Pharmaceutical Chemistry Journal (v.47, #1)

Available information concerning methods for the synthesis of coumestan derivatives and data on their biological activity are reviewed and systematized.
Keywords: coumestan derivatives; natural and synthetic; biological activity; synthesis

Synthesis and receptor activity of 2-substituted 8-methyl-5-(2-pyridinylethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles by A. V. Ivachtchenko; O. D. Mitkin; V. M. Kysil; V. I. Kazey; I. M. Okun (12-19).
A series of new 2-substituted 8-methyl-5-(2-pyridinylethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles have been synthesized. Their activity profiles were studied on a broad panel of therapeutic targets including GPC-receptors, ion channels, and neurotransmitter transporters. One of the studied compounds, 2-methyl-3-{2-[8-methyl-5-(2-pyridin-2-ylethyl)-2,3,4,5-tetrahydropyridino[4,3-b]indol-2-yl]ethyl}-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, was found to be a highly active antagonist of adrenergic α1A, α1B, α1D, and α2A receptors and serotonin 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. The results were considered in terms of structure—activity relationships. It was established that introduction of bulky substituents into the 2-position of the other synthesized 8-methyl-5-(2-pyridinylethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles led to an activity decrease of the corresponding derivatives as compared with that of the 2,8-dimethyl analogs.
Keywords: 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole derivatives; pharmacological activity; GPC-receptors; ion channels; neurotransmitter transporters; structure—activity relationships

Synthesis of BDNF-mimetic dimeric dipeptide GSB-106, a potential neuroprotector drug by A. V. Tarasyuk; S. V. Pomogaibo; D. V. Kurilov; T. A. Gudasheva (20-27).
The BDNF-mimetic dimeric dipeptide bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106) based on the structure of beta-turn loop 4 (BDNF-Asp93-Ser94-Lys95-Lys96-) was synthesized. GSB-106 showed neuroprotective activity in vitro at concentrations 10–6-10–8 M and antidepressant activity in vivo in rats at i.p. injected doses of 0.1-1 mg/kg. The target peptide GSB-106 was obtained using three schemes in order to select the optimum synthetic pathway. The first scheme was based on the strategy of Boc/Z protecting groups using the method of pentafluorophenyl esters. The second scheme also used the Boc/Z strategy and the N-hydroxysuccinimide ester method. The third scheme used the Z/Boc strategy and the azide method. These three methods for synthesizing GSB-106 were compared with respect to yield and optical purity. The optimum result was obtained by using the third scheme that involved Z/Boc protecting groups and the azide method of peptide bond formation.
Keywords: peptide mimetic; dipeptide; peptide synthesis; BDNF

Synthesis and pharmacological activity of (2-chloroethoxy-4′-dimethylaminophenyl)phosphorylacetic acid hydrazide (CAPAH) and its metabolite (N-acetyl derivative) by I. I. Semina; V. P. Balashov; T. V. Kurmysheva; R. I. Tarasova; E. V. Shilovskaya; O. V. Voskresenskaya; A. Z. Baichurina; M. I. Al’myasheva (28-30).
The new compound (2-chloroethoxy-4′-dimethylaminophenyl)phosphorylacetic acid N-acetylhydrazide (II) was synthesized. Compound II was proposed as a metabolite of (2-chloroethoxy-4′-dimethylaminophenyl)phosphorylacetic acid hydrazide (CAPAH, I), a drug possessing nootropic activity. The psychotropic and antiarrhythmic properties of II were compared with those of I. It was established that II did not possess nootropic and antidepressant activities although its antiarrhythmic properties were more pronounced. It was suggested that the C(O)CH3 fragment, being a substituent on the hydrazide in II, decreased penetration of the compound through the blood―brain barrier, which could explain the absence of psychotropic activity.
Keywords: synthesis; (2-chloroethoxy-4′-dimethylaminophenyl)phosphorylacetic acid hydrazide (CAPAH); pharmacological activity

Synthesis and Antimicrobial Activity of Carboxymethylchitin Derivatives by V. G. Dudarev; O. M. Tikhomirova; A. A. Iozep (31-34).
6-Aminopenicillanic acid, ampicillin, amoxycillin, cephalexin, and 5-nitrofurfural were covalently attached to carboxymethylchitin using its hydrazide and azide. The resulting polymeric analogs of drugs retained antimicrobial activity, albeit on a somewhat decreased level.
Keywords: carboxymethylchitin derivatives; synthesis; antimicrobial activity

Synthesis and Structure of Dimephosphone Pyridinoylhydrazones with Antimycobacterial Activity by B. I. Buzykin; V. N. Nabiullin; R. S. Garaev; R. V. Chestnova; L. R. Kashapov; R. Sh. Valeev; V. F. Mironov (35-39).
Nicotinoyl- and isonicotinoylhydrazones of 2-dimethoxyphosphoryl-2-methylpentan-4-one (the active ingredient of the medicinal preparation Dimephosphone) were synthesized. It was shown that crystals of both hydrazones contained a single spatial form of the EC=N isomer. The dimephosphone pyridinoylhydrazones existed in slightly polar and polar solvents as a mixture of two amide conformers of a single EC=N isomer. This was due to hindered rotation of the molecular fragments around the (O=)C–N amide bond. The ratio of conformers was determined by the solvent and the time of solution preparation. Both hydrazones possessed low toxicity and high antimycobacterial activity.
Keywords: dimephosphone pyridinoylhydrazones; dimephosphone nicotinoylhydrazone; dimephosphone isonicotinoylhydrazone; structure of acylhydrazones; geometric isomers; amide conformers; IR spectroscopy; NMR spectroscopy; biological activity; toxicity; antituberculosis activity

