SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF BUTADIENE SULFIDE COPOLYMERS

N. S. Shaglaeva,1 S. V. Amosova,1 G. A. Zavarzina,2 R. G. Sultangareev,1

A. P. Fedoseev,2 R. G. Kibort,2 and E. N. Sergeeva2

Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 2, pp. 20 – 21, February, 2005.

Original article submitted October 21, 2003.

New water-soluble copolymers of butadiene sulfide and 1-methyl-4-vinylpyridinium (MVP) methylsulfatehave been synthesized and their antimicrobial properties were studied. The introduction of butadiene sulfideunits into the macromolecules of poly(MVP methylsulfate) leads to a significant increase in the antimicrobialactivity.

Wide use of synthetic polymers in medicine implies theneed for establishing relationships between their structureand biological activity, which is necessary for correct predic-tions ensuring the effective search for new, and modificationof, existing preparations. Butadiene (divinyl) sulfide copoly-mers are of considerable interest in this respect, since boththe monomer unit and lower oligomers (contained in variousspecies of garlic) are known to exhibit a high bactericidal ac-tivity [1].

This study was aimed at the synthesis of copolymers ofbutadiene sulfide and 1-methyl-4-vinylpyridinium (MVP)methylsulfate and characterization of their antimicrobialproperties.

EXPERIMENTAL CHEMICAL PART

Butadiene sulfide was synthesized as described in [2].MVP was synthesized from a commercial 4-vinylpyridine(VP) monomer purified by repeated vacuum distillation. Themonomer purity was checked by chromatography. The IRspectra were measured with an IFS-25 spectrophotometer(Germany) using samples prepared as KBr disks and nujolmulls. The UV spectra were recorded on a Specord UV-VISspectrophotometer (Germany) using sample solutions inethyl alcohol with concentrations within 0.05 – 0.1 M. The13C NMR spectra were measured on a VXR-500S spectrom-eter (Varian, USA; working frequency, 125.5 MHz) usingsamples dissolved in DMSO-d6. The measurements were

performed in a regime with 90° pulses and a relaxation delayof 2.5 sec (chromium tris-acetonate solution, 0.02 M).

1-Methyl-4-vinylpyridinium methylsulfate. To a solu-tion of 11.03 ml (0.1 mole) of 4-vinylpyridine in 50 ml of ac-etone at –40°C was added with stirring 9.46 ml (0.1 mole) ofdimethyl sulfate. The precipitate was separated by filtrationand recrystallized from ethanol to obtain 14 g (80%) of MVPmethylsulfate in the form of hygroscopic white crystals;m.p., 70 – 71°C.

The data of elemental analyses agree with analytical cal-culations according to an empirical formula of C9H13NSO4.The proposed structure was confirmed by the data of IR, UV,and elemental analyses. The IR spectra exhibit an absorptionband characteristic of the vinyl group (1640 cm – 1); a shift ofthe band from 1600 to 1630 cm – 1 is indicative of the forma-tion of a pyridinium cation. The UV spectra of the quaternarysalts show two main absorption maxima (at 224 and266 nm), while the spectra of VP and MVP display a singlemaximum at 245 nm.

Butadiene sulfide – MVP methylsulfate copolymer(I). The radical copolymerization of monomers was carriedout for 5 h in a glacial acetic acid at 60°C in the presence ofAIBN (0.5 wt.% of the monomer weight). The target copoly-mer was precipitated from the reaction mixture withisopropyl alcohol, reprecipitated from methanol withisopropyl ester, and dried in vacuum at 60°C. According tocalculations based on the data of elemental analysis, the con-tent of butadiene sulfide units in the copolymer was19.37 mol.%.

The IR spectrum of the copolymer contains no absorp-tion bands due to the vinyl group (1640 cm – 1), but retainsthe bands characteristic of pyridinium cation (1630, 1580,

740091-150X/05/3902-0074 © 2005 Springer Science+Business Media, Inc.

Pharmaceutical Chemistry Journal Vol. 39, No. 2, 2005

1 Favorsky Institute of Chemistry, Siberian Division, Russian Academy ofSciences, Irkutsk, Russia.

2 Irkutsk State Medical University, Irkutsk, Russia.

1490, 1020 cm – 1). A new wide intense band at1190 – 1250 cm – 1 is characteristic of sulfate anions (SO4

2–),and a narrow symmetric band at 1580 cm – 1 is indicative ofthe presence of free –S–CH=CH2 groups. In the 13C NMRspectrum, the chemical shifts of �-carbon atoms in thethiovinyl group (–S–CH=CH2) amount to 132 ppm, whilethe signals from �-carbon atoms are shifted to 109 ppm.

Poly(1-methyl-4-vinylpyridinium methylsulfate) (II).The radical copolymerization of monomers was carried outat 60°C in an aqueous medium. The target copolymer wasprecipitated from the reaction mixture with isopropyl alco-hol, reprecipitated from methanol with isopropyl ester, anddried in vacuum at 60°C.

The IR spectrum of the homopolymer contains no ab-sorption bands due to the vinyl group (1640 cm – 1), but re-tains the bands characteristic of pyridinium cation (1630,1580, 1490, 1020 cm – 1).

EXPERIMENTAL BIOLOGICAL PART

The antimicrobial activity of copolymer I andhomopolymer II with respect to various Gram-positive andGram-negative microbes was determined by the method ofdouble serial dilutions in meat infusion broth in a 1 : 500 di-lution [3]. The tests were performed using a daily grown agarculture washed-off with isotonic NaCl solution and adjustedat 2.5 � 105 cells�ml with respect to the turbidity standard.The samples were incubated at 37°C for 18 – 20 h, and thenthe results were evaluated in terms of the observed bacterialgrowth (increased turbidity) or inhibition due to abacteriostatic activity of the compounds tested. The activitywas expressed in terms of the minimum inhibiting concentra-tion (MIC, �g�ml) arresting the test microbe growth understandard experimental conditions.

It was found that both copolymer I and homopolymer II

possess a relatively weak antimicrobial activity (Table 1) and

do not differ much in the spectrum of activity. Nevertheless,

the introduction of butadiene sulfide units into the

macromolecules of poly(MVP methylsulfate) leads to a sig-

nificant increase in the antimicrobial activity.

REFERENCES

1. B. A. Trofimov and S. V. Amosova, Diivinylsulfide and Its De-rivatives [in Russian], Novosibirsk (1983), p. 164.

2. UK Patent No. 1369280; Chem. Abstr., 83, 27563 (1982).3. Methods of Experimental Chemotherapy [in Russian],

G. N. Pershin (ed.), Medgiz, Moscow (1971), p. 474.

Synthesis and Antimicrobial Activity of Butadiene Sulfide Copolymers 75

TABLE 1. Comparative Antimicrobial Activity of a Butadiene Sul-fide – MVP Methylsulfate Copolymer (I) and Poly(MVPmethylsulfate) (II)

Test microbeMIC, �g�ml

I II

S. aureus 200 300

Sarcina 200 400

Anthracoides 100 300

S. zonnal 500 700

Proteus N�A* N�A

Citrobacter N�A N�A

S. albus 500 700

Pseudomonas N�A N�A

Klebsiella N�A N�A

E. coli. N�A N�A

* N�A = no antimicrobial activity.