Tetrahydropyrrol-2,3-diones and their derivatives are present in the fragments of many medicinal agents (piracetam, atropine, Iminem, glimepiride, etc. [1]. Published data indicate that 3-hydroxypyrrolin-2-ones with alkoxyalkyl substituents in position 1 are low-toxicity compounds and have various types of biological activity [2]. With the aim of synthesizing novel 3-hydroxypyrrolin-2-ones and studying the effects of structure on their chemical properties and antimicrobial actions, we have prepared tetrahydropyrrol-2,3-diones containing a hydrophilic 2-(2-hydroxyethoxy)ethyl substituent in position 1 of the heterocycle to identify how structural changes affect the water solubility and antimicrobial activity of these compounds.

Using a known method [3], we studied the interaction of 2-(2-aminoethoxy)ethanol with a mixture of an aromatic aldehyde and an acylpyruvic acid methyl ester at an equimolar ratio in dioxane or glacial acetic acid at room temperature. In these conditions, the sole product was a 5-aryl-4-acyl-3-hydroxy-1-[2-(2-hydroxyethoxy)ethyl]-3-pyrrolin-2-one.

Table 1 Yields and Melting Temperatures of 5-Aryl-4-acyl-3-hydroxy-1-[2-(2-hydroxyethoxy)ethyl]-3-pyrrolin-2-ones
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Table 2 Spectral Characteristics of Compounds I – XIV
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The resulting compounds (I – XIV) were yellow crystalline substances, soluble in ethanol, dimethysulfoxide (DMSO), and dimethylformamide, and insoluble in water.

Substances I – V, containing the acetyl fragment, were soluble in water on heating.

The 1H NMR spectra of compounds I – XIV contained signals from aromatic protons at 6.82 – 7.62 ppm, a singlet from the methine group at position 5 of the heterocycle at 5.15 – 5.70 ppm, two multiplets from protons in the methylene group at position 1 at the nitrogen atom at 2.55 – 2.85 and 3.40 – 3.83 ppm, and a multiplet from the three methylene groups at 3.38 – 3.80 ppm.

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The IR spectra of compounds III – XI (Table 3) contained absorption bands due to stretch vibrations of the lactam carbonyl group at 1680 – 1700 cm–1, the ketone carbonyl group at 1620 – 1650 cm–1, the enol hydroxyl group at 3080 – 3170 cm–1, and the alcohol hydroxyl group at 3370 – 3470 cm–1.

Table 3 IR Spectra of Compounds III – XI
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Table 4 Antimicrobial Activity of 5-Aryl-4-acyl-3-hydroxy-1-[2-(2-hydroxyethoxy)ethyl]-3-pyrrolin-2-ones (III – XIV)
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The mass spectra of the compounds synthesized here (I, III, IV, and X) showed a molecular ion peak (see Table 1) and ion fragment peaks confirming the structures.

All compounds gave an intense cherry color with ethanolic iron (III) chloride solution. Spectral data and qualitative reactions with ethanolic iron (III) chloride provided evidence that compounds I – XIV were in the enol form.

Experimental Chemical Section

1H NMR spectra were recorded on a Bruker AM-300 and a Bruker AM-500 with working frequencies of 300 and 500 MHz in DMSO-d6 with tetramethysilane as internal standard. IR spectra were recorded on a Specord M-80 in Vaseline grease. Mass spectra were taken on a Finnigan MAT ICOS-50 instrument (ionizing energy 70 eV). Melting temperatures were measured on a Melting Point M-565 instrument. Elemental analysis data were consistent with molecular formulas.

5-Aryl-4-acyl-3-hydroxy-1-[2-(2-hydroxyethoxy)ethyl]-3-pyrrolin-2-ones (I – XIV).

General method. Equimolar quantities of aromatic aldehyde and 2-(2-aminoethoxy)ethanol were added to 0.05 mol of acetylpyruvic acid methyl ester or benzoylpyruvic acid dissolved in 10 ml of dioxane for compounds I – V or 10 ml of acetic acid for compounds VI – XIV. The reaction mixture was held at room temperature for one day. The resulting precipitate was collected by filtration and recrystallized from ethanol.

Experimental Biological Section

Antimicrobial activity against strains of E. coli and S. aureus was determined by twofold serial dilutions in meat-peptone broth with a bacterial load of 250,000 microbial units per ml of solution. The active dose was taken as the minimum inhibitory concentration (MIC) of the compound, i.e., the maximum dilution leading to complete suppression of test microbe growth. Reference agents were mercury dichloride and ethacridine lactate.

The study compounds had low levels of antimicrobial activity against both strains. Some increase in the antimicrobial activity of compound XII against S. aureus and compound IV against E. coli should be noted, apparently due to the presence of the phenol hydroxyl in these compounds.