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Amidinohydrazones were prepared by the condensation of 4-arylamino-2-oxo-5-formyl-1,2-dihydropyridine-3-carbonitriles and 4-arylamino-2-oxo-1,2-dihydropyridine-3-carbaldehydes with aminoguanidinium carbonate with the purpose to investigate their biological activity as putative NO donors. The reaction of 5- и 3-formylpyridones with diguanidinium carbonate was studied. The formation of stable complexes of 4-arylamino-5-formyl-2-oxo-1,2-dihydropyridine-3-carbonitriles with aminoguanidine and guanidine was discovered. Amidinohydrazones obtained possess antiinflammatory, antidiabetic, and antihypertensive activities.

Reactions of salts of 1,3,5-triazine dinitromethyl derivatives with nitrogen dioxide that result mainly in 1,3,5-triazinenitrolic acids are investigated. The behavior of nitrolic acid in electroreduction at a mercury drop electrode at various pH was studied; oxygen was shown to accelerate the process. The promoting effect of nitrolic acids on the activity of soluble guanylate cyclase of human platelets was shown. The studied nitrolic acids are active donors of nitric oxide, a universal and important regulator of cell metabolism functions. NO-releasing properties of furoxans are investigated.

The alkylation of N-acetoxy-N-(benzofuran-2-yl)urea is performed in the presence of sodium hydride. This process is accompanied by the migration of the acetyl group with the formation of O-acetylisourea. The kinetic parameters of O-acetylisourea hydrolysis in basic and acidic media are determined.

Alkaline hydrolysis of mono-and dinitro derivatives of five-membered heterocycles, viz., pyrazole, imidazole, 1,2,4-triazole, and isoxazole, is accompanied by the elimination of the nitro group in the form of a nitrite anion. The hydrolysis kinetics was studied by the polarographic and photometric methods. The experimentally determined hydrolysis rate constants depend on the nature of the heterocycle. A possible mechanism for hydrolytic transformations of the compounds under study was proposed on the basis of the calculated thermodynamic parameters of the reaction (Δ G≠, ΔH≠, ΔS≠).

On heating at pH 6.86, 4-(N,N-dialkylthiocarbamoylthio)-5-nitropyrimidines are transformed into dithiolopyrimidines, which are either oxidized to bis(4-dialkylthiocarbamoylpyrimidin-5-yl) disulfides or converted into 4,6-diamino-5-nitropyrimidine derivatives with carbon disulfide elimination. The direction of the reaction is determined by the nature of a substituent in position 2 of pyrimidine and the bulk of the thiocarbamate substituent. Mechanistic schemes for these processes were proposed.

The half-wave potentials of polarographic reduction of the carbonyl group in unsubstituted and N-methyl- and N-phenylsulfonyl-substituted 1- and 4-oxotetrahydrocarbazoles and their reactivities in reactions with nucleophilic (NaBH4, malonodinitrile, and cyanoacetamide) and electrophilic (DMF dimethyl acetal) reagents were compared. 4-Oxotetrahydrocarbazoles are much less reactive than 1-oxotetrahydrocarbazoles.

The elimination of nitro groups in the form of nitrite anions in the course of reduction and alkaline hydrolysis of the antitumor drug nifuroxazide has been studied using polarographic and photometric techniques. The experimentally determined reaction rate constants are used to calculate the thermodynamic parameters (ΔG≠, Δ H≠, ΔS≠). It is suggested that the therapeutic action of nifuroxazide is related not only to the formation of nitro radical anions in vivo, but also to the production of nitric oxide as a result of the biotransformation of this drug.

The kinetics of alkaline hydrolysis of N-(5-nitro-2-thiazolyl)-2-thiophenylcarboxamide (tenonitrozole or atrican) has been studied by photometric and polarographic techniques, and the thermodynamic parameters in the intermediate state of this process were determined. A mechanism explaining the nitric oxide (NO) production during the hydrolytic decomposition of tenonitrozole is proposed. It is suggested that the antiprotozoal and antimicrobial activity of this drug under anaerobic conditions is related to the formation of nitro radical anions and NO. Under aerobic and microaerophilic conditions, the hydrolysis of tenonitrozole may lead to the formation of a peroxynitrite anion, which is a strong cytotoxic agent.

