Enantioseperation of 2-(1H-imidazol-1-yl)-1-(naphthalen-2-yl)ethan-1-ol which is active metabolite of anticonvulsant nafimidone

Year 2023, Volume: 2 Issue: 1, 85 - 95, 13.12.2023

Esma Karaca , Zeynep Özdemir , Yaren Nur Zenni , Arzu Karakurt

Abstract

Nafimidone and nafimidone alcohol, which were synthesized in 1981 and whose anticonvulsant activities were determined, are important anticonvulsant compounds in the structure of (arylalkyl)azole, which reached the stage of clinical human studies but could not pass this stage. In this study, the commercially available chiral stationary phase amylose tris(3,5-dimethyphenylcarbamate) (Chiralpak AD) was used to establish direct enantiomeric separations of nafimidone alcohol which is the methabolite of nafimidone in the normal phase HPLC mode. Investigations were also done into the compositional influences of the mobile phase. When the mobile phase was switched from methanol to n-hexane, the retention times were shortened. The mobile phase of methanol/n-hexane (70:30 v/v) at a flow rate of 0.2 mL/min produced the best results, with an enantiomer resolution of 0.83. Consequently, further chemical and pharmacological research on nafimidone alcohol and its enantiomers can be facilitated by the proposed HPLC approach.

Keywords

Amylose tris(3, 5-dimethyphenylcarbamate), Chiralpak AD, arylalkylazole, nafimidone alcohol

References

• Nardi D, Tajana A, Leonardi A, Pennini R, Portioli F, Magistretti MJ, Subissi A. Synthesis and anticonvulsant activity of N-(benzoylalkyl)imidazoles and N-(omega-phenyl-omega-hydroxyalkyl)imidazoles. J Med Chem., 1981; 24(6):727-73.
• Walker KA, Wallach MB, Hirschfeld DR. 1-(Naphthylalkyl)-1H-imidazole derivatives, a new class of anticonvulsant agents. J Med Chem., 1981; 24(1):67-74.
• Wingrove PB, Wafford KA, Bain C, Whiting PJ. The Modulatory Action of Loreclezole at the Gamma-Aminobutyric-Acid Type-a Receptor Is Determined by a Single Amino-Acid in the Beta-2 and Beta-3 Subunit. P Natl Acad Sci USA., 1994; 91(10):4569-4573.
• Graham DJM, Eadie J, Leadbetter BM, Metcalf R. Simultaneous Determination of Nafimidone [1-(2-Naphthoylmethyl)Imidazole], a New Anti-Convulsant Agent, and a Major Metabolite in Plasma by High-Performance Liquid-Chromatography. J Chromatogr., 1983; 275(1):211-216.
• Yang L, Li Y, Hong H, Chang CW, Guo LW, Lyn-Cook B, Shi L, Ning B. Sex Differences in the Expression of Drug-Metabolizing and Transporter Genes in Human. Liver J Drug Metab Toxicol., 2012; 3(3):e111.
• Özdemir Z, Karakurt A. İlaç Metabolizması ve Farmasötik Kimyada Önemi. Ann. Med. Health Sci. Res. 2016; 5:35-46.
• Fura A. Role of pharmacologically active metabolites in drug discovery and development. Drug Disc Today., 2006; 11:133-142.
• Das N, Dhanawat M, Dash B, Nagarwal RC, Shrivastava SK. Codrug: An efficient approach for drug optimization. Eur J Pharm Sci., 2010; 41:571-588.
• Kapetanovic IM, Kupferberg HJ. Nafimidone, an imidazole anticonvulsant, and its metabolite as potent inhibitors of microsomal metabolism of phenytoin and carbamazepine. Drug Metab. Dispos., 1984; 12(5):560-564.
• Brooks WH, Guida WC, Daniel KG. The significance of chirality in drug design and development. Curr Top Med Chem., 2011; 11(7):760-770.
• Bahar A, Sönmez Nİ, Vızdıklar C, Aydın V, Akıcı A. The concept of chirality and its association with drug safety: Raditional review. J Lit Pharm Sci., 2022; 11:77-85.
• Gal J. The discovery of stereoselectivity at biological receptors arnaldo piutti and the taste of the asparagine enantiomers historyand analysis on the 125th anniversary. Chiralty., 2012; 24: 959-976.
• FDA-US Food and Drug Administration (2022, 4 Nov). Development of new stereoisomeric drugs. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-new-stereoisomeric-drug.
• Ye X, Liu Y, Li F. Biomarkers of oxidative stress in the assessment of enantioselective toxicity of chiral pesticides. Curr Protein Pept Sci., 2017; 18:33-40.
• Zhang ZH, Xie SM, Yuan LM. Recent progress in the development of chiral stationary phases for high-performance liquid chromatography. J Sep Sci., 2022; 45:51-77.
• Remelli M. Chiral ligand–exchange chromatography of pharmaceutical compounds on dynamically coated(home-made) stationary phases. Curr Med Chem., 2017; 24:818-828.
• Fernandes C, Carraro ML, Riberio J, Araujo J, Tititan ME, Pinto MM. Synthetic chiral derivatives of xanthones: Biological activities and enantioselectivity studies. Molecules., 2019; 24:791.
• Karakurt A, Saraç S, Dalkara S. Enantioseparation of some new 1-(2-naphthyl)-1-ethanol ester derivatives by HPLC on Chiralcel OD, Chromatographia., 2012; 75(19-20):1191-1197.
• Sarı S, Akkaya D, Zengin M, Sabuncuoğlu S, Özdemir Z, Alagöz MA, Karakurt A, Barut B. Antifungal azole derivatives featuring naphthalene prove potent and competitive cholinesterase ınhibitors with potential cns penetration according to the in vitro and in silico studies. Chem Biodiversity., 2022; 19:27.
• Bozbey İ, Uslu H, Türkmenoğlu B, Özdemir Z, Karakurt A, Levent S. Conventional and microwave prompted synthesis of aryl(alkyl)azole oximes, 1H-NMR spectroscopic determination of E/Z isomer ratio and homo-lumo analysis. J Mol Struct., 2022; 1251:1-12.
• Karakurt A, Bozbey I, Uslu H, Sarı S, Özdemir Z, Şalva E. Synthesis and cytotoxicity studies on new pyrazole-containing oxime ester derivatives. Trop J Pharm Res., 2019; 18:1315-1322.
• Gambacorta N, Özdemir Z, Doğan İS, Ciriaco F, Zenni YN, Karakurt A, Saraç S, Nicolotti O. Integrated experimental and theoretical approaches to investigate the molecular mechanisms of the enantioseparation of chiral anticonvulsant and antifungal compounds. J Mol Struct., 2022; 1270, 133905.