Yu. N. Studnev

Synthesis, Antibacterial and Immunotropic Activity of Poly(fluoroalkyl-N-arylcarbamates)

As is known, carbamate fragments enter into the compositions of numerous drugs and pesticides. Many poly(fluoroalkyl-N-arylcarbamates) have been synthesized in the search for new antitumor agents [1, 2], tranquilizers [3], antihypertensive and antithrombotic drugs [4], anthelmintics [5], and pesticides [6]. Some of these compounds were patented as agents imparting water and oil resistant properties to various fabrics [7, 8] and used as indicators of poly(fluoroalcohols) [9 – 12] and diols [13, 14] and as model systems for elucidating the mechanism of carbamate hydrolysis [15, 16]. On the whole, however, this class of compounds is still insufficiently studied. In order to study the biological activity of poly(fluoroalkyl-N-arylcarbamates) in more detail, we have synthesized a series of new compounds via reactions of poly(fluoroalcohols) with arylisocyanates catalyzed by triethylamine:

Synthesis and Anticonvulsant Properties of Polyfluorinated Aliphatic Acid Amides

The class of fluorine-containing organic compounds contains a large number of effective drugs representing various pharmacological groups (neuroleptics, antidepressants, cerebrovascular and antianginal agents, effective antiinflammatory fluorosteroids, antibacterial, antifungal, and antitumor agents, and some other) [1 – 7]. Pharmacologically active substances are especially frequently found among the fluorine-substituted cyclic and aromatic compounds with molecules containing a small number of fluorine atoms; examples are phenazepam, ftoracizine (fluoracizine), fluoxetine, foridon, etc. [3]. Although aliphatic monoand (especially) polyand perfluorinated derivatives are pharmacologically characterized to a smaller extent, these groups contain unique substances such as the blood substitute perftoran [8] and highly effective inhalation anesthetics (ftorotan, methoxyflurane, etc.) [3]. In searching for new pharmacologically active substances among fluoroorganic compounds, we synthesized a series of N-polyfluoroacyl derivatives of some amines and -, -, and -aminocarboxylic acids known to specifically influence CNS function. The synthesis was performed using the following schemes:

Synthesis and bactericidal activity of poly(fluoroalkylcarbamates)

New preparative methods for the syntheses of carbamates have been developed and a series of poly(fluoroalkylcarbamates) have been obtained. It is established that some of the newly synthesized poly(fluoroalkyl-N-arylcarbamates) possess significant bactericidal activity.

Structural Features of the Binding Site for Diphenin and other Anticonvulsants belonging to the Group of Sodium Channel Blockers

Quantum-mechanical calculations of the structural parameters of the binding site of receptor proteins for diphenin and other anticonvulsants, whose mechanism of action is based on sodium channel blocking, have been performed using the AM-1 method. A learning set for the theoretical conformation analysis of the binding site structure has been selected and the calculations have been performed taking into account the known general requirements on the structure of anticonvulsants.

Some aspects in the search for anticonvulsants (a review)

Functional organization of the central nervous system (CNS) relies upon a fine interplay between two principal processes involved in nervous activity: excitation and inhibition. Violation of this interaction leads to the development of cerebral pathologies. Both the excitation and inhibition processes are mediated by intercell and intracell chemical neurotransmitters (endogenous ligands). In particular, interference with the neuromediator function of only -aminobutyric acid (GABA) causes a number of pathologies, primarily convulsive states, determining the symptomatics of disorders such as epilepsy, drug intoxication (strychnine, corazole, bemegride, novocain, organophosphorus compounds, insecticides, etc.), infectious diseases (meningitis, toxic influenza, tetanus, etc.), cerebral traumas, brain edemas, and others. In practice, such convulsions can be arrested using drugs belonging to various pharmacological groups, including pure anticonvulsants, barbiturates, bromides, tranquilizers, hypnotics, etc., which are capable of preventing the development or decreasing the intensity of convulsions, reducing the frequency of attacks, or eliminating the accompanying disturbances (loss of consciousness, behavioral and vegetative disorders, etc.). However, the group of anticonvulsants presently administered in practice contains no one highly effective drug of universal use. This is related not only to the variety of forms of the convulsive states, but also to the complexity of interactions between neuromediator systems, primarily those of inhibiting (GABA) and exciting amino acids [1 – 5]. The continuous search for new anticonvulsants (see, e.g., [6 – 20]) needs no additional justification. This paper addresses certain features and rules in the search for compounds possessing anticonvulsant activity. Biochemical disorders in CNS, which are capable of inducing the development of convulsions, include changes in (i) the transmembrane concentration gradients of sodium, potassium, calcium, and chlorine ions (factors providing for the membrane rest and action potentials), (ii) the energy balance in neurons, and (iii) the level and metabolism of synaptic mediators including GABA, glutamic and asparagic acids (exPharmaceutical Chemistry Journal Vol. 38, No. 9, 2004

