Pharmaceutical Chemistry Journal (v.46, #7)

Influence of polymer nature on porphyrincatalyzed photooxidation processes by N. A. Aksenova; K. V. Aleksanyan; N. N. Glagolev; A. B. Solov’eva; S. Z. Rogovina (389-391).
The photocatalytic activity of some porphyrin photosensitizers (PPSs) in the model reaction of tryptophan photooxidation was shown to decrease in the presence of the biodegradable polymers chitosan and polylactide. Also, the degree of decrease in substrate photooxidation $ left( {k_{{emathrm{ff}}}^1} ight) $ depended on the nature of the polymer. The constant decreased by factors of 4 and 1.1 in the presence of chitosan and polylactide, respectively. This influence of the polymers on the photocatalytic activity of PPSs may have been related to the interaction of macromolecular fragments with the porphyrins. However, preliminary solubilization of PPSs by Pluronic® F-127 enabled $ k_{{emathrm{ff}}}^1 $ to be increased 4 times (in chitosan systems) or 1.3 times (in polylactide systems).
Keywords: porphyrin photosensitizers; chitosan; polylactide

Methods for the synthesis of 4-chlorophenylsulfonylacetic acid and its tris-(2-hydroxyethyl)ammonium salt (sulfacetamine) were developed. Results of in vitro and in vivo experiments showed that sulfacetamine possessed high antithrombotic, membrane-stabilizing, antioxidant, hypocholesterolemic, and adaptogenic activity with low toxicity to animals.
Keywords: 4-chlorophenylsulfonylacetic acid; tris-(2-hydroxyethyl)ammonium 4-chlorophenylsulfonylacetate (sulfacetamine); antithrombotic; membrane-stabilizing; antioxidant; hypocholesterolemic; adaptogenic activity

Synthesis and biological activity of new 6-benzylisocytosine derivatives: non-nucleoside HIV-1 reverse transcriptase inhibitors by V. T. Valuev-Elliston; A. V. Ivanov; B. S. Orlinson; E. N. Gerasimov; L. L. Brunilina; S. N. Kochetkov; I. A. Novakov; M. B. Navrotskii (397-401).
New 6-benzylisocytosine derivatives were synthesized by aminolysis of 6-benzyl-2-(methylsulfanyl)pyrimidin-4(3H)-ones with aliphatic aromatic and cage-structured amines. Some of the synthesized compounds appeared to be effective HIV-1 reverse transcriptase inhibitors. Among these, 6-(2,6-difluorobenzyl)-5-methyl-2-[(2-phenylethyl)amino]pyrimidin-4(3H)-one showed the most pronounced inhibitory properties, being nine times more effective than the reference anti-HIV drug nevirapine.
Keywords: 6-benzylisocytosine derivatives; HIV-1 reverse transcriptase inhibitors

Synthesis of pyrimidylhydrazones and substituted pyrimidyl-aryl- and –yclohexylthiosemicarbazides and study of their influence on DNA methylation by L. A. Grigoryan; M. A. Kaldrikyan; R. G. Melik-Ogandzhanyan; J. V. Garibyan; L. E. Nersesyan; A. S. Agaronyan (402-405).
Reactions of 4,6-dihydrazino-5-nitro- and 2-methylthio-4-hydrazino-6-chloro-5-(p-alkoxybenzyl)pyrimidines with carbonyl compounds and aryl- and cyclohexylisothiocyanates were studied. The influence of the products on DNA methylation and their in vitro antitumor properties were studied.
Keywords: hydrazinopyrimidines; hydrazones; carbonyl compounds; thiosemicarbazides; DNA methylation

In continuation of studies on 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidine derivatives as 5-HT6 receptor antagonists, new compounds with a pyridine moiety in the 5-and/or 7-position were obtained and their antagonistic activity was screened. It was established that the introduced pyridine changed the 5-HT6 activity. Some of the obtained 5-pyridin-3-yl-3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidines 5-HT6 receptor antagonists with K i = 0.2 – 4.5 nM had therapeutic significance for the treatment of some CNS diseases.
Keywords: 2,5,7-substituted 3-arylsulfonylpyrazolo[1,5-a]pyrimidines; serotonin 5-HT6 receptors; antagonists; structure—activity relationship

3-Methoxy-11-methylthio-∆11 – 12-aza-D-homonorketoequilenine was synthesized and its neurotropic activity was evaluated. The compound (50 mg/kg) stimulated locomotor and exploratory activity in the open-field test, reduced the immobilization time in the behavioral despair test, and had a positive effect on passive avoidance learning. The analgesic properties of this compound were of particular interest. The synthesized compound at a dose of 50 mg/kg demonstrated a statistically significant analgesic effect in the hot-plate, hot-plate on an inflamed paw, and acetic-acid-induced writhing tests, the effect being comparable with that of analgin.
Keywords: 3-methoxy-11-methylthio-∆11-12-aza-D-homonorketoequilenine; open-field test; elevated plus-maze test; behavioral despair test; hot-plate test; acetic-acid writhing; passive avoidance learning

