R. E. Trifonov

Medicinal chemistry of tetrazoles

Properties of responsible for biological activity tetrazoles are considered. Examples are given of active pharmaceutical ingredients of modern drugs containing the tetrazole ring in the molecular structure. New publications on the synthesis and investigations of biological activity of promising tetrazole-containing compounds are cited.

Basicity of N-H- and N-Methyl-1,2,3-triazoles in the Gas Phase, in Solution, and in the Solid State − An Experimental and Theoretical Study

The gas-phase and aqueous basicities of six 1,2,3-triazoles have been determined, the former by FT-ICR and the latter by spectrophotometry and 1H NMR. The gas-phase experiments agree very well with the Gibbs free energies calculated at the B3LYP/6-31G* level. In contrast, only semiquantitative ascertainments are possible when basicities in the gas phase and in solution are compared. It is possible, with the aid of calculations, to obtain a complete picture of the complex equilibria involved in C-substituted N-H-1,2,3-triazoles. The crystal structures of 4(5)-phenyl-1,2,3-triazole (4) and 4(5)-nitro-1,2,3-triazole (15) have been determined. In the gas phase, 2H tautomers b always predominate, while in aqueous solution, both 1H and 2H tautomers − a and b − are present. Finally, in the solid state, 1 exists as a 1:1 mixture of 1a and 1b, while 4 is in the 4b tautomeric form and 15 is a 1H tautomer 15a. These conclusions − a in the gas phase, a + b in solution, and equal probabilities of finding either a or b in the crystal − are probably general for all 1,2,3-triazoles.

Influence of medium acidity upon the luminescence properties of 2,5-diphenyl-1,3,4-oxadiazole and 2,5-diphenyl-1,3-oxazole

Abstract The luminescence properties of 2,5-diphenyl-1,3,4-oxadiazole and 2,5-diphenyl-1,3-oxazole in aqueous solutions of sulfuric acid (pH 7 to Ho − 10) were studied. The spectral parameters are essentially acidity dependent, which is due to the acid-base equilibria of these heterocycles both in the ground and in the first excited singlet states. The difference between these two compounds is governed by their dissimilar solvation. The basicity constants of 2,5-diphenyl-1,3,4-oxadiazole in the S0 state (pKBH+ = − 2.49) and 2,5-diphenyl-1,3-oxazole in the S0 and S1 states ( p K BH+ = −1.93, p K BH+ ∗ = 1.95) were experimentally obtained. The enthalpies of formation, electron charge density, and geometry of the bases and corresponding conjugate acids in the S0 and S1 states were calculated by the MNDO method.

Kinetics of azidation of isomeric benzenedicarbonitriles

Rate constants and activation parameters of two-step azidation of isomeric dicyanobenzenes with dimethylammonium azide in DMF at 70–100°C were determined. Tetrazole rings are formed from cyano groups in dicyanobenzenes in a stepwise mode following the 1,3-dipolar cycloaddition pattern. The rate of azidation of isomeric dicyanobenzenes is considerably higher than the rate of subsequent azidation of intermediate cyanophenyltetrazolides. The azidation rate constant decrease in going from m-dicyanobenzene to its para and ortho isomers.

Synthesis of tetrazol-1-yl analogs of L-lysine and L-ornithine

Tetrazole group is known to be a promising pharmacophore that is widely used in designing highly efficient drugs [1, 2]. Tetrazolyl analogs of amino acids exhibit versatile biologic activity, and some of them are known pharmaceuticals [3]. Compounds of this type may be utilized in development of radiopharmaceuticals for positron emission tomography [4]. We have formerly demonstrated that natural diamino monocarboxylic acids are convenient substrates for the synthesis of the corresponding tetrazolyl analogs [5].

Synthesis and properties of 2-cyanoethoxy derivatives of dammarane triterpenoids

Cyanoethylation of dammaran-3β-ols and 3-oxime dammarene, semisynthetic derivatives of the natural dipterocarpol, afforded a series of new dammarane triterpenoids containing 2-cyanoethoxy fragment at the carbon atom in the position 3 of the tetracyclic scaffold. A notable antiviral activity was found in 20(S)-3-[(2-cyanoethoxy)imino]-dammar-24-en-20-ol and 20(S)-3-О-(2-cyanoethyl)-25,26,27-trinor-20,24-olidedammarane.

Synthesis of tetrazol-5-ylethyl derivatives of dipterocarpol

Naturally occurring triterpenoids of dammarane series exhibit various types of biological activity [1–3]. These compounds are regarded as the base for designing new antimicrobial and antitumor drugs, and also pharmaceuticals used in diagnostics of diseases, in particular, applying positron emission tomography [4]. However the information on preparation and properties of semisynthetic azolyl derivatives of these compounds are scanty or absent. It is known that the introducing in the structure of a drug of metabolically stable tetrazolyl fragment may enhance the biologic availability of the medicinal preparation, prolong its biologic action, and decrease the toxicity [5–7]. Semisynthetic 3-tetrazolylethoxy betulin derivatives were synthesized [8], yet no tetrazolyl derivatives of dammarane triterpenoids were known up till now.

Hydrogen bonding of 1- and 2-substituted tetrazoles with conventional proton donors

Dissociation constants of H-complexes formed by 1- and 2-substituted tetrazoles with 4-fluorophenol in carbon tetrachloride and methylene chloride were determined by Fourier-transform IR spectroscopy. The nature of substituents on the endocyclic nitrogen and carbon atoms was found to weakly affect the pKHB value. By contrast, the position of the N-substituent is significant. For example, 1-methyl-5-phenyl-1H-tetrazole (pKHB = 0.66 in CH2Cl2) is a stronger proton acceptor than 2-methyl-5-phenyl-2H-tetrazole (pKHB = 0.05 in CH2Cl2). The proton affinity of the examined compounds appreciably decreases in going from less polar carbon tetrachloride to more polar methylene chloride. No general correlation was revealed between the pKHB values of substituted 1H- and 2H-tetrazoles and shifts of the OH stretching vibration frequency of methanol (Δν) upon formation of H-complexes.

Basicity of isomeric ditetrazolylbenzenes and their N-tert-butyl derivatives

AbstractThe basicity constants