Pharmaceutical Chemistry Journal (v.44, #4)

Molecular-biological problems of drug design and mechanism of drug action by N. V. Mesonzhnik; S. S. Boiko; S. A. Appolonova; G. M. Rodchenkov; V. P. Zherdev (167-170).
Major metabolites of the new original peptide (neurotensin analog) dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester), which was designed at the Zakusov Institute of Pharmacology, were isolated and identified using an HPLC—MS/MS method. The structures of the metabolites were confirmed using reference compounds obtained by retro synthesis. The stability of dilept in vitro in human and rat plasma and in vivo upon peroral administration in rats was studied. It is established that dilept is rapidly hydrolyzed in rat plasma to N-caproyl-L-prolyl-L-tyrosine (metabolite M1) whereas it is more stable in human plasma in vitro. In experiments with peroral administration of dilept in rats, metabolite M2 (N-caproyl-L-proline) was found besides M1 in the blood stream. It is suggested that M2 is a product of the enzymatic hydrolysis of dilept by peptidases.
Keywords: dilept; dipeptide; neuroleptic; HPLC—MS; metabolism

Pharmacokinetics of thiophane upon intragastric administration by G. A. Chernysheva; R. V. Gurto; V. A. Khazanov; M. B. Plotnikov; V. I. Smol’yakova; A. E. Prosenko; A. E. Kandalintseva (171-174).
The pharmacokinetics of thiophane have been studied using HPLC. It is demonstrated that the absorption of thiophane upon intragastric administration at a dose of 100 mg/kg does not exceed 50%. The drug is not excreted with urine but is eliminated in an unchanged form with bile and is partly metabolized. Thiophane distributes in organs with high perfusion (brain, heart), accumulates extensively in the liver, and is almost not found in organs with low perfusion
Keywords: thiophane; pharmacokinetics; HPLC

Antitumor activity of imidazole derivatives: dacarbazine and the new alkylating agent imidazene (Review) by M. A. Iradyan; N. S. Iradyan; G. M. Stepanyan; F. G. Arsenyan; B. T. Garibdzhanyan (175-182).
The physicochemical properties and antitumor activity of dacarbazine, its analogs, and the new alkylating agent imidazene are reviewed. It is shown that the activity of dacarbazine is superior to most of its analogs. Imidazene exhibits an advantage over dacarbazine with respect to both stability and activity and can be used for the treatment of malignant melanoma and sarcoma of soft tissues and in combined chemotherapy.
Keywords: dacarbazine; substituted triazenoimidazolcarboxamides; phenyltriazenes; imidazene; antitumor activity; chemotherapy; mechanism of biochemical action

Methods for the synthesis of condensed thieno[3,2-d]pyrimidines based on 3,3-dimethyl-8-morpholino-6thioxo-3,4,6,7-tetrahydro-1H-pyrano[3,4-c]pyridine-5-yl cyanide have been developed. The neurotropic properties of the synthesized compounds have been investigated. Compounds possessing anticonvulsant activity and sedative properties are found. These compounds also exhibit an activating effect that makes them analogous to the well-known drug diazepam.
Keywords: pyrano[3,4-c]pyridines; thieno[3,2-d]pyrimidines; neurotropic activity; anticonvulsive activity; diazepam; cyclization; condensation

Synthesis and hypoglycemic activity of benzenesulfonylurea and toluenesulfonamidopyrimidine derivatives by L. A. Grigoryan; M. A. Kaldrikyan; N. O. Stepanyan; Zh. M. Bunatyan (186-188).
The compounds N-(4-propoxybenzenesulfonyl)-N′-(4-methoxybenzyl)urea and 2-p-toluenesulfonamido-4,6-dihydroxy-5-(3-carbomethoxy-4-propoxybenzyl)pyrimidine have been synthesized. It is established that these compounds possess pronounced hypoglycemic activity.
Keywords: sulfonylurea; sulfoamidopyrimidine; cyclization; toluenesulfonylchloride; hypoglycemic activity

