Pharmaceutical Chemistry Journal (v.47, #7)

Virtual Screening for Potential Substances for the Prophylaxis of HIV Infection in Libraries of Commercially Available Organic Compounds by A. A. Lagunin; D. A. Filimonov; T. A. Gloriozova; O. A. Tarasova; A. V. Zakharov; L. Guasch; M. C. Nicklaus; V. V. Poroikov (343-360).
The search for new substances for the treatment and prophylaxis of HIV-AIDS remains relevant despite advances in highly active antiretroviral therapy (HAART), both because of the appearance of resistance to existing agents and because of their side effects and toxicity. Preventing the spread of HIV infection via sexual contacts by treating the uninfected partner has some advantage, as prophylactic effects can be obtained using simpler treatment (for example, using one agent rather than combinations of three drugs), as the need is to block the transfer of small numbers of infective virions. On the other hand, agents acting on the uninfected partner must be relatively nontoxic as they have to be used for long periods of time in healthy people. Effective chemoprophylaxis can be obtained using agents blocking the life cycle of the virus before integration into the human genome. Two widely used classes of agent therefore have potential – non-nucleoside reverse transcriptase (RT) inhibitors and integrase (IN) strand transfer inhibitors. In addition, proteins such as CD4, gp120, CCR5, CXCR4, and gp41 can be regarded as potential targets, as their functional roles at different stages in the interaction between virion and host cell have been established. As it is now known that all antiretroviral agents approved for medical use induce resistant viral strains, new anti-HIV agents must have chemical structures which are significantly different from known drugs and (if possible) must act on multiple pharmacological targets. Candidates can be sought by virtual screening of libraries of commercially available samples of chemical compounds; such libraries currently contain several million structural formulas for compounds which have been synthesized and are available for biological testing. Virtual screening can be performed using the computer programs PASS and PharmaExpert, allowing identification of substances with potential for experimental studies on the basis of a number of prognostic criteria (presence of the required types of activity, absence of side and toxic effects, appropriate physicochemical properties).We present here data on the current state of the search for new agents for the treatment and prophylaxis of HIV/AIDS, our approach to virtual screening for new potential substances for the prophylaxis of HIV/AIDS, and the results of using this approach in databases of chemical compounds available for screening. The potential for detection of anti-HIV compounds acting on multiple pharmacological targets among substances which have already been synthesized is discussed. We conclude that there is potential for the rational design of such drugs using computerized drug construction methods.
Keywords: HIV/AIDS; prophylaxis; treatment; reverse transcriptase inhibitors; integrase strand transfer inhibitors; CD4; gp120; CCR5; CXCR4; gp41 inhibitors; virtual screening; PASS; PharmaExpert; ChemNavigator

Reduction of N-[β-(4-substituted benzoyl)ethyl]amino acids with sodium borohydride yielded arylaliphatic aminopropanols containing amino acid fragments – N-[3-(4-substituted phenyl)-3-hydroxypropyl]valines,-tryptophans, and 3-{[3-hydroxy-3-(4-substituted phenyl)propyl]amino}-3-phenylpropanoic acids. Studies of the biological activities of these compounds showed that some had anti-inflammatory and anticonvulsive activities.
Keywords: N-[β-(4-substituted benzoyl)ethyl]amino acids; synthesis; reduction with NaBH4 ; N-[3-(4-substituted phenyl)-3-hydroxypropyl]amino acids; 3-{[3-hydroxy-3-(4-substituted phenyl)propyl]amino}-3-phenylpropanoic acids; anti-inflammatory and anticonvulsive activities

Synthesis and Analgesic Activity of Substituted 4-(Het)aryl-4-oxo-2-thienylaminobut-2-enoic Acids by S. A. Shipilovskikh; R. R. Makhmudov; D. Yu. Lupach; P. T. Pavlov; E. V. Babushkina; A. E. Rubtsov (366-370).
A series of 4-aryl-4-oxo-2-thienylaminobut-2-enoic acids was synthesized by interaction of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids with Gewald 2-aminothiophenes. All the compounds synthesized were found to have analgesic activity at or above the levels of the reference compounds.
Keywords: substituted 4-aryl-4-oxo-2-thienylaminobut-2-enoic acids; synthesis; analgesic activity

