On the Dependence of the Physiological Activity of Acyl Derivatives of 4-Aminoantipyrine on the Rate of Their Hydrolysis
Abstract Generated abstract
This study examines whether the antipyretic activity of acyl derivatives of 4-aminoantipyrine is related to their hydrolysis rate, on the assumption that physiological action depends on cleavage of the molecule in the organism. Several derivatives were prepared or selected, hydrolyzed under controlled conditions, and analyzed quantitatively for liberated 4-aminoantipyrine by colorimetry and for carboxylic acids by electrical conductivity. The authors report that hydrolysis rate varies inversely with the strength of the acid residue in the acyl derivative and directly with antipyretic activity. Among the tested compounds, 4-aminobenzoylaminoantipyrine hydrolyzed most readily and showed the strongest antipyretic action, while the benzoyl derivative of 4-aminobenzoylaminoantipyrine was among the least active and slowest to hydrolyze.
Full Text
On the Dependence of the Physiological Activity of Acyl Derivatives of 4-Aminoantipyrine on Their Hydrolysis Rate
L. P. Kutev, G. M. Stepnova
The physiological activity of antipyretic agents belonging to the class of anilide-substituted compounds (phenacetin, antifebrin, etc.) must be closely connected with the cleavage of the molecule of the medicinal substance inside the organism and with the liberation of aniline, on which, it must be supposed, the antipyretic action of this substance chiefly depends [1].
In order to study this relationship, we obtained a series of compounds described in the literature—acyl derivatives of aminoantipyrine—and determined their physiological activity and the comparative rate of their hydrolysis. In terms of decreasing antipyretic action, as was reported earlier [2], the compounds obtained are arranged in the following order: 4-aminobenzoylaminoantipyrine, cinnamoylaminoantipyrine, benzoylaminoantipyrine, 4-chlorobenzoylaminoantipyrine, and the acetic acid derivative of 4-aminobenzoylaminoantipyrine.
Upon hydrolysis of the acyl derivatives, 4-aminoantipyrine and a carboxylic acid are obtained. The substances formed were determined quantitatively by the colorimetric method (aminoantipyrine) and by the electrical-conductivity method (aromatic carboxylic acid).
In all cases a direct dependence was established between the antipyretic activity and the comparative rate of hydrolysis of the acyl derivatives of aminoantipyrine.
Experimental Part
Hydrolysis of the acyl derivatives of aminoantipyrine was carried out as follows. A weighed portion of the substance was placed in a flask with heated water. The flask was fitted with a reflux condenser and placed in a thermostat at a constant temperature (99°). From the flask, at definite time intervals (from 30 to 120 min), 10 ml of the solution was withdrawn, in which the content of aminoantipyrine was determined by the colorimetric method, or the content of carboxylic acid by the electrical-conductivity method. The colorimetric method is based on the color reaction of aminoantipyrine with ferric chloride. To the test solution was added 0.1 ml of ferric chloride solution ($T = 0.0052$); the resulting coloration was compared with the coloration of previously prepared solutions of aminoantipyrine.
To determine the concentration of the carboxylic acid, a sample of the solution was poured into a vessel for measuring electrical conductivity by the compensation method, placed in the thermostat ($T = 60^\circ \pm 0.05^\circ$). The acid concentration was found from the electrical conductivity with the aid of calibration curves, which had been constructed beforehand for each acyl derivative. The standard solutions required for this contained a mixture of the acyl derivative, carboxylic acid, and aminoantipyrine in amounts corresponding to different degrees of hydrolysis of the acyl derivative. For each substance studied, six standard solutions were prepared.
The results of the experiments are presented in the figure.
Fig. 1. Hydrolysis-rate curves of acyl derivatives of 4-aminoantipyrine
The curves characterize the rate of hydrolysis:
I — 4-aminobenzoylaminoantipyrine, II — cinnamoylaminoantipyrine, III — benzoylaminoantipyrine, IV — 4-nitrobenzoylaminoantipyrine, V — 4-chlorobenzoylaminoantipyrine, VI — the benzoyl derivative of 4-aminobenzoylaminoantipyrine.
Conclusions
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By the colorimetric method and by the electrical-conductivity method, the comparative rate of hydrolysis was determined for 4-aminobenzoylaminoantipyrine, cinnamoylaminoantipyrine, benzoylaminoantipyrine, 4-chlorobenzoylaminoantipyrine, the benzoyl derivative of 4-aminobenzoylaminoantipyrine, and 4-nitrobenzoylaminoantipyrine.
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It was established that the rate of hydrolysis of these compounds is inversely dependent on the strength of the acid whose residue is included in the molecule of the acyl derivative of aminoantipyrine.
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It was found that there is a direct dependence between the antipyretic activity and the rate of hydrolysis of the compounds studied. The most readily hydrolyzed 4-aminobenzoylaminoantipyrine possesses the strongest antipyretic action; the weakest is the benzoyl derivative of 4-aminobenzoylaminoantipyrine, which occupies the last place in the series of tested acyl derivatives with respect to hydrolysis rate.
Literature
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A. M. Berkengeim, Chemistry and Technology of Synthetic Medicinal Agents, 88, ONTI NKTP, 1935.
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G. M. Stepnova, Dissertation, 51, Tomsk, 1955.