Chiral Switching of Zileuton via Enantiospecific Cocrystal Engineering

Chiral switches refer to chiral medications originally claimed, approved, and marketed as racemic compounds or racemic conglomerates, which later undergo redevelopment into more potent single-enantiomer forms. Such stereoisomeric refinement holds promise for enhancing therapeutic effectiveness while cutting down on adverse effects. Zileuton (ZIL), a 5-lipoxygenase inhibitor, is primarily used to control and prevent symptoms caused by asthma and is commercially available as a racemate (rac-ZIL). The R-enantiomer of ZIL (R-ZIL) has shown superior efficacy in inhibiting 5-lipoxygenase activity compared to S-ZIL. In order to separate the target enantiomer from the rac-ZIL compound, an enantiospecific cocrystal of R-ZIL with L-phenylalanine (L-PHE) was developed in this contribution. The chemical composition of the cocrystal was verified using electron cryomicroscopy (cryoEM) method microcrystal electron diffraction (MicroED), 1H NMR spectrum, and dynamic vapor sorption (DVS). The absolute configuration of ZIL in this sample was also clearly identified by reference to the configuration-defined PHE within the crystal structure. The pseudopolymorphic behavior of R-ZIL-L-PHE was disclosed via in situ humidity-controlled XRD measurements. Subsequently, an enantiopure sample of R-ZIL was collected through a simple aqueous slurry process. Chiral chromatography analysis indicates that both the R-ZIL-L-PHE cocrystal and the R-ZIL product exhibit high optical purity (ee >98.5%), which lays a solid foundation for the further development of crystallization-based resolution processes. Compared with the rac-ZIL sample, R-ZIL demonstrated improved dissolution properties and physical stability against hydration. These advancements are expected to significantly benefit the pharmaceutical applications of enantiomerically pure ZIL along with its enhanced pharmacological property.