Synthesis, Bioactivities, and <i>in Silico</i> Studies of Novel Benzo[ <i>d</i> ][1,3]Dioxole-Based Pyrazoline Sulfonamides

In this study, benzo[d][1, 3]dioxole-based pyrazoline sulfonamides were investigated for their biological effects on carbonic anhydrases (CAs), acetylcholinesterase (AChE), and the growth of cancer/noncancer cell lines. The synthesized 11 compounds were tested for cytotoxic efficacy against four human OSCC cell lines (Ca9-22, HSC-2, HSC-3, HSC-4) and three human normal oral cells (HGF, HPLF, and HPC). The CC50 values were in the range of 9.6–28.1 µM (toward Ca9-22), 10.3–44.0 µM (HSC-2), 8.6–32.1 µM (HSC-3) and 7.7–29.5 µM (HSC-4). All of these compounds showed reduced viable cell number of all oral cancer cells dose-dependently and ultimately killed them at the higher concentration (25 ∼ 100 µM), in contrast to the reference compound 5-FU that showed cytostatic growth inhibition without killing out even at the highest concentration (1000 µM). Among the series, compounds 7 (TS = 7.0, PSE= 22.4), 10 (TS = 9.0, PSE= 49.6), and 11 (TS = 6.9, PSE= 28.4) exhibited comparable antitumor-potential with reference drug 5-FU (TS = 13.0, PSE = 17.1), based on tumor-selectivity index (TS) and potency selectivity expression (PSE) values. In addition, compounds 7, 6, and 1 showed the most potent inhibition of hCA I (Ki = 17.23 ± 4.96 µM), hCA II (Ki = 3.10 ± 0.05 µM), and AChE (Ki = 0.26 ± 0.005 nM) in bioassays. To gain deeper insight into the electronic properties of the studied molecules, frontier molecular orbital and molecular electrostatic potential analyses were performed using density functional theory. Molecular docking studies were conducted to comprehend the interactions between enzymes studied and lead compounds 1, 6, and 7. Compounds 7 and 6 formed strong hydrogen bonds with key residues of hCA I and hCA II and these interactions likely contribute to its enhanced inhibitory effect. Compound 1 also displayed strong hydrogen bonds with key residues for acetylcholinesterase inhibition. Enzyme inhibition and cytotoxicity study findings have revealed promising lead compounds, which can serve as templates for designing novel molecules in drug discovery.