Structural properties of newly 4,7-dihydroxycoumarin derivatives as potential inhibitors of XIIa, Xa, IIa factors of coagulation

Abstract

Some coumarin derivatives show notable anticoagulant properties through their ability to interrupt the enzymatic function of vitamin K epoxide reductase. The current challenge lies in the development of novel derivatives that are more efficient and less harmful, specifically targeting the direct inhibition of coagulation factors. This study examined the direct inhibitory potential of two recently synthesized coumarin derivatives, 3-(1-(3-hydroxy-4-methoxyphenyl)-amino)-ethyldiene)-2,4-dioxochroman-7-yl acetate (A-3OH) and 3-(1-(4-hydroxy-3-methoxyphenyl)-amino)-ethyldiene)-2,4-dioxochroman-7-yl acetate (A-4OH), according to coagulation factors IIa, Xa, and XIIa. Accurately defining the structural properties of compounds is of great importance for a comprehensive understanding of the biological activity of pharmaceutical agents. In regard, this study aimed to analyze the structural (Potential Energy Surface (PES)), spectroscopic (FT-IR, NMR, and UV–Vis), and electronic properties (Quantum Theory of Atoms in Molecules (QTAIM)) of two newly synthesized compounds. These properties are determined using a combination of experimental and theoretical methods (B3LYP-D3BJ/6–311++G(d,p) level of theory). The investigated compounds deviate from planarity based on the results of structural properties. The results of QTAIM analysis show the presence of partially covalent hydrogen bonds and closed-shell van der Waals interactions that stabilize the examined compounds. Based on the large correlation coefficient (R) and low mean absolute error (MAE) of the spectroscopic data showed that the applied level of theory effectively replicated the experimental finding. The results from the molecular docking study suggest that both compounds demonstrate similar inhibitory effects on IIa when compared to the standard inhibitor dabigatran (DAB). The efficacy of A-3OH in inhibiting Xa is similar to that of conventional inhibitors apixaban (API), and rivaroxaban (RIV). The observed inhibitory effect of both compounds on coagulation factor XIIa was more potent than that of the conventional co-crystallized inhibitor. The results of this study add to the understanding of the structure-activity relationship of coumarin derivatives and provide possibilities for enhancing anticoagulant therapy and clinical outcomes for coagulation-related illnesses. The findings lay a foundation for further in vitro and in vivo investigations into the anticoagulant activities of the compounds, contributing to their potential pharmaceutical application.