Synthesis and antiviral activity of sterically hindered o-aminophenol derivatives by O. I. Shadyro; V. L. Sorokin; G. A. Ksendzova; O. V. Savinova; N. I. Pavlova; E. I. Boreko (414-417).
A series of new sterically hindered alkylsulfonate-and adamantane-N-substituted o-aminophenol derivatives were synthesized. The antiviral properties of these compounds were studied in cell culture against Herpes simplex type-1 (HSV-1) and influenza A (H7N1) viruses. The ability of many compounds (8 of 13, 61.5%) to suppress replication of HSV-1 was established. Among the tested compounds, N-(2-hydroxy-3,5-diisopropylphenyl)benzenesulfonamide displayed the highest activity in suppressing replication of HSV-1 virus.
Keywords: Synthesis; sterically hindered o-aminophenol derivatives; antiviral activity

Synthesis and characterization of polysulfanilamide and its copolymers: bioactivity and drug release by Abdulhakeem Alsughayer; Abdel-Zaher A. Elassar; Fakhreia Al Sagheer; Seham Mustafa (418-428).
Sulfanilamide reacted with acryloyl chloride to give 4-(N-acrylamido)benzenesulfonamide (ABA), which converted to the corresponding polymer (PABA) upon treatment with initiator at 75°C. Various copolymers formed from ABA with acrylamide (AA), acrylonitrile (AN), and N-(thiazol-2-yl)acrylamide (TA) at different ratios (50 : 50, 70 : 30 and 30 : 70) were prepared. The polymer and copolymers were characterized using IR, 1H NMR, 13C NMR and mass spectroscopy, thermogravimetry, and scanning electron microscopy. The drug release from polymeric chain and copolymers was studied at 37°C and pH 8.4. The drug release was highly increased upon adding sodium chloride at various concentrations, 0.1%, 0.5% and 0.9%. The drug release from the polymer and copolymer chains was measured using a UV-visible spectroscopy technique. Antimicrobial activity of the polymer and copolymers was studied. It is established that the ABA copolymer with TA is more effective as compared to other copolymers.
Keywords: 4-(N-acrylamido)benzenesulfonamide (ABA); poly(ABA); copolymers with acrylamide; acrylonitrile; N-(thiazol-2-yl)acrylamide; synthesis; antimicrobial activity

In an attempt to find a new class of antimicrobial agents, a series of indolothiazolidinone, oxazolidinone, and azetidene analogs of benzenesulfonyl chloride have been synthesized and evaluated for their antibacterial activity against S. aureus, S. typhi and E. coli, expressed as the minimum inhibitory concentration (MIC50,μg/mL). Some of the synthesized compounds (4a–4d, 5a– 5d, and 6a–6d) exhibit promising antibacterial activity that is attributed to their spiro structure.
Keywords: Indolothiazolidinone; oxazolidinone; azetidene; antimicrobial activity

Biologically active compounds from Viola brachyceras herb by A. M. Martynov; T. D. Dargaeva; E. V. Chuparina (435-437).
The composition of phenolic compounds of short-spurred violet herb Viola brachyceras Turcz. was investigated. Thirteen compounds of flavonoid structure were identified by high-performance liquid chromatography as tannin; epicatechin; gallic, chlorogenic, caffeic, chicoric, ferulic, neochlorogenic, and cinnamic acids; and the flavonoids rutin, apigenin, luteolin, and naringenin. The contents of 20 elements (Na, Mg, Al, Si, P, S. Cl, K, Ca, Ti, Cr, Mn, Fe, Ni, Cu, Zn, Br, Rb, Sr, and Ba) were measured by x-ray fluorescence spectrometry. Phenolic compounds and the elemental composition of V. brachyceras were reported for the first time. The results were of interest for further investigation of the pharmacological properties of V. brachyceras as a valuable raw material for producing new drugs.
Keywords: Viola brachyceras Turcz.; phenolic compounds; macro- and trace elements

