The emergence of new synthetic cathinones continues to be a matter of public health concern. In fact, already known products (drugs) are being rapidly replaced by new structurally related alternatives, whereby modifications in the basic cathinone structure are used by manufacturers to circumvent the legislation. On the other hand, some derivatives of synthetic cathinones represent important pharmaceuticals with antidepressant properties. In the search for pharmaceutically relevant analogs, the main goal of the present study was to design and characterize novel cyclic α-tetralone-based derivatives of synthetic cathinones. We synthesized a series of derivatives and verified their chemical structure. Subsequently, chiral separation has been accomplished by high-performance liquid chromatography (HPLC) equipped with a circular dichroism (CD) detector, which directly provided CD spectra of the enantiomers of the analyzed substances at 252 nm. Using density functional theory calculations, we have obtained stable conformers of selected enantiomers in solution and their relative abundances, which we used to simulate their spectra. The experimental and calculated data have been used to assign the absolute configuration of six as-yet unknown synthetic cathinones.

Department of Analytical Chemistry University of Chemistry and Technology Prague 6 Czech Republic

Department of Organic Chemistry University of Chemistry and Technology Prague 6 Czech Republic

Forensic Laboratory of Biologically Active Substances Department of Natural Compounds University of Chemistry and Technology Prague 6 Czech Republic

Psychedelic Research Centre National Institute of Mental Health Klecany Czech Republic

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European Monitoring Centre for Drugs and Drug Addiction. European drug report 2022: Trends and developments. Publications Office of the European Union; 2022.

European Monitoring Centre for Drugs and Drug Addiction. European drug report 2021: Trends and developments. Publications Office of the European Union; 2021.

Fass JA, Fass AD, Garcia AS. Synthetic cathinones (bath salts): legal status and patterns of abuse. Ann Pharmacother. 2012;46(3):436-441. doi:10.1345/aph.1Q628

Hassan NAGM, Gunaid AA, Murray Lyon IM. Khat (Catha edulis): health aspects of khat chewing. East Mediterr Health J. 2007;13(3):706-718.

German CL, Fleckenstein AE, Hanson GR. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci. 2014;97(1):2-8. doi:10.1016/j.lfs.2013.07.023

Ezaki J, Ro A, Hasegawa M, Kibayashi K. Fatal overdose from synthetic cannabinoids and cathinones in Japan: demographics and autopsy findings. Am J Drug Alcohol Abuse. 2016;42(5):520-529. doi:10.3109/00952990.2016.1172594

James D, Adams RD, Spears R, et al. Clinical characteristics of mephedrone toxicity reported to the U.K. National Poisons Information Service. Emerg Med J. 2011;28(8):686-689. doi:10.1136/emj.2010.096636

La Maida N, Di Trana A, Giorgetti R, Tagliabracci A, Busardò FP, Huestis MA. A review of synthetic cathinone-related fatalities from 2017 to 2020. Ther Drug Monit. 2021;43(1):52-68. doi:10.1097/FTD.0000000000000808

Coppola M, Mondola R. 3, 4-methylenedioxypyrovalerone (MDPV): chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online. Toxicol Lett. 2012;208(1):12-15. doi:10.1016/j.toxlet.2011.10.002

Papaseit E, Moltó J, Muga R, Torrens M, de la Torre R, Farré M. Clinical pharmacology of the synthetic cathinone Mephedrone. Curr Top Behav Neurosci. 2017;32:313-331. doi:10.1007/7854_2016_61

Spiller HA, Ryan ML, Weston RG, Jansen J. Clinical experience with and analytical confirmation of “bath salts” and “legal highs”(synthetic cathinones) in the United States. Clin Toxicol. 2011;49(6):499-505. doi:10.3109/15563650.2011.590812

Weinstein AM, Rosca P, Fattore L, London ED. Synthetic cathinone and cannabinoid designer drugs pose a major risk for public health. Front Psych. 2017;8:156. doi:10.3389/fpsyt.2017.00156

Almeida AS, Silva B, Pinho PG, Remião F, Fernandes C. Synthetic Cathinones: recent developments, Enantioselectivity studies and Enantioseparation methods. Molecules. 2022;27(7):2057. doi:10.3390/molecules27072057

Silva B, Fernandes C, Guedes de Pinho P, Remião F. Chiral resolution and Enantioselectivity of synthetic Cathinones: a brief review. J Anal Toxicol. 2018;42(1):17-24. doi:10.1093/jat/bkx074

Dal Cason TA, Young R, Glennon RA. Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs. Pharmacol Biochem Behav. 1997;58(4):1109-1116. doi:10.1016/S0091-3057(97)00323-7

Flack HD, Bernardinelli G. The use of X-ray crystallography to determine absolute configuration. Chirality. 2008;20(5):681-690. doi:10.1002/chir.20473

Parsons S. Determination of absolute configuration using X-ray diffraction. Tetrahedron. 2017;28(10):1304-1313. doi:10.1016/j.tetasy.2017.08.018

Kerti G, Kurtán T, Illyés T-Z, et al. Enantioselective synthesis of 3-Methylisochromans and determination of their absolute configurations by circular dichroism. Eur J Org Chem. 2007;2007(2):296-305. doi:10.1002/ejoc.200600678

Pescitelli G, Berova N, Xiao TL, Rozhkov RV, Larock RC, Armstrong DW. Assignment of absolute configuration of a chiral phenyl-substituted dihydrofuroangelicin. Org Biomol Chem. 2003;1(1):186-190. doi:10.1039/b207652g

Polavarapu PL. Determination of the absolute configurations of chiral drugs using Chiroptical spectroscopy. Molecules. 2016;21(8):1056. doi:10.3390/molecules21081056

Tichotová M, Landovský T, Lang J, et al. Enantiodiscrimination of inherently chiral Thiacalixarenes by residual dipolar couplings. J Org Chem. 2023. doi:10.1021/acs.joc.2c02594

Wenzel TJ. Strategies for using NMR spectroscopy to determine absolute configuration. Tetrahedron. 2017;28(10):1212-1219. doi:10.1016/j.tetasy.2017.09.009

Favretto D, Pascali JP, Tagliaro F. New challenges and innovation in forensic toxicology: focus on the “new psychoactive substances”. J Chromatogr A. 2013;1287:84-95. doi:10.1016/j.chroma.2012.12.049

Gerace E, Caneparo D, Borio F, Salomone A, Vincenti M. Determination of several synthetic cathinones and an amphetamine-like compound in urine by gas chromatography with mass spectrometry. Method validation and application to real cases. J Sep Sci. 2019;42(8):1577-1584. doi:10.1002/jssc.201801249

Kolderová N, Jurásek B, Kuchař M, Lindner W, Kohout M. Gradient supercritical fluid chromatography coupled to mass spectrometry with a gradient flow of make-up solvent for enantioseparation of cathinones. J Chromatogr A. 2020;1625:461286. doi:10.1016/j.chroma.2020.461286

Bringmann G, Gulder TAM, Reichert M, Gulder T. The online assignment of the absolute configuration of natural products: HPLC-CD in combination with quantum chemical CD calculations. Chirality. 2008;20(5):628-642. doi:10.1002/chir.20557

Kirkpatrick D, Fain M, Yang J, Trehy M. Enantiomeric impurity analysis using circular dichroism spectroscopy with United States Pharmacopeia liquid chromatographic methods. J Pharm Biomed Anal. 2018;156:366-371. doi:10.1016/j.jpba.2018.04.033

Lecoeur-Lorin M, Delépée R, Adamczyk M, Morin P. Simultaneous determination of optical and chemical purities of a drug with two chiral centers by liquid chromatography-circular dichroism detection on a non-chiral stationary phase. J Chromatogr A. 2008;1206(2):123-130. doi:10.1016/j.chroma.2008.08.004

Luykx DM, Goerdayal SS, Dingemanse PJ, Jiskoot W, Jongen PM. HPLC and tandem detection to monitor conformational properties of biopharmaceuticals. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;821(1):45-52. doi:10.1016/j.jchromb.2005.04.005

Sánchez FG, Díaz AN, de Vicente AB. Enantiomeric resolution of bupivacaine by high-performance liquid chromatography and chiroptical detection. J Chromatogr A. 2008;1188(2):314-317. doi:10.1016/j.chroma.2008.02.070

Eto S, Yamaguchi M, Bounoshita M, Mizukoshi T, Miyano H. High-throughput comprehensive analysis of D- and L-amino acids using ultra-high performance liquid chromatography with a circular dichroism (CD) detector and its application to food samples. J Chromatogr B Analyt Technol Biomed Life Sci. 2011;879(29):3317-3325. doi:10.1016/j.jchromb.2011.07.025

