DOI: 10.6084/m9.figshare.29155805
title: Synthesis, Bioactivities, and <i>in Silico</i> Studies of Novel Benzo[<i>d</i>][1,3]Dioxole-Based Pyrazoline Sulfonamides

description: In this study, benzo[<i>d</i>][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 <b>11</b> 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 CC<sub>50</sub> 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 <b>7</b> (TS = 7.0, PSE= 22.4), <b>10</b> (TS = 9.0, PSE= 49.6), and <b>11</b> (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 <b>i</b>ndex (TS) and potency selectivity expression (PSE) values. In addition, compounds <b>7</b>, <b>6</b>, and <b>1</b> 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 <b>1</b>, <b>6</b>, and <b>7</b>. Compounds <b>7</b> and <b>6</b> formed strong hydrogen bonds with key residues of hCA I and hCA II and these interactions likely contribute to its enhanced inhibitory effect. Compound <b>1</b> 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. This study presents a novel novel benzo[<i>d</i>][1, 3]dioxole-based pyrazoline sulfonamides These derivatives were biological investigated for their anticancer, anti- carbonic anhydrase and anti-Alzheimer’s potential. The structural confirmation of the synthesized compounds was achieved via spectroscopic analysis. These derivatives were subjected to in silico molecular docking study to gain insight into the binding interactions with target enzymes. These derivatives were also investigated for their pharmacokinetic properties through ADME analysis to study their drug likeness attributes. Compound <b>10</b> demonstrated higher tumor specificity (TS1 = 9, TS2 = 28.6, PSE = 49.6) than compound <b>11</b> (TS1 = 6.9, TS2 = 17.2, PSE = 28.4). Inhibition tests of CA and AChE revealed that compounds <b>7</b>, <b>6</b>, and <b>1</b> inhibited most potently hCA I (Ki = 17.23 ± 4.96 µM), hCA II (Ki = 3.10 ± 0.05 µM), and AChE (Ki = 0.2199 ± 0.030 µM), respectively. In subsequent research, compounds <b>1</b>, <b>6</b>, <b>7</b>, and <b>10</b> may be employed as lead compounds.