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, 10–13, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds 10–13 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 10–13. 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 E. Biological results revealed that all the screened compounds 10–13 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 E-forms with respect to Z-forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors.