I. G. Ovchinnikova

Aminoazoles in the three-component synthesis of 7-substituted 6-ethoxycarbonyl-5-methyl-4,7-dihydroazolo[1,5-a]pyrimidines

The three-component synthesis of 7-substituted 6-ethoxycarbonyl-5-methyl-4,7-dihydroazolo[1,5-a]pyrimidines was carried out for the first time by the reactions of aminoazoles (3-aminopyrazole, 3-amino-1,2,4-triazole, or 5-aminotetrazole) with acetoacetic ester and aliphatic, aromatic, or heteroaromatic aldehyde.

Multicomponent sonochemical synthesis of podands.

An efficient sonochemical methodology is described for the synthesis of new podands containing substituted dihydropyrimidines.

Sonochemical synthesis of Biginelli compounds

The ultrasound effect accelerates the Biginelli reaction 40 and more times. A sonochemical method for the synthesis of ethyl 4-R-6-methyl-2-oxo- and 4-R-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates was developed. The target products were obtained within 2 to 5 min in 90—95% yields.

Theoretical Investigation of the Antituberculous Activity of Membranotropic Podands

The discovery of the antituberculous properties of streptomycin (in 1944), as well as of the same activity of isoniazid and pyrazinamide (in 1952), significantly increased the efficacy of chemotherapy in the treatment of tuberculosis and noticeably reduced the death rate caused by this disorder [1]. However, a new episode in the disease rate took place in 1985 [1] and, despite a large number of antituberculous drugs, the treatment of tuberculosis is among the main problems in modern medicine. This is explained primarily by the rapid development of drug resistance in Mycobacterium tuberculosis and by the high toxicity of the existing preparations [1, 2]. Therefore, creation of new, effective antituberculous drugs is an important current task. The multilayer membrane shell of tubercle bacillus is a serious obstacle to delivering drugs to targets. For this reason, a promising direction in the development of effective antituberculous preparations is the search for agents possessing a high ability to penetrate through cell membranes. In recent years, our research has been concentrated on the synthesis and characterization of macrocyclic polyesters and their noncyclic analogs – podands, possessing an increased ability to penetrate through biological membranes. Among these, there are compounds exhibiting high antituberculous activity [3 – 7]. Tables 1 – 3 present data on the structures of synthesized podands and on the antituberculous activity of these compounds expressed in terms of logarithms of the experimentally determined and calculated minimum inhibiting concentrations (lg MICexp and lg MICcalcd, respectively) for these compounds. Our preliminary analysis of these data revealed the following empirical relationships. (i) A high tuberculostatic activity is inherent in formyl podands I and II not containing clearly pronounced pharmacophore fragments. (ii) Hydrazones of semicarbazide and hydrazones of nicotinic and benzoic acid hydrazides acquire tuberculostatic activity in the form of the corresponding podands (compounds VII – XI, XIII – XV, XVII) [6]. (iii) Tuberculostatic activity increases by two orders in magnitude on passage from crown esters (compounds XXVI, XXVII) to podands representing their noncyclic analogs (compounds XXVIII – XXXIII) [4]. (iv) A comparison of the antibacterial activity of pefloxacin (fluoroquinolone antibiotic) and the corresponding fluoroquinolone podands (compounds XXXVII – XLVI) shows that the latter compounds exhibit significant selectivity with respect to Mycobacterium tuberculosis [5]. These results suggest that the polyester fragment of podands plays an important role in the action upon certain targets in the given bacterial species. In order to verify this assumption, we have theoretically studied the quantitative structure – activity relationship (QSAR) between the conformation of these compounds and their tuberculostatic properties. Calculations performed within the framework of the semiempirical quantum-chemical PM3 approximation showed that the most favorable structure is represented by the podand chain possessing a circular conformation (Fig. 1). This configuration provides for the parallel orientation of the planes of (hetero)aromatic rings on the ends of the podand chain and for the formation of a pseudocyclic structure due to the – interaction between these rings. This allows metal cations to be incorporated into a molecular cavity by forming donor – acceptor bonds with heteroatoms (nitrogen, oxygen, sulfur, etc.) present in the chain. This conclusion is consistent with data obtained by the IR and H NMR spectroscopic techniques for the structure of podand complexes with metal cations in chloroform solutions [8]. The complex formation in these systems is accompanied by considerable modification of the spectra of (hetero)aromatic fragments, while variations in the spectra of ethylene oxide fragments are minimal Pharmaceutical Chemistry Journal Vol. 37, No. 9, 2003

