A. A. Mandrugin

Synthesis and study of NOS-inhibiting activity of 2-N-acylamino-5,6-dihydro-4H-1,3-thiazine

The synthesis and results of in vitro and in vivo testing of 2-N-acetylamino-, 2-N-benzoylamino-,2-N-cyclohexanecarbonylamino-, and 2-N-(1-adamantanecarbonyl)amino-5,6-dihydro-4H-1,3-thiazines for NOS-inhibiting activity have been described.

Structure and activity of NO synthase inhibitors specific to the L-arginine binding site

Synthesis of compounds containing a fragment similar to the guanidine group of L-arginine, which is a substrate of nitric oxide synthase (NOS), is the main direction in creating NOS inhibitors. The inhibitory effect of such compounds is caused not only by their competition with the substrate for the L-arginine-binding site and/or oxidizing center of the enzyme (heme) but also by interaction with peptide motifs of the enzyme that influence its dimerization, affinity for cofactors, and interaction with associated proteins. Structures, activities, and relative in vitro and in vivo specificities of various NOS inhibitors (amino acid and non-amino acid) with linear or cyclic structure and containing guanidine, amidine, or isothiuronium group are considered. These properties are mainly analyzed by comparison with effects of the inhibitors on the inducible NOS.

Nitric oxide inhibitor activity of 2-amino-2-thiazoline derivatives

A series of 2-amino-2-thiazoline derivatives have been synthesized and characterized with respect to NOS-inhibitor activity in vivo. It was established that the dimensions of the substituents in 2-N-mono-and 2-N,N-disubstituted 2-amino-2-thiazolines are not significant for the biological activity of the products.

Antihypotensive activity of 2-acetylamino-5,6-dihydro-4H-1,3-thiazine for an endotoxic shock model in rats

The high anti-hypotonic activity of the new NOS inhibitor 2-acetylamino-5,6-dihydro-4H-1,3-thiazine hydro-bromide was demonstrated for an endotoxic shock model in rats.

Adsorption of NO synthase inhibitor on dehydroxylated silica

A series of thiazine derivatives with the NO inhibiting effect was synthesized. These derivatives can be used in the treatment of gastrointestinal diseases, as well as antihypotensive (antishock) drugs. The potentially prolonged effect of these substances was studied by the adsorption of 2-N-benzoyl-2-amino-5,6-dihydro-4H-1,3-thiazine hydrobromide (I) on silica (nonporous Polysorb MP with specific surface area S = 330 m2/g and narrow-porous KSS-3 silica gel with S = 600 m2/g). The dehydroxylation of a silica surface significantly increased the adsorption of I. The adsorption kinetic curves of I showed a peak due to the rehydroxylation and deactivation of the silica surface in aqueous solutions. The adsorption rate in physiological solution of I was shown to decrease at a lower concentration of I on the surface of dehydroxylated silica and larger silica particles.

Synthesis of putative radioprotectors on the basis of cyclic isotioureas derivatives

The present work deals with the synthesis of sixteen compounds with putative inhibiting activity towards NO-synthase on the basis of 2-amino-2-thiazoline and 2-amino-5,6-dihydro-4H-1,3-thiazine.

Conversion of Heterocycles of The Dihydrothiazine–Thiazoline Series in Aqueous Solutions

When heterocycles of the dihydrothiazine–thiazoline series are treated with an aqueous solution of base, they undergo ring opening, leading to formation of ureidoalkanethiols. Study of solvolysis of the heterocycles when treated with ammonia permitted us to observe a novel heterocyclic ring opening reaction, occurring with formation of 2(3)-guanidinoalkanethiols. We have developed a novel preparative method for obtaining 2(3)-guanidinoalkanethiols.

Synthesis of N-derivatives of guanidinoethanethiols and their antiradiation activity on the yeastSaccharomyces Cerevisiae

Sulfur-containing compounds such as 2-aminoethanethiol and 2-guanidinoethanethiol are among the most radioprotective substances known [5, 8]. The literature contains several of reports of the antiradiation effects and toxicity of a number of derivatives of guanidinoalkanethiols in experiments on mice [6, 9, 10] and cells [7, 10]. We report here a method for the synthesis of a number of different N-derivatives of guanidinoaikanethiols, along with studies of their toxicity and antiradiation efficacy. The starting compounds were N-substituted thiourea (I), and 2-bromoalkylamines, which were reacted to produce the corresponding N-substituted S-(2aminoalkyi)isothioureas (II). A subsequent transguanidinylation reaction produced the corresponding N-substituted guanidinoalkanethiols (III) [8], which were isolated in the form of water-insoluble N-derivatives of guanidinoalkanetrithiocarbonates (IV), by reaction with CSs:

Intramolecular cyclization of guanidinoalkanethiols in aqueous solution

We have demonstrated the basic possibility of cyclizing guanidinoalkanethiols of different structure to thiazolines and thiazines. The rate of reaction depends on the pH of the medium. The concentration of buffer and the addition of heavy water and α-D,L-alanine have virtually no effect on the rate of reaction.

Formation of derivatives of thiazoline by the reaction of thiourea with 2-bromo-3-aminopropionic acid

Depending on the conditions employed, thiourea reacts with the hydrobromide of 2-bromo-3-aminopropionic acid to give a dihydrobromide or an internal salt S-(2-amino-1-carboxyethyl)isothiourea. This compound can also lose ammonia to give a thiazoline derivative.