Enantioselective polar-organic mode high-performance liquid chromatographic separation of lifitegrast on immobilized polysaccharide stationary phase and its application to pH-dependent chiral interconversion studies.

(S)-Lifitegrast (LFT) is the novel integrin antagonist, approved by the Food and drug administration, to treat signs and symptoms of dry eye disease. Synthesis of racemic LFT, preparative and analytical enantiomer separation, and chiral interconversion studies are lacking in the literature. Hence, in our study, synthesis of LFT racemate, chiral preparative purification procedure of enantiomer, and comprehensive analytical advancements are focused on rapid enantioselective separation and pH-dependent chiral interconversion studies. The synthesis of LFT racemate employed 2-amino-3-(3-(methylsulfonyl)phenyl)propanoic acid hydrochloride and 2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carbonyl chloride as starting materials. (R)-LFT was isolated from the racemate by preparative chiral HPLC and characterized using Q-TOF, FT-IR, NMR spectroscopy, and chiral HPLC. The purity of (R)-LFT was determined to have an enantiomeric excess of 99.12%. A precise, accurate, rapid HPLC-DAD enantioselective analytical method has been developed on Chiralpak IC [tris(3,5-dichloro phenyl carbamate) immobilized on cellulose] using water and methanol as mobile phase. The chiral interconversion study reveals 0.22% and 0.21% of interconversion of (S)-LFT into (R)-LFT at 80°C in pH 7.4 and 9.5 buffers, respectively, on the 24th day. An alternative route to enantioselective synthesis of LFT enantiomers by chromatographic separation is proposed. The validated enantioselective HPLC method will help to test the regular quality control samples.

Design, synthesis, and histone deacetylase inhibition study of novel 4-(2-aminoethyl) phenol derivatives.

Histone deacetylases (HDACs) have been identified as promising targets for anticancer treatment. The study demonstrates virtual screening, molecular docking, and synthesis of 4-(2-aminoethyl) phenol derivatives as HDAC inhibitors. The virtual screening and molecular docking analysis led to the identification of 10 representative compounds, which were evaluated based on their drug-like properties. The results demonstrated that these compounds effectively interacted with the active site pocket of HDAC 3 through π-stacking, Zn2+ coordination, hydrogen bonding, and hydrophobic interactions with catalytic residues. Furthermore, a series of 4-(2-aminoethyl) phenol derivatives were synthesized, and their HDAC inhibitory activity was evaluated. Compounds 18 and 20 showed significant HDAC inhibitory activity of 64.94 ± 1.17% and 52.45 ± 1.45%, respectively, compared to the solvent control. The promising results of this study encourage further research on 4-(2-aminoethyl) phenol derivatives and may provide significant insight into the design of novel small molecule HDAC inhibitors to fight against target-specific malignancies of chronic obstructive pulmonary disease and nonsmall cell lung cancer in the future.

One-Step Synthesis of 7-Bromobenzo[c]chromeno[4,3,2-gh]phenanthridines through a Sequential Bromination/Cyclization/Aromatization Reaction Using N-Bromosuccinimide (NBS).

Herein, metal- and oxidant-free synthesis of 7-bromobenzo[c]chromeno[4,3,2-gh]phenanthridines is reported using N-bromosuccinimide. Sequential regioselective bromination, intramolecular ring cyclization, and aromatization reactions occur in a single step through a successive radical-catalyzed pathway. The mechanistic pathway for the cyclization is supported by a DFT study. Selective bromination in the fully aromatic skeleton is accomplished without involving additional aromatic electrophilic ring bromination. As a synthetic application, the Suzuki coupling reaction of compound 5a with boronic acid is reported to get compound 8a. Aggregation-induced emission of one of the synthesized compounds (5h) is also investigated in THF/hexane solvent along with concentration-dependent emission spectroscopy.

Advances and challenges in the pharmacokinetics and bioanalysis of chiral drugs.

Enantioselective analytical approaches are essential for monitoring pharmacokinetics and acquiring accurate data to better understand the role of stereochemistry in pharmacokinetics. Enantioselectivity significantly impacts the pharmacokinetics of chiral drugs, especially in metabolic profile, leading to toxicity of enantiomer. Consequently, there is a need to study the pharmacokinetics of enantiomerically pure drugs and racemates as they differ in affinity with enzymes and proteins. Combining the best enantioseparation conditions with the specified biological matrix and the intended purpose of the analysis is a challenging task. This review discusses the importance of chirality in stereoselective pharmacokinetics with more relevant examples, various enantioselective analytical techniques, and stationary phases employed. Challenges such as lack of universal chiral columns, biological inversion of the isomers, and others have been discussed. Further presented the recent advances in the screening of chiral drugs and innovative improvements in the analytical approaches for chiral molecule analysis such as supercritical fluid chromatography, simulated moving bed chromatography, and other techniques are discussed.

A validated chiral chromatographic method for the enantiomeric separation of acalabrutinib.

Acalabrutinib is aided in the treatment of various cancers, which acts by inhibiting Bruton tyrosine kinase. Acalabrutinib belongs to the imidazopyrazine class consisting of a chiral carbon, resulting in two enantiomers. Currently, no methods exist for the separation and quantification of these enantiomers. A novel and selective enantiomeric chromatographic technique has been established to estimate the enantiomeric purity of acalabrutinib. Chiral separation was carried out on an immobilized amylose-based chiral stationary phase with methyl tert-butyl ether/ethanol/ethylenediamine (60:40:0.1% v/v) mixture as a mobile phase. The total runtime is 20 min, and the resolution (Rs ) between the enantiomers was more than 2.5. The detection and quantification thresholds for the R-enantiomer were 0.06 and 0.2 µg mL-1 , respectively, for a test concentration of acalabrutinib (1000 µg mL-1 ). The linearity of the technique for the R-enantiomer was excellent (R2 > 0.999) over the range from the limit of quantification to 0.3%. Recovery of the R-enantiomer was ranged from 95% to 102%, indicating the greater accuracy of the technique. For a 48-h research period, the drug was shown to be stable.