The synthesis of new heterocyclic systems containing pharmacophore groups constitutes a potential direction in organic chemistry. Previous investigations produced 3-hydroxy- 3-pyrrolin-2-ones containing sulfamide groups, namely, the 4-aminosulfonylphenyl and 4-guanylsulfonylphenyl fragments [1, 2]. With the aim of seeking new biologically active substances, we investigated the possibility of preparing tetrahydropyrrol-2,3-diones containing an aminosulfonylphenylethyl group at position 1, this being present in the known drug glibenclamide (Maninyl).

figure a

Glibenclamide (Maninyl) is the main of the second-generation antidiabetic agents, and also has antidiuretic and hypocholesterolemic actions, and decreases platelet aggregation [3].

The target 1-[2-(4-aminosulfonylphenyl)ethyl]-5-aryl- 4-aroyl-3-hydroxy-3-pyrrolin-2-ones (I – IX) were synthesized using a three-component reaction of the methyl esters of aroylpyruvic acids with mixtures of 4-(2-aminoethyl)- benzenesulfonamide and an aromatic aldehyde.

Reactions were run with brief boiling of equimolar quantities of starting reagents in 1,4-dioxane medium.

Compounds I – IX were crystalline substances which were white or light yellow in color, soluble in DMF and DMSO and, with heating, in glacial acetic acid, acetonitrile, and dioxane, poorly soluble in ethanol, and insoluble in water. The physicochemical characteristics of compounds I – IX are shown in Table 1.

Table 1 Physicochemical Properties of Compounds I – IX
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figure b

The structures of the compounds synthesized here were confirmed by 1H NMR and IR spectroscopy and mass spectrometry.

The IR spectra of compounds I – IX contained bands corresponding to stretch vibrations of the NH2 group at 3456 – 3280 cm-1, the hydroxyl group at 3140 – 3100 cm-1, the lactam carbonyl at 1688 – 1664 cm-1, the ketone carbonyl at 1632 – 1616 cm-1, and the SO2 group at two ranges, 1380 – 1344 and 1168 – 1160 cm-1.

The 1H NMR spectra of compounds I – IX contained signals from aromatic protons and sulfamide group protons as a multiplet at 6.45 – 8.26 ppm, a singlet at 5.41 – 6.11 ppm from the methine proton in position 5 of the heterocycle, two multiplets from protons of the enantiomeric methylene group at position 1 of the aliphatic chain at 2.88 – 3.13 ppm (C1HAHB) and 3.80 – 3.94 ppm (C1HAHB), a multiplet from two methylene group protons in position 2 of the aliphatic chain at 2.73 – 2.93 ppm, and a broad singlet from the enol hydroxy at position 3 of the heterocycle at 11.50 – 12.10 ppm. The absence of a signal from the proton of the enol hydroxyl at position 3 of the heterocycle in some 1H NMR spectra was probably due to significant broadening due to exchange processes. The spectral characteristics of the compounds are presented in Table 2.

Table 2 Spectral Characteristics of Compounds I – IX
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The mass spectra of compounds II, V – VII, and IX showed a molecular ion peak (Table 1) and peaks corresponding to ion fragments confirming the structure. The presence of bromine atoms in the molecular structures of compounds II, VI, VII, and IX caused the molecular peak to form a doublet of ion peaks with a 2-unit difference in mass [4].

Experimental Chemical Section

IR spectra were recorded on a Specord M-80 as pastes in Vaseline grease. 1H NMR spectra were recorded on a Bruker DRX 500 instrument (working frequency 500.13 MHz) and a Bruker AM-300 (300 MHz) instrument, with DMSO-d6 as solvent and TMS as internal standard. Mass spectra were recorded on a Finnigan MAT INCOS-50 instrument with an ionization energy of 70 eV. Elemental analysis data obtained on a Perkin Elmer 2400 instrument were consistent with calculated values. The melting temperatures of the compounds synthesized here were determined using an M-565 melting point apparatus.

1-[2-(4-Aminosulfonylphenyl)ethyl]-5-aryl-4-aroyl-3-hydroxy-3-pyrrolin-2-ones (I – IX). A solution of 0.01 mol of 4-(2-aminoethyl)benzenesulfonamide and 0.01 mol of aromatic aldehyde in 5 – 10 ml of dioxane was supplemented with a solution of 0.01 mol of aroylpyruvic acid methyl ester in 5 – 10 ml of dioxane. The reaction mix was boiled for 5 min. The resulting precipitate was collected by filtration and recrystallized from dioxane.

Experimental Biological Section

The antibacterial activity of study compounds I-IX against test strains of Staph. aureus ATCC 6538-P and E. coli ATCC 25922 was assessed by twofold serial dilutions in liquid nutritive medium with a bacterial load of 250,000 cells/ml of solution [5]. The active dose was taken as the minimum inhibitory concentration (MIC). MIC values were determined in terms of the absence of signs of growth on nutritive medium and the last tube with delayed growth (transparent solution) corresponded to the MIC of the compound against the strain concerned. The bacteriostatic effects of the compounds synthesized here were compared with those of furacillin and chloramine B. Test results are shown in Table 3.

Table 3 Antibacterial Activity of Compounds I – IX
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Studies of the antibacterial activity of the study compounds showed that compounds II – IV, VI, and VII were active at the level of furacillin and chloramine B against Staph. aureus ATCC 6538-P.