Electrochemical reduction of 1-aryl-2-oxo-1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indole 4-oxides, 2-oxo-1-phenyl-1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indole, and 2-oxo-1-phenyl-1,2,3,4,5,6-hexahydro[1,4]diazepino[6,5-b]indole was studied. The results obtained were compared with previous data for the reduction of 4-oxides with formamidinesulfinic acid.

There are a number of drugs used in clinical practice whose activity is related to the ability of producing nitric oxide (NO) in the organism. These preparations are essentially the so-called prodrugs, since their pharmacological effect is determined by the metabolic formation of NO, the true active agent. The group of such prodrugs includes, for example, the well-known peripheral vasodilators nitroglycerin, isosorbide mononitrate, nitrosorbide, erynit, amylnitrite, sodium nitroprusside, and molsidomine [1]. As is known, the production of endogenous nitric oxide in the organism of animals and humans proceeds via transformation of a guanidine fragment of L-arginine under the action of enzymes (NO synthases) according to the following scheme [2]

The electroreduction of benzo[b][1,6]naphthyridine derivatives in anhydrous media by the polarographic method was studied. It is found that the first step of the process is the transfer of an electron to position 10 of the molecule, which is consistent with the addition of nucleophilic reagents to this particular position of the tricyclic system in question.

The presence of in vitro NO-donor characteristics in the antihypertensive drugs clonidine and guanfacine, the structure of which contains a guanidine grouping that relates these drugs to arginine (the main substrate of the enzyme NO-synthase, producing NO in vivo) was established by chemical oxidation of the drugs followed by polarographic detection of the produced nitric oxide in the form of nitroprusside ion. It was shown that under the investigated conditions in vitro the NO-donor activity of clonidine and guanfacine is comparable in magnitude with the NO-donor activity of arginine. It was also found that guanfacine and clonidine (the latter in the presence of NAD+) activate the soluble guanidatecyclase enzyme, which is a characteristic indication of NO donors. It is suggested on the basis of the obtained data that clonidine and guanfacine can undergo enzymatic oxidation to NO in vivo and that the pharmacologica l action of clonidine and guanfacine may be due to some extent to the NO-donor characteristics of these drugs.

We have conducted an electrochemical study of the oxidation-reduction properties of synthesized dienediamines: derivatives of indole, pyrrole, and thiophene. We have established that reduction of the indicated compounds occurs with successive transfer of two electrons, the first transfer being reversible. We consider the effect of structural factors and the nature of the heterocycle on the ease of reduction of the given compounds. We present the results of an initial study of the NO-donor ability of the compounds upon oxidation.

7-Aryl-4a-hydroxy-4a,6,7,7a-tetrahydroisoxazolo[4,5-b]quinuclidines have been prepared from 2-arylmethylene-3-quinuclidones and hydroxylamine and they are able to release NO upon mild oxidation with K3[Fe(CN6)] in basic medium.

Proof of the nitrogen oxide generation during the chemical reduction of a series of nitrofuran derivatives is obtained by polarographic detection of the nitroprusside anion. A hypothesis is made about the mechanism of the peroxynitrite anion formation, which is responsible for the biological activity of nitrofurans during the course of their reduction.

The oxidation-reduction characteristics of both the free radical and the reduced forms of dipyrimido[4,5-b][4′,5′-e][1,4]thiazine derivatives were studied by polarography. It was found that these compounds can participate in oxidation-reduction reactions, such as the oxidation of thiols and ascorbic acid (the radical form) and the reduction of oxygen (the reduced from). This makes it possible to regard them as a system capable of modelling certain oxidation-reduction processes that take place in the living organism.

7-Aryl-4a-hydroxy-4a,6,7,7a-tetrahydroisoxazolo[4,5-b]quinuclidines have been prepared from 2-arylmethylene-3-quinuclidones and hydroxylamine and they are able to release NO upon mild oxidation with K3[Fe(CN6)] in basic medium.

Oximes of quinuclidin-3-ones give NO under mild biomimetic oxidative conditions and activate soluble guanylate cyclase.

We have conducted an electrochemical study of the oxidation-reduction properties of synthesized dienediamines: derivatives of indole, pyrrole, and thiophene. We have established that reduction of the indicated compounds occurs with successive transfer of two electrons, the first transfer being reversible. We consider the effect of structural factors and the nature of the heterocycle on the ease of reduction of the given compounds. We present the results of an initial study of the NO-donor ability of the compounds upon oxidation.

