The synthesis of new phosphonopeptidomimetics and their effect on the functional cardiac output

E. R. Abdurakhmanova, N. O. Dorofeyeva, O. I. Lukashuk, O. V. Holovchenko, V. S. Brovarets

Abstract


The article presents the synthesis of new phosphorylated peptidomimetics, and the biological activity of the compounds synthesized has been assessed for the fi rst time on the experimental animals – male rats. On the basis of a diethyl ester of 1-benzoylamino-2,2,2-trihloroethylphosphonic acids a novel derivative of 1,3-oxazol-4-phosphonic acid diethyl ester containing the residue of methylaminoethan-1-ol in position 5 of the oxazole ring has been synthesized. The optimal conditions for cleavage of the 1,3-oxazole ring in the acidic medium with formation of phosphorylated peptidomimetics have been found. Thus, when treating it with 85 % aqueous trifl uoroacetic acid a diethyl ester of {benzoylamino[(2-ydroxyethyl)carbamoyl]methyl} phosphonic acid has been obtained, and  the action of hydrogen chloride under anhydrous conditions gives a diethyl ester of {benzoylamino[(2-chloroethyl) carbamoyl]methyl} phosphonic acid. The method developed is very convenient and preparative because reactions proceed in mild conditions without formation of undesirable by-products. Moreover, peptidomimetics are isolated with high yields, and their isolation does not require chromatography. Monitoring of different functional parameters of cardiac hemodynamics was performed in rats in vivo using a microcatheter and the Millar Pressure-Volume System. The study of the effect of the compounds obtained on the cardiac output has shown that their intraperitoneal introduction results in the heart rate decrease and stimulation of the contractile activity of the myocardium.

Keywords


heart; contractility; 4-phosphorylated 5-amino-1,3-oxazoles; phosphonopeptidomimetics; amino alcohols

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DOI: https://doi.org/10.24959/ophcj.16.882

Abbreviated key title: Ž. org. farm. hìm.

ISSN 2518-1548 (Online), ISSN 2308-8303 (Print)