Adaptogenic properties of polyprenols isolated from fir greenery in a rat-immobilization stress model by V. N. Syrov; T. V. Hurshkainen; A. V. Tsaruk; F. R. Egamova; Z. A. Khushbaktova; A. V. Kuchin (438-440).
The adaptogenic effect of polyprenols isolated from fir greenery was studied. It was established that a single oral administration of polyprenols at a dose of 0.25 mL/100 g in male rats (140 – 150 g) under conditions of immobilization stress prevented significantly involution of the thymic-lymphatic system and hypertrophy of the adrenal glands and reduced the content of ascorbic acid and cholesterol. In addition, there was a decrease in the level of stress-activated lipid peroxidation processes and normalization of the functioning of antioxidant and NO-ergic systems of liver hepatocytes.
Keywords: polyprenols of fir greenery; immobilization stress; adaptogenic effect

The influence of Echinacea purpurea tincture on the state of rat kidney antioxidant system under carbon tetrachloride intoxication was studied. It was established that the content of TBA reaction products increased, the activity of catalase and glutathione transferase decreased, and the reduced glutathione level and the glutathione peroxidase activity increased in kidney supernatants from rats intoxicated with carbon tetrachloride. Administration of E. purpurea tincture for 5 d after carbon tetrachloride intoxication restored the glutathione peroxidase activity and corrected other antioxidant system parameters in rat kidneys.
Keywords: Echinacea purpurea ; carbon tetrachloride intoxication; rat kidney antioxidant system

The in vivo biodistributions of the monopotassium salt of hydroxyethylidenediphosphonate labeled with 188Re (188Re-KHEDP) were studied in rats for drug batches prepared with and without Re carrier. Also, the pharmacokinetics of two batches of 188Re-KHEDP that were synthesized at different temperatures (20 and 100°C) were studied. The results showed that all 188Re-KHEDP preparations accumulated in bone. The excretory pathway of 188Re-KHEDP was through the kidneys. Only kidney and thyroid exhibited a relatively high drug uptake among the soft tissue organs. The results showed that carrier-added 188Re-KHEDP had better pharmacokinetic parameters than the carrier-free radiopharmaceutical as manifested by higher bone uptake and faster blood clearance. It was also found that the presence of Re carrier increased significantly the stability of 188Re-KHEDP. The skeleton-to-muscle ratio was 249.1 ± 42.1 for carrier-added 188Re-KHEDP and <21 for the carrier-free drug. The biodistributions of 188Re-KHEDP differed for drugs prepared at 20 and 100°C. The maximum skeleton-to-muscle and skeleton-to-blood ratios were 157.3 ± 24.4 and 21.4 ± 4.85 for 188Re-KHEDP prepared at 20°C and 467.2 ± 123.2 and 77.9 ± 11.9 for that prepared at 100°C. These results showed a statistically significant difference (p < 0.05) in favor of 188Re-KHEDP prepared at 100°C. The results indicated that all versions of 188Re-KHEDP had promising properties as potential therapeutic bone-metastasis agents. However, carrier-added 188Re-KHEDP and that prepared at 100°C exhibited better properties than the other types of the examined radiopharmaceutical.
Keywords: 1-hydroxyethylidenediphosphoric acid; rhenium-188

Suspension based on calcium carbonate and sodium hyaluronate for the prevention and treatment of bone diseases by A. E. Bol’shakova; N. B. Mel’nikova; L. N. Nistratova; I. P. P’yanzina; T. V. Salikova; S. A. Gavrilova; E. V. Krasil’nikova (449-455).
A combined drug based on natural calcium carbonate and sodium hyaluronate was developed for the prevention and treatment of bone diseases. A modified Dische method was proposed for the analysis of sodium hyaluronate in the presence of fructose in the complex dosage form. Quantitative analytical chemical techniques for determining sodium hydrogen phosphate, potassium dihydrogen phosphate, and excipients (fructose and methylparaben) in the drug suspension were developed.
Keywords: calcium carbonate; sodium hyaluronate; bone disease; animal experiments

An in vitro model for evaluation of the release rate of hydrophobic compounds from coenzyme Q10 lozenges and in vivo/in vitro correlation by M. V. Karlina; O. N. Pozharitskaya; V. M. Kosman; A. N. Shikov; A. A. Zabozlaev; M. N. Makarova; V. G. Makarov (456-459).
An original in vitro two-phase model was proposed for evaluating the dissolution of hydrophobic compounds from oral lozenges. The new model was used for biopharmaceutical evaluation of lozenges with coenzyme Q10. The mechanism of drug release was determined. The main pharmacokinetic parameters of coenzyme Q10 in tablets studied in vivo and in vitro were compared in order to check the adequacy of the proposed model. A correlation of power A (r = 0.8991) between drug release and pharmacokinetic parameters was found and provided the correct prognosis of the experimental pharmacokinetic profile of coenzyme Q10 according to its release rate. This confirmed the validity of the proposed in vitro model.
Keywords: oral lozenges; coenzyme Q10; two-phase dissolution medium model