Synthesis and Antibacterial Activity of 1-(4-Aminosulfonylphenyl)-5-aryl-4-acyl-3-hydroxy-3-pyrrolin-2-ones by V. L. Gein; T. F. Odegova; K. A. Tkachenko; O. V. Bobrovskaya; M. I. Vakhrin (371-373).
Interaction of 4-aminobenzenesulfamide with a mixture of an aromatic aldehyde and the methyl ester of an acylpyruvic acid was used to prepare 1-(4-aminosulfonylphenyl)-5-aryl-4-acyl-3-hydroxy-3-pyrrolin-2-ones. The antibacterial activity of these compounds was studied.
Keywords: 1-(4-aminosulfonylphenyl)-5-aryl-4-acyl-3-hydroxy-3-pyrrolin-2-ones; synthesis; antibacterial activity

Chronic experiments on rats, guinea pigs, and rabbits showed that the synthetic sulfonic acid derivative sulfobisanion SB-VII had marked hypolipidemic and antiatherosclerotic actions. The lipid-reducing properties of SB-VII were comparable with those of the standard hypolipidemic agent gemfibrozil.
Keywords: sulfobisanion; gemfibrozil; sigetin; dyslipoproteinemia; atherosclerosis

A New Liquid-Phase Method for the Synthesis of Octreotide by A. N. Balaev; V. N. Osipov; K. A. Okhmanovich; E. V. Reshetnikov; and V. E. Fedorov (378-381).
A method was developed for the production of octreotide – a synthetic analog of the natural hormone somatostatin - by liquid-phase peptide synthesis using the 4 + 2 + 2 strategy. The new method is easily scalable and produces the target peptide with a yield of 56.4%.
Keywords: octreotide; liquid-phase synthesis; production

Preparation of Micronized Ibuprofen Substance and Assessment of Its Bioavailability by Yu. A. Obidchenko; N. S. Khuchua; R. A. Abramovich; A. Yu. Savochkina; A. S. Karamyan; S. S. Barsegyan; Yu. Yu. Khomyakov; M. V. Ovcharov; V. V. Chistyakov (382-386).
A Buchi B-290 mini spray dryer (Switzerland) designed to dry aqueous solutions or suspensions was used to prepare micronized ibuprofen substance, which differed from the starting substance in terms of decreased crystal size. The bioavailability of ibuprofen given as oral capsules containing micronized ibuprofen substance (crystal size 30 μm) and capsules containing commercial ibuprofen substance (crystal size 150 μm) was studied in Chinchilla rabbits. Concentrations of unaltered ibuprofen were measured by reverse-phase HPLC with spectrophotometric detection at 220 nm. Ibuprofen was extracted from rabbit serum by liquid:liquid extraction and averaged 78 %. The detection limit was 0.1 μg/ml. The bioavailability of micronized ibuprofen was more than twice that of the commercial substance (mean crystal size 150 μm). There were no differences in the rates of absorption or elimination of ibuprofen from the systemic circulation.
Keywords: ibuprofen; micronization; HPLC; bioavailability

Preparation and Antitumor Activity of a Gel-Forming Prospidine Formulation by P. M. Bychkovski; T. L. Yurkshtovich; N. V. Golub; V. A. Alinovskaya; R. I. Kosterova; S. O. Solomevich; A. A. Kladiev; Yu. P. Istomin; E. N. Aleksandrova; S. A. Krasnyi; N. A. Petrovskaya; M. Yu. Revtovich; A. I. Shmak; Z. B. Kvacheva (387-392).
A new, long-acting form of prospidine was formulated by immobilization of the cytostatic agent on biodegradable dextran phosphate. Results from in vitro and in vivo studies of the antitumor activity of the long-acting prospidine formulation are presented. In vitro experiments established that the rate of release of prospidine from the hydrogel slowed with increases in the polymer:carrier mass ratio. Experiments using a Zaidel’s hepatoma model showed an increase in the antitumor activity of the long-acting prospidine formulation as compared with native substance.
Keywords: dextran phosphate; long-acting prospidine formulation; immobilization; antitumor activity

Effects of Liquid Crystal Systems Based on Cholesterol Esters on Skin Permeability by Yu. A. Boiko; I. A. Kravchenko; N. S. Novikova; A. V. Egorova; D. I. Aleksandrova (393-396).
The mechanisms of the influences of liquid crystal systems based on cholesterol esters on skin permeability were investigated. The effects of liquid crystal systems based on cholesterol esters on the transcutaneous penetration of phenazepam from transdermal therapeutic patches were studied in in vitro conditions. Changes in the fluidity of phospholipid liposomes and liposomes prepared from stratum corneum lipids were studied using fluorescence spectroscopy. Liquid crystal systems based on cholesterol were shown to be effective enhancers of skin permeability.
Keywords: cholesterol esters; liquid crystals; transdermal