Abstract
In the paper, a series of six pharmacologically active compounds (β-adrenolytics) derived from 4-hydroxyphenylethanone and 4-hydroxyphenylpropan-1-one are reported. The compounds incorporate pyrrolidin-1-yl and 4-methylpiperazin-1-yl substituents in the hydrophilic part of the molecule and ethoxymethyl and methoxyethoxymethyl side chains on the aromatic ring in the lipophilic moiety. They were prepared by a four-step synthesis from 4-hydroxyalkanones via chloromethyl, alkoxymethyl, and oxirane intermediates. The purity of the target compounds was checked by TLC and their structures were confirmed by the interpretation of the IR, UV, 1H NMR, and 13C NMR spectra. The pharmacological evaluation of the obtained compounds confirmed their vasodilatory and specific antiisoprenaline activities. All evaluated compounds at conc. 10−6 mol dm−3 inhibited vasoconstrictory effect of phenylephrine (8.22–33.7%) on isolated rat aorta. The ability to inhibit positive chronotropic effect of isoprenaline was observed on isolated spontaneously beating rat’s atria after pre-treatment with the evaluated compounds at conc. 10−7 and 10−6 mol dm−3. The calculated pA2 values of specific antagonistic effect against isoprenaline, related to their apparent β-adrenolytic activity, ranged between 6.54 and 7.57. The value for the standard compound carvedilol was 8.15 ± 0.22. The majority of the evaluated compounds at conc. 10−6–10−7 mol dm−3 also showed negative chronotropic effect on the basic heart rate of atria. Enantioseparation of the prepared compounds was performed by chiral HPLC on an amylose tris(3,5-dimethylphenylcarbamate) column (Chiralpak AD) and a native teicoplanin column (Chirobiotic T). The chromatographic characteristics as retention, separation, and resolution factors were reported.
Graphical abstract
Similar content being viewed by others
References
Aelling WH (1982) Am Heart J 104:346
http://www.rxlist.com/visken-drug.htm. Accessed 21 Mar 2018
Nagamoto T, Hosohata Y, Ohnuki T, Nakamura T, Hattori K, Ishiguro M (2001) Cardiovasc Drug Rev 19:9
Ruffolo RR Jr, Gellai M, Hieble JP, Willette RN, Nichols AJ (1990) Eur J Clin Pharmacol 38:2
Book WM (2002) Congest Heart Fail 8:173
Dandona P, Ghanim H, Brooks DP (2007) J Hypertens 25:731
Čižmáriková R, Valentová J, Némethy A, Pechová I (2015) Antihypertensive drugs as chiral agents. In: Caldwell S (ed) Antihypertensive drugs: pharmacology, medical uses and potential side effects. Nova Science Publishers, New York
Ceccheli V, Schiaffella F, Tabarini O, Fravolini A (2000) Bioorg Med Chem Lett 10:465
Szkaradek N, Rapacz A, Pytka K, Filipek B, Siwek A, Cegła M, Marona H (2013) Bioorg Med Chem 21:514
Huang JJ, Huang YJ, Zhu L, Yuan M, Huang L (2014) Pharmazie 69:578
Demir OU, Yurttas L, Ozkay Y (2013) Arch Pharm Res 36:802
Farag NA, Mohamed SR, Soliman GA (2008) Bioorg Med Chem 16:9009
Takei R, Ikegaki I, Shibata K, Tsujimoto G, Asano T (1999) Jpn J Pharmacol 79:447
Sponer G, Borbe HO, Muller-Beckmann B, Freud P, Jakob B (1992) J Cardiovasc Pharmacol 20:1006
Kirsten R, Breidert M, Nelson K, Heine A, Rosenkrans S, Erdeg B, Niebch G, Borbe HO, Siebert-Weigel M, Respondek J (1994) Eur J Clin Pharmacol 46:271
Garimella PS, Fink HA, MacDonald R, Wilt TJ (2008) Int J Cancer 122:444
Čižmáriková R, Račanská E, Hronoňová K, Lehotay J, Ághová Z, Halešová D (2003) Pharmazie 58:237
Lehotay J, Hronoňová K, Čižmárik J, Čelková H (1999) Pharmazie 54:74
Park KL, Kim KH, Jung SH, Lim HM, Hong ChH, Kang JS (2002) Pharm Biomed Anal 27:569
Imre S, Ormenişan A, Tero-Vescan A, Muntean DL, Vari CE (2016) J Chromatogr Sci 54:1578
Aboul-Enein HY, Serignese V (1995) Cellulose 2:215
Valentová J, Čižmáriková R, Bui TTT, Drake AF, Hutt AJ (2003) Chromatographia 58:733
Bruchatá K, Némethy A, Čižmáriková R, Račanská E, Habala L (2016) Arch Pharm Chem Life Sci 349:733
Čižmáriková R, Polakovičová M, Mišíková E (2002) Chem Pap 56:256
Bruchatá K, Sedláková S, Čižmáriková R, Hroboňová K, Lehotay J, Račanská E (2007) Acta Fac Pharm Univ Comen 54:54
Mlynárová R, Račanská E (1997) Pharmazie 52:234
Račanská E, Kurfürst P, Csöllei J, Švec P (2004) Acta Fac Pharm Univ Comen 51:182
Acknowledgements
This publication utilizes research results of the CEBV project, ITMS: 26240120034. This work was supported by the Slovak Research and Development Agency under the contract no. APVV-0516-12; Vedecká Grantová Agentúra MŠVVaŠ SR a SAV (VEGA 1/0346/16).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Čižmáriková, R., Némethy, A., Habala, L. et al. Synthesis, pharmacological activity, and chromatographic enantioseparation of new heterocyclic compounds of the aryloxyaminopropanol type derived from 4-hydroxyphenylalkanones. Monatsh Chem 149, 969–976 (2018). https://doi.org/10.1007/s00706-018-2185-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00706-018-2185-z