Synthesis and turbeculostatic activity of podands with fluoroquinolone fragments

Fluorine-substituted quinolonecarboxylic acids are known as synthetic antibacterial drugs with a broad spectrum of activity, which are successfully used for the therapy of various bacterial diseases, including tuberculosis [1 ]. Nevertheless, problems pertaining to the appearance of bacterial strains resistant to quinolones stimulate researchers to continue investigations aimed at a modification of the known fluroquinolones [2]. We have attempted to modify a fluoroquinolone fragment responsible for penetration into bacterial ceils, with the pttrpose of increasing the transport function of the molecule, since it is known that fluoroquinolones (in particular, pefloxacin) penetrate into bacterial cells by a simple diffusion mechanism [3]. In order to find reaction pathways to fluoroquinolones possessing increased penetrating ability with respect to the cell membranes, we have synthesized compounds containing podand residues that are known [4] to readily pass through the cellular barriers. Because of the low nucleophilicity of glycols, the oxygen-containing podands IV were obtained under rigid conditions from the ethyl ester of 1-ethyl-6,7-difluoro-4-oxo-l,4dihydro-3-quinolinecarboxylic acid (Ib), in which the mobility of a fluorine atom in position 7 is somewhat higher than in the acid (Ia). Podands V and VI were obtained by direct interaction of acid Ia with polyethylene polyamines. Potassium carbonate was used as the acceptor of hydrogen chloride in the synthesis of compounds IV and VI, whereas triethylamine was used for the same purpose in the synthesis of compounds V known to form strong complexes with potassium cations. Podands-hydrazones VII were obtained by heating formylpodands III with 7-hydrazino-4-oxo-6-ftor-l-ethyl-l,4dihydro-3-quinolinecarboxylic acid (II) in DMF.

Synthesis andin vitro tuberculostatic activity of podands containing semicarbazide or thiosemicarbazide fragments

Previously we have reported on a significant tuberculostatic activity of podands containing thioureide fragments [I]. In continuation of that work, we have synthesized a series of new podands, containing semicarbazide or thiosemicarbazide fragments, and characterized their tuberculostatic activity in vitro. The new compounds (I Ia-IIc and IIIa-IIIc) were synthesized using the reactions of formylpodands (Ia-Ic) , differing in the length of the hydroxyethylene fragment, with semicarbazide or thiosemicarbazide in a D M F H 2 0 ~H3COOH medium:

Synthesis, photochemical and luminescent properties of (E)-2-(2-hydroxyarylethylene)-3-phenylquinazolin-4(3H)-ones

Photoinduced transformations of 2-styrylquinazolinones in solutions were studied using absorption and NMR spectroscopy methods. A possibility of control of the photochemical isomerization rate of quinazolinone 2-(hydroxyaryl)ethenyl derivatives by changing the pH of the medium was demonstrated. The bases and the solvent nature also affect the luminescence intensity of solutions of these compounds in the wavelength range of 550—650 nm. The differences in the steric organization of the ortho-hydroxystyryldiazinone system in crystals and in solutions related to the turn of the aryl group were found. Their influence on the competing processes of luminescence and photochemical transformation of the ethylene fragment were shown. The fact of reversible photo/thermal E-Z-isomerization was established for (E)-2-(2-hydroxystyryl)-3-phenylquinazolin-4(3H)-one.

Specific features of heterocyclization of (E)-3-(2-ethoxyphenyl)-1-phenylprop-2-en-1-one with aminoazoles

A reaction of 3-(2-ethoxyphenyl)-substituted chalcone with aminoazoles was studied. The nature of aza groups in aminoazoles was found to affect the regioselectivity of β-amination in the course of the formation of isomeric pyrazolo[3,4-b]pyridine, azolo[1,5-a]- and [4,3-a]-pyrimidine systems and the depth of the reaction were determined. A regulatory role of catalysts and solvents in the direction of the cascade reactions was established. Mechanisms of the reactions were suggested. A significance of the alkoxy substituent in chalcone for stereoselective synthesis of Michael adducts, including 3-(2-ethoxyphenyl)-3-(7-(2-ethoxyphenyl)-5-phenyl-6,7-dihydroazolopyrimidin-6-yl)-1-phenylpropan-1-ones, was demonstrated. The structures of products synthesized were established by 1H and 13C NMR spectroscopy and X-ray diffraction analysis.

Theoretical investigation of the antituberculosis activity of compounds of the dihydropyrimidine series

An analysis of the tuberculostatic activity of dihydropyrimidine derivatives has been carried out using the 3D QSAR algorithm BiS/MC. Conformers responsible for the biological action of these compounds have been found and their complexes with receptors have been modeled. It is shown that oxygen atoms of the podand chain or ether group of most biologically active compounds interact with postiviely charged atoms of the receptor. Pharmacophore and antipharmacophore fragments have been identified. The relationship of the tuberculostatic activity and characteristics of the receptor-ligand complexes have been established (correlation coefficient, 0.99). The results can be used for directed synthesis of effective antituberculosis agents and for predicting the tuberculostatic activity of new compounds.

Synthesis and Tuberculostatic Activity of Pyrrolyl and Pyrazolinyl Podands

New podands containing pyrrole or pyrazoline fragments have been synthesized. A hypothesis was proposed that closure of the pyrrole ring in the presence of alumina nanoparticles may proceed through 1,4-addition of nitroethane to the chalcone podand to give the Michael adduct rather than through an iminium intermediate usually observed in the reactions of α,β-unsaturated ketones (chalcones) in the presence of Lewis acids. Moderate tuberculostatic activity was found for the starting chalcone podands. Much greater such activity was found upon subsequent modification of the chalcone fragment to give a five-membered heterocycle. Pyrrole derivatives displayed greatest activity among the hetaryl podands obtained.