Guanidine thiol derivatives--a new class of soluble guanylate cyclase activators--have been studied. Guanidine thiols contain in their molecule both the guanidine and thiol groups which act as donors acceptors of nitric oxide (NO), respectively. The role of the guanidine thiol SH-groups in the mechanism of soluble guanylate cyclase activation has been evaluated. The effect of three guanidine thiol derivatives: mercaptoethylguanidine (MEG), mercaptoethylguanidine disulfide (MEG disulfide) and S-methyl mercaptoethylguanidine (S-methyl MEG) on human platelet guanylate cyclase activity, has been examined. It was found that all the compounds tested in this study were substrates for NO-synthase and guanylate cyclase activators. The stimulatory effects of MEG and MEG disulfide surpassed the L-arginine-induced activation of guanylate cyclase-2- and 4-fold, respectively. The enzyme stimulation by S-methyl MEG was of the same order as that of L-arginine. The important role of S-acceptor groups of guanidine thiols in the mechanism of directed increase of guanylate cyclase activation was established. This mechanism explains the nature of differences in the intensity of guanylate cyclase activation by the guanidine thiols under study. The NO-acceptor properties of disulfide bond of guanidine thiols in the case of the NO-synthase mechanism of NO formation have been established.

The effects of aminoethylisothiuronium bromide known as a radioprotector on the activity of human platelet soluble guanylate cyclase and on ADP-induced aggregation of human platelets have been studied. It has been shown that in Tris-buffer and at definite pH values aminoethylisothiuronium bromide is converted into mercaptoethylguanidine as a result of a transguanidine rearrangement. The latter contains in its molecule both guanidine and SH-groups which appear to be the donor and acceptor of nitric oxide, respectively. It was found that after its rearrangement into mercaptoethylguanidine, aminoethylisothiuronium bromide activates human platelet soluble guanylate cyclase, inhibits ADP-induced aggregation of human platelets and accelerates their spontaneous disaggregation. The stimulating effect of aminoethylisothiuronium bromide depends on the effectiveness of its transguanidine rearrangement into mercaptoethylguanidine. A molecular mechanism of the hypotensive side effect of aminoethylisothiuronium bromide is proposed.

Diacetidine-di-N-oxide derivatives have been found to be capable of generating nitric oxide (NO) non-enzymatically, via an entirely new mechanism--NO splitting at physiological pH. The effects of the synthesized compounds on the human platelet soluble guanylate cyclase activity and ADP-induced human platelet aggregation have been investigated. Four out of seven derivatives tested exhibited a distinct correlation between the intensity of platelet guanylate cyclase activation, inhibition of platelet aggregation and acceleration of their disaggregation. The ability of the compounds to be decomposed under the given experimental conditions with NO formation and the observed correlation between the amount of the NO formed and the intensity of guanylate cyclase activation suggest that the NO-dependent mechanism of guanylate cyclase activation and the intraplatelet cGMP accumulation are responsible for the antiaggregating/disaggregating properties of the compounds used. The data obtained suggest that 1.2-diacetidine-di-N-oxide derivatives may be regarded as antiaggregating agents of a new class.

It was demonstrated [1] that some quaternary pyridine aldoximes (2-PAM, 4-PPM, etc.), which have proved to be effective antidotes (cholinesterase reactivators) against organic compounds, are capable of generating nitric oxide during oxiclarion. It was therefore of interest to study the electrochemical reduction of these compounds on a mercury dropping electrode with a view to finding a method of their quantitative determination. At present, the most widely used quantitative method of oxime determination is based on their hydrolysis with concentrated sulfuric acid, followed by analysis of a distilled carbonyl compound or a bottom residue of hydroxylamine hydrochioride [2]. Other methods are based on the reaction of oxime reduction to amines (predominantly by trivalent titanium salts [3]). As is known, oximes exhibit electrochemical reduction on a mercury dropping electrode, which is a promising method for the synthesis of functionally substituted amines [4]. A general scheme of the electrochemical reduction of oximes in acid media according to Lurid [5] is as follows. The first stage is the rupture of nitrogen-oxygen bonds with the formation ofimines. This is followed by the reduction ofimines to amines

Electrochemical reduction of N-nitropyrazoles, and chemical reduction by cysteine or potassium ferrocyanide, results in nitrogen monoxide.