Synthesis and antioxidant activity of 3,5-dimethyl-4-hydroxybenzylthiododecane by M. B. Plotnikov; A. E. Prosenko; V. I. Smol’yakova; I. S. Ivanov; G. A. Chernysheva; N. V. Kandalintseva (189-191).
The new multifunctional antioxidant 3,5-dimethyl-4-hydroxybenzylthiododecane (DHBD) demonstrated high activity both in vitro and in vivo. Experiments in vitro showed that the antioxidant activity of DHBD significantly exceeded that of the well-known reference drug ionol. A course of DHBD administration (100 mg/kg, p.o.) significantly decreased the content of lipid peroxidation products in rat brain on the model of long-term incomplete cerebral ischemia.
Keywords: 3,5-dimethyl-4-hydroxybenzylthiododecane; synthesis; antioxidant activity

Synthesis and analgesic activity of N',N'-dialkylhydradizes of aliphatic carboxylic acids by T. D. Batueva; L. V. Anikina; V. Yu. Gusev; O. A. Maiorova; A. V. Radushev (192-194).
A series of new N',N'-dialkylhydrazides of aliphatic carboxylic acids have been obtained. It is shown that some of these compounds possess central analgesic activity and exhibit low toxicity. N',N'-dialkylhydrazides of octanoic acid are of interest for further investigation in the search for new neurotropic agents.
Keywords: N',N'-dialkylhydrazides of aliphatic carboxylic acids; synthesis; analgesic activity

Computer-aided analysis of the structure—activity relationship and purposeful design (SARD) of effective bronchodilators in a series of thiazolo[3,2-a]benzimidazole derivatives has been carried out. The reliability of the created mathematical model is 76 – 81% as determined by the level of recognition of the active and inactive “learning” structures with respect to the property under consideration and depends on the particular group of compounds and the employed algorithm. The results of the prediction agree well with the experimental data because almost all (~90%) of the tested thiazolo[3,2-a]benzimidazole derivatives showed the predicted activity.
Keywords: SARD computer program; structure—activity relationship; thiazolobenzimidazoles; bronchodilator activity

Quantitative spectrophotometric determination of alkaloids in roots of Vinca herbacea by V. Yu. Vachnadze; E. Z. Dzhakeli; I. A. Dadeshidze; L. G. Kintsurashvili (199-201).
A new spectrophotometric method has been developed for the quantitative determination of pharmacologically active alkaloids (maydine, reserpinine, kopsinine, tabersonine, norfluorocurarine) and their sum in roots of Vinca herbacea Walds. et Kit. The proposed technique is highly reproducible and adequately reflects the content of alkaloids in the roots and preparations of Vinca herbacea, which allows this method to be used for their standardization.
Keywords: Vinca herbacea Walds. et Kit; alkaloids; spectrophotometry

Determining the kinetic characteristics of plant raw material extraction by repercolation by V. Yu. Myasnikov; E. V. Ivanov; E. I. Sakanyan (202-204).
The kinetic laws of the plant-raw-material extraction process in pulsating equipment using a repercolation method have been studied. The rate of the extraction process was determined as a function of the temperature, concentration of extractable compounds, and the solid phase state. Conclusions are made concerning the possibility of using mathematical modeling for the calculation and optimization of commercial extraction processes.
Keywords: kinetic characteristics; plant raw material; repercolation; percolation; extraction; enhancement

Chemical properties and immunotropic activity of the products from reaction of N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrimidinesulfone)-N′-isonicotinoylhydrazide with acids and bases in aqueous media by E. S. Ryzhova; D. A. Panteleev; Yu. V. Chudetskaya; A. A. Volkov; N. B. Mel’nikova; M. V. Gulenova; V. K. Osmanov; A. V. Borisov (205-212).
The effect of tautomerism on the structure of products from the reaction of N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrimidinesulfone)-N′-isonicotinoylhydrazide (kristafon) with acids (hydrochloric, phosphoric, acetic, oxalic, succinic, citric, hyaluronic) and bases [sodium hydroxide, triethanolamine, tris-(hydroxymethyl)aminomethane] in aqueous media has been studied using UV, IR, PMR, and 13C NMR spectroscopy techniques. The properties of kristafon are compared to those of analogous compounds containing pyridine (isonicotine hydrazide, sulfotolylisonicotine hydrazide) and pyrimidine [bis-p-(2,4-dioxo-6-methylpyrimidinyl-5-sulfonamino)-diphenylsulfone] fragments in acid–base media. It is shown that the immunotropic activity of kristafon phosphate and kristafon are improved in hyaluronic acid solution.
Keywords: tautomerism; pyridine and pyrimidine derivatives; acid–base reactions; organic acids; hyaluronic acid; tris-(hydroxymethyl)aminomethane; triethanolamine; specific immunotropic activity

