Synthesis and characterization of novel imino derivatives of acenocoumarol: chiral separation, absolute configuration and determination of biological activity

Abstract

Acenocoumarol (an anticoagulant agent) is not capable of work quickly enough in some patients due to its narrow half-life range. Therefore, the anticoagulant activity of acenocoumarol was increased by synthesizing and characterizing, via chiral separation, five new imino derivatives (3a–e). These derivatives are racemic, and the existing 20 stereoisomers were separated via chiral HPLC using a Chiralpak® IB column under a normal mobile phase mode. The values for the retention, separation, and resolution factors were 0.11–0.63, 1.11–2.21, and 0.28–2.16, respectively. The absolute configuration of all 20 stereoisomers was determined through ECD and HPLC results. The geometry optimization of all 20 stereoisomers was carried out via DFT calculations. The enhanced biological activities of the isomers were also predicted using DFT calculations. The 102 R/Z, 103 R/Z, 104 R/E, 105 R/E, and 106 R/Z isomers were the most stable structures among the twenty stereoisomers studied. The energy difference between E_HOMO and E_LUMO (−0.1353 to −0.22271 eV) indicated the good biological activities of these derivatives. Their high dipole moment values (7.20–18.8) are an indication of good receptor interactions through non-covalent bonding. These synthesized, characterized, and optical-activity-separated stereoisomers are better anticoagulant agents than acenocoumarol. This work will provide better medication in the future for all patients.