Structural features of gabaa-receptor ligands-potential anticonvulsants

The directed search for anticonvulsants should by guided by all the known criteria established for this type of pharmacological activity, the most important of which is the ~5-rule [1]. An important direction in the development of new anticonvulsants is the synthesis of substances capable of stimulating the GABA-ergic system. The functioning of GABA involves its interactions with GABA-receptors of various types, differing by their localization and sensitivity toward various xenobiotics, for example, bicuculline (I) and baclofen. These types include postsynaptic GABAh-rece ptors, presynaptic GABA Aand GABAB-receptors , and GABA-autoreceptors; the GABAA-receptors are divided into GABA Mand GABAA2-receptors not representing different conformations of the same protein molecule but still possessing similar profiles of pharmacological activity (see, e.g., [2]). A GABAa-receptor is essentially a channel in which the ion current is directly controlled by the receptor ligands. The purpose of this work was to assess the properties and evaluate the parameters of bicuculline-sensitive GABAA-receptors stimulated, for example, by barbiturates and pyrazolopyridines [3, 4], and blocked by the polypeptide GABA-modulin [3, 5]. This analysis would provide additional structural restrictions for the potential anticonvulsants conforming to the 8-rule. The structure of bicuculline (I), a powerful convulsant and competitive GABAh-receptor antagonist, includes amine nitrogen, ester oxygens (O1, 03, 04, 05, and O6), carbonyl oxygen (O2), and a benzene core, which do not carry significant charges. From the results of calculations performed by the AMI method included into the HyperChem program package, the structure of compound I with cis hydrogen at the k-bond linking two cyclic fragments is characterized by

Reaction of chlorine fluorosulfate and peroxydisulfuryl difluoride with perfluoronitrosoalkanes

ConclusionsThe replacement of the nitroso group in perfluoronitrosoalkanes in the presence of chlorine fluorosulfate and peroxydisulfuryl difluoride was studied. A hypothesis concerning the possible reaction mechanism was stated.

Reactions of fluoroolefins with hydrogen sulfide and mercaptans

One of the main differences between perfluoroolefins and their hydrocarbon analogs is the unusual ease of reactions with nucleophiles. This is generally attributed to the strong inductive effect of fluorine, the most electronegative element, which is only partially compensated by the reverse mesomeric effect due to the p electrons. As a result, the loss of a considerable portion of the electron density by the sp2-hybridized C atom promotes nucleophilic attack, and the small size of the F atom, which facilitates the ~ interaction, and the large inductive effect make it possible to easily realize a biradical state in fluoroolefins (especially tetrafluoroethylene), which favors the attack of radicals and polymerization according to a radical mechanism.

Reaction of pentafluoroguanidine with electrophilic reagents

1. Pentafluoroguanidine reacts easily with electrophilic reagents: chlorine fluorosulfate, peroxydisulfuryl fluoride, and nitryl chloride. 2. In bis(difluoroamino)fluorochloroaminomethyl and bis(difluoroamino)fluorosulfatemethyl fluorosulfates the difluoroamino groups are easily replaced by fluorosulfate groups uncer the influence of either chlorine fluorosulfate or peroxydisulfuryl fluoride.