Gergely A, Szász G, Szentesi A, et al. Evaluation of CD detection in an HPLC system for analysis of DHEA and related steroids. Anal Bioanal Chem. 2006;384(7-8):1506-1510. doi:10.1007/s00216-006-0318-4

Rebizi MN, Sekkoum K, Petri A, Pescitelli G, Belboukhari N. Synthesis, enantioseparation, and absolute configuration assignment of iminoflavans by chiral high-performance liquid chromatography combined with online chiroptical detection. J Sep Sci. 2021;44(19):3551-3561. doi:10.1002/jssc.202100474

Frisch MJ, Trucks GW, Schlegel HB, et al. Gaussian 16 Rev. C.01. Wallingford, CT; 2016.

Salthammer T, Grimme S, Stahn M, Hohm U, Palm W-U. Technology. Quantum chemical calculation and evaluation of partition coefficients for classical and emerging environmentally relevant organic compounds. Environ Sci Technol. 2021;56(1):379-391. doi:10.1021/acs.est.1c06935

Wang H, Heger M, Al-Jabiri MH, Xu Y. Vibrational spectroscopy of homo- and Heterochiral amino acid dimers: conformational landscapes. Molecules. 2022;27(1):38. doi:10.3390/molecules27010038

Xie F, Fusè M, Hazrah AS, Jäger W, Barone V, Xu Y. Discovering the elusive global minimum in a ternary chiral cluster: rotational spectra of propylene oxide trimer. Angew Chem Int Ed. 2020;59(50):22427-22430. doi:10.1002/anie.202010055

Covington CL, Polavarapu PL. Similarity in dissymmetry factor spectra: a quantitative measure of comparison between experimental and predicted vibrational circular dichroism. J Phys Chem A. 2013;117(16):3377-3386. doi:10.1021/jp401079s

Polavarapu PL, Covington CL. Comparison of experimental and calculated chiroptical spectra for chiral molecular structure determination. Chirality. 2014;26(9):539-552. doi:10.1002/chir.22316

Kohout M, Vandenbussche J, Roller A, et al. Absolute configuration of the antimalarial erythro-mefloquine - vibrational circular dichroism and X-ray diffraction studies of mefloquine and its thiourea derivative. RSC Adv. 2016;6(85):81461-81465. doi:10.1039/C6RA19367F

Kuppens T, Langenaeker W, Tollenaere JP, Bultinck P. Determination of the stereochemistry of 3-Hydroxymethyl-2,3-dihydro-[1,4]dioxino[2,3-b]- pyridine by vibrational circular dichroism and the effect of DFT integration grids. J Phys Chem A. 2003;107(4):542-553. doi:10.1021/jp021822g

Bruhn T, Schaumlöffel A, Hemberger Y, Bringmann G. SpecDis: quantifying the comparison of calculated and experimental electronic circular dichroism spectra. Chirality. 2013;25(4):243-249. doi:10.1002/chir.22138

Dobšíková K, Javorská Ž, Paškan M, et al. Enantioseparation and a comprehensive spectroscopic analysis of novel synthetic cathinones laterally substituted with a trifluoromethyl group. Spectrochim Acta A Mol Biomol Spectrosc. 2023;291:122320. doi:10.1016/j.saa.2023.122320

Paškan M, Rimpelová S, Svobodová Pavlíčková V, et al. 4-Isobutylmethcathinone: a novel synthetic cathinone with high in vitro cytotoxicity and strong receptor binding preference of enantiomers. Pharmaceuticals. 2022;15(12):1495. doi:10.3390/ph15121495

Spálovská D, Maříková T, Kohout M, Králík F, Kuchař M, Setnička V. Methylone and pentylone: structural analysis of new psychoactive substances. Forensic Toxicol. 2019;37(2):366-377. doi:10.1007/s11419-019-00468-z

Spálovská D, Paškan M, Jurásek B, Kuchař M, Kohout M, Setnička V. Structural spectroscopic study of enantiomerically pure synthetic cathinones and their major metabolites. New J Chem. 2021;45(2):850-860. doi:10.1039/D0NJ05065B

Carroll FI, Blough BE, Abraham P, et al. Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction. J Med Chem. 2009;52(21):6768-6781. doi:10.1021/jm901189z