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Pharmaceutical Chemistry Journal, Vol. 54, No. 9, December, 2020 (Russian Original Vol. 54, No. 9, September, 2020)

SEARCH FOR NEW DRUGS SYNTHESIS, ANTIAGGREGANT, AND ANTIOXIDANT ACTIVITY OF 2-{[1-ISO-BUTYL-3-METHYL-7-(THIETANYL-3)XANTHIN8-YL]THIO}ACETIC ACID SALTS F. A. Khaliullin,1,* Zh. K. Mamatov,1 G. A. Timirkhanova,1 A. V. Samorodov,1 and L. I. Bashirova2 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 9, pp. 9 – 14, September, 2020.

Original article submitted June 19, 2020. 8-Bromo-1-iso-butyl-3-methyl-7-(thietanyl-3)xanthine (II) was synthesized by alkylation of 8-bromo-3-methyl-7-(thietanyl-3)xanthine (I) with isobutyl bromide. Nucleophilic substitution of II with thioglycolic acid gave 2{[1-iso-butyl-3-methyl-7-(thietanyl-3)xanthin-8-yl]thio}acetic acid (III). A series of water-soluble salts of 2{[1-iso-butyl-3-methyl-7-(thietanyl-3)xanthin-8-yl]thio}acetic acid (IVa-h) were synthesized by reaction of III with organic and inorganic bases. Compounds possessing antiaggregant activity on the level of acetylsalicylic acid were found among salts IV. All obtained compounds except for IVa and IVc suppressed lipid peroxidation less than ascorbic acid. However, all synthesized compounds suppressed generation of reactive oxygen species by phagocytes, in contrast to ascorbic acid. Keywords: thietanes, xanthines, antiaggregant activity, antioxidant activity.

Natural methylxanthines are nonspecific phosphodiesterase inhibitors [1] and adenosine receptor antagonists [2]; possess cardiotonic, bronchodilator, and diuretic activity; and stimulate the central nervous system [3, 4]. The search for biologically active compounds, development of new ones, and optimization of known synthetic methods for xanthine derivatives are driven by the capability of xanthine for monosubstitution at several positions, di- and tri-substitution in several combinations, and the enormous potential for pharmacological activity [5 – 7]. Synthetic derivatives of xanthine with antidiabetic [8 – 10], antidepressant [11, 12], and anti-inflammatory activity [13] that affect blood rheological properties [4, 4 – 18] are known. The biological activity of 3-iso-butyl-1-methylxanthine and its binding mechanism to various types of phosphodiesterase are known [19 – 22]. Xanthine derivatives that exhibit antioxidant activity were synthesized [23 – 25]. 1 2 *

The goals of the present research were to synthesize salts of 2-{[1-iso-butyl-3-methyl-7-(thietanyl-3)xanthin-8-yl]thio}acetic acid and to study their antiaggregant and antioxidant activity. The 1-iso-butyl substituent was introduced by reacting 8-bromo-3-methyl-7-(thietanyl-3)xanthine (I) with iso-butyl bromide in the presence of KOH in DMF to produce 8-bromo-1-iso-butyl-3-methyl-7-(thietanyl-3)xanthine (II) in 62% yield. The reaction of II with thioglycolic acid and KOH in H2O–EtOH (1:1, v/v) preserved the thietane ring and substituted the Br atom to form 2-{[1-iso-butyl-3-methyl-7-(thietanyl-3)xanthin-8-yl]thio}acetic acid (III) in 91% yield. Salts of 2-{[1-iso-butyl-3-methyl-7-(t