Development of granulation technology for lipophilic extracts by S. A. Minina; M. G. Ozhigova (213-215).
A new method for the granulation of lipophilic substances is described using as examples an extract from the bark of Pygeum africanum (Hook. f. Kalkman) and polyextracts from leaves of Urtica dioica L. The proposed method is based on a combined process of melting and dispersion in aqueous solutions of surfactants followed by the use of the resulting dispersed solution as a binding agent for granulation. This technology is recommended for the production of solid dosage forms of drugs containing lipophilic substances.
Keywords: granulation technology; lipophilic substances; surfactants

Complex filler for direct molding based on lactose and microcrystalline cellulose by N. N. Zhuikova; O. S. Sablina; E. A. Shtokareva; A. S. Gavrilov (216-218).
The effects of lactose and microcrystalline cellulose on the flowability and moldability of a tabletting mixture and the quality of tablets obtained by direct pressing have been investigated. The optimum composition of a complex filler for direct pressing of tablets is proposed. The possibility of replacing the technology of wet granulation by direct pressing for five well-known medicinal preparations is established.
Keywords: lactose; microcrystalline cellulose; direct pressing; complex filler

Synthesis, characterization, and in vitro antimicrobial evaluation of hydrazone and bishydrazone derivatives of isatin by Hadi Adibi; Mohammad Mehdi Khodaei; Parvaneh Pakravan; Ramin Abiri (219-227).
A new series of hydrazone and bishydrazone derivatives was synthesized starting from adipic dihydrazide, oxalyl dihydrazide, 4-hydroxybenzhydrazide, 2-furancarboxylic acid hydrazide, acetohydrazide, 4-pyridinecarboxylic acid hydrazide, and isatin. The chemical structures were confirmed by means of 1H-NMR, UV, and IR spectral data and elemental analysis. The synthesized compounds were evaluated in vitro as antimicrobial agents against representative strains of Gram-positive (clinical strains of Staphylococcus saprophyticus, Bacillus cereus, Enterococcus faesium), Gram-negative bacteria (clinical strains of Klebsiella pneumonia, Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, Shigella dysenteriae, Salmonella typhi), and antifungal agent against Candida albicans (clinical isolated) by the minimal inhibitory concentration (MIC) method. MIC was defined as the lowest concentration of compound inhibiting the growth of each strain. All the bacteria and fungi studied were screened against some antibiotics and their chemical zone diameters compared.
Keywords: isatin; antibacterial activity; hydrazone derivatives; bishydrazone derivatives

In a search for new leads towards potent antifungal agents against candidiasis, a series of novel (2E)-ethyl-2(2-(2,4-dinitrophenyl)hydrazono)-4-(naphthalen-2-yl)-6-arylcyclohex-3-ene carboxylates 17–24 is synthesized and characterized by their physical and analytical data. In vitro microbiological evaluations for all the newly synthesized compounds against clinically isolated Candida sp. are carried out, and their structure-activity effect is discussed.
Keywords: ethyl-4-(naphthalen-2-yl)-2-oxo-6-arylcyclohex-3-ene carboxylates; (2E)-ethyl-2-(2-(2,4-dinitrophenyl)hydrazono)-4-(naphthalen-2-yl)-6-arylcyclohex-3-ene carboxylates; 2,4-dinitrophenylhydrazine; candidiasis; antifungal agent