Synthesis, Docking, and DFT Studies on Novel Schiff Base Sulfonamide Analogues as Selective COX-1 Inhibitors with Anti-Platelet Aggregation Activity

Abstract

Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective COX-1-inhibitory activities of four newly synthesized compounds, <b>10</b>-<b>13</b>, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds <b>10</b>-<b>13</b> were synthesized using the conventional method, sonication, and microwave-assisted methods. Microanalytical and spectral data were utilized to elucidate the structures of the new compounds <b>10</b>-<b>13</b>. Additionally, a spectral NMR experiment [NOESY] was conducted to emphasize the configuration around the double bond of the imine group C=N. The obtained results revealed no observed correlation between any of the neighboring protons, suggesting that the configuration at the C=N double bond is <i>E</i>. Biological results revealed that all the screened compounds <b>10</b>-<b>13</b> might serve as selective COX-1 inhibitors. They showed IC₅₀ values ranging from 0.71 μM to 4.82 μM against COX-1 and IC₅₀ values ranging from 9.26 μM to 15.24 μM against COX-2. Their COX-1 selectivity indices ranged between 2.87 and 18.69. These compounds show promise as promising anti-platelet aggregation agents. They effectively prevented platelet aggregation induced by ADP with IC₅₀ values ranging from 0.11 μM to 0.37 μM, surpassing the standard aspirin with an IC₅₀ value of 0.49 μM. Additionally, they inhibited the platelet aggregation induced by collagen with IC₅₀ values ranging from 0.12 μM to 1.03 μM, demonstrating superior efficacy compared to aspirin, which has an IC₅₀ value of 0.51 μM. In silico molecular modeling was performed for all the target compounds within the active sites of COX-1 and COX-2 to rationalize their selective inhibitory activities towards COX-1. It was found that the binding interactions of the designed compounds within the COX-1 active site had remained unaffected by the presence of celecoxib. Molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were performed to study the stability of <i>E</i>-forms with respect to <i>Z</i>-forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors.