, which are frequently found in the structures of such inhibitors. Based on this view, new benzofuran/benzothiophene and thiosemicarbazone hybrid compounds were synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro fluorometric method. The compounds including methoxyethyl substituent (2b and 2h) were found to be the most effective agents in the series against MAO-B enzyme with the IC50 value of 0.042 ± 0.002 µM and 0.056 ± 0.002 µM, respectively. The mechanism of hMAO-B inhibition of compounds 2b and 2h was investigated by Lineweaver–Burk graphics. Compounds 2b and 2h were reversible and non-competitive inhibitors with similar inhibition features as the substrates. The Ki values of compounds 2b and 2h were calculated as 0.035 µM and 0.046 µM, respectively, with the help of secondary plots. The docking study of compound 2b and 2h revealed that there is a strong interaction between the active sites of hMAO-B and analyzed compound

Synthesis and Anticancer Activities of Pyrazole–Thiadiazole-Based EGFR Inhibitors

Lung cancer is one of the most common cancer types of cancer with the highest mortality rates. However, while epidermal growth factor receptor (EGFR) is an important parameter for lung cancer, EGFR inhibitors also show great promise in the treatment of the disease. Therefore, a series of new EGFR inhibitor candidates containing thiadiazole and pyrazole rings have been developed. The activities of the synthesized compounds were elucidated by in vitro MTT, (which is chemically 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), cytotoxicity assay, analysis of mitochondrial membrane potential (MMP) by flow cytometry, and EGFR inhibition experiments. Molecular docking and molecular dynamics simulations were performed as in silico studies. Compounds 6d, 6g, and 6j showed inhibitor activity against the A549 cell line with IC50 = 5.176 ± 0.164; 1.537 ± 0.097; and 8.493 ± 0.667 μM values, respectively. As a result of MMP by flow cytometry, compound 6g showed 80.93% mitochondrial membrane potential. According to the results of the obtained EGFR inhibitory assay, compound 6g shows inhibitory activity on the EGFR enzyme with a value of IC50 = 0.024 ± 0.002 μM

Synthesis and Anticancer Activities of Pyrazole–Thiadiazole-Based EGFR Inhibitors

Lung cancer is one of the most common cancer types of cancer with the highest mortality rates. However, while epidermal growth factor receptor (EGFR) is an important parameter for lung cancer, EGFR inhibitors also show great promise in the treatment of the disease. Therefore, a series of new EGFR inhibitor candidates containing thiadiazole and pyrazole rings have been developed. The activities of the synthesized compounds were elucidated by in vitro MTT, (which is chemically 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), cytotoxicity assay, analysis of mitochondrial membrane potential (MMP) by flow cytometry, and EGFR inhibition experiments. Molecular docking and molecular dynamics simulations were performed as in silico studies. Compounds 6d, 6g, and 6j showed inhibitor activity against the A549 cell line with IC50 = 5.176 ± 0.164; 1.537 ± 0.097; and 8.493 ± 0.667 μM values, respectively. As a result of MMP by flow cytometry, compound 6g showed 80.93% mitochondrial membrane potential. According to the results of the obtained EGFR inhibitory assay, compound 6g shows inhibitory activity on the EGFR enzyme with a value of IC50 = 0.024 ± 0.002 μM