Synthesis and analgesic activity of 3,5-diaryl-2-oxaspiro[5,6]dodec-3-en-1-ones by N. F. Kirillov; R. R. Makhmudov; A. G. Gavrilov; L. G. Mardanova; M. I. Vakhrin (40-41).
3,5-Diaryl-2-oxaspiro[5,6]dodec-3-en-1-ones were prepared by the reaction of methyl-1-bromocycloheptane carboxylates with zinc and 1,3-diarylprop-2-en-1-ones. The synthesized compounds possessed analgesic activity and exhibited low toxicity.
Keywords: analgesic activity; Reformatsky reagent; spirodihydropyranones

Activity of some enzymes in rat liver homogenate upon adding magnesium hydroxoaluminate by T. S. Mironycheva; L. K. Kamenek; N. V. Terekhina (42-43).
The effect of magnesium hydroxoaluminate (MHA), a compound possessing antacid properties, on the activity of liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) was studied in white-rat liver homogenate. It was established that administration of MHA reduced the activity of LDH whereas it did not influence the activity of ALT, AST, and ALP.
Keywords: magnesium hydroxoaluminate; alanine aminotransferase; aspartate aminotransferase; alkaline phosphatase; lactate dehydrogenase

Mixtures of bauerenol (1a), α-amyrin (1b) and β-amyrin (1c) extracted from the leaves of Ardisia cf. elliptica (subgenus Tinus) were tested at ratios of 2 : 2 : 1, 2 : 2 : 3 and 1 : 1 : 1, respectively, for their angio-suppressive effects on duck chorioallantoic membrane (CAM). Amixture with the maximum proportion of bauerenol (2 : 2 : 3) was found to be the most effective in limiting the number of blood vessels appearing in a given chorioallantoic membrane segment in a non-concentration-dependent interaction. All the three ratios of components were found effective in promoting intense expression of the von Willebrand factor (F8), but limited expression of epithelial membrane antigen was observed. Results of the present study indicate that the development of vasculature in duck CAM was limited by high expression of F8 along endothelial surfaces, thus suggesting high impact angio-suppressive effects of substances studied.
Keywords: Ardisia cf. elliptica ; Myrsinaceae; bauerenol; α-amyrin; β-amyrin; angio-suppressive

During the last few decades, a substantial body of research has been directed toward the free-radical scavenging activity. Inflammation reactions and other cell damage frequently begin with oxidative stress, over-production of reactive oxygen species, and development of multidrug-resistant bacteria. Rhizophora mucronata is a mangrove species that belongs to Rhizophoraceae family and widely occurs on the south-east coast of India. Due to evidently inadequate scientific evaluation of this species, our present investigation was focused on the isolation and quantification of alkaloid-rich extracts of R. mucronata and in vitro estimation of their free-radical scavenging potential. As a result, it was established that the alkaloid-rich extracts contain ajmalicine, vindoline, catharanthine, and serpentine bioactive components. Antimicrobial activity tests showed maximum zone of inhibition (19.56 ± 0.19) in Staphylococcus aureus in comparison to other bacteria isolated from diabetic foot ulcer. The results obtained in the present study indicate that alkaloid-rich fraction of R. mucronata is a high-quality source of natural antibacterial and antioxidant formulations.
Keywords: antioxidants; mangroves; Rhizophora mucronata ; alkaloid rich extracts

Hypoglycemic Potential of Triterpenes from Alstonia scholaris by Consolacion Y. Ragasa; Kosta Fremmielle Lim; Chien-Chang Shen; Dennis D. Raga (54-57).
A dichloromethane extract of air-dry leaves of Alstonia scholaris (L.) R. Br. contains a mixture of cycloeucalenol (1a), cycloartanol (1b) and lupeol (1c); lupeol acetate (2); and betulin (3). The structures of these triterpenes were elucidated by extensive 1D and 2D NMR spectroscopy and confirmed by comparison of their 13C NMR data to those reported in the literature. A previous study reported that the powdered leaves of Alstonia scholaris produced a highly significant decrease in blood glucose and a mechanism of this action was upon insulin triggering and direct insulin-like effects. Betulin and lupeol acetate were reported to exhibit hypoglycemic activity. Thus, only a mixture of 1a – 1c was tested for hypoglycemic potential using the oral glucose tolerance test (OGTT). A possible hypoglycemic activity was observed for a mixture of 1a – 1c at a dose of 25 mg/kg BW administered orally to normoglycemic mice.
Keywords: Alstonia scholaris ; Apocynaceae; cycloeucalenol; cycloartanol; lupeol; lupeol acetate; betulin

Chemical Composition and In Vitro Antioxidant Activity of Essential Oil from a Hepatoprotective Herbal Mix by P. B. Lubsandorzhieva; N. B. Boldanova; Zh. B. Dashinamzhilov (58-61).
The chemical composition of essential oil (EO) (0.57 – 0.80% yield) from a hepatoprotective herbal mix was analyzed by GC/MS. The major constituents of the EO were 4-epiacorenone (15.04%), dihydroisocalamendiol (11.55%), shyobunone (7.75%), thymol (6.91%), isoshyobunone (3.87%), Z-azarone (3.55%), a-selinene (3.19%), isocalamendiol (2.09%), camphor (1.23%), a-calacorene (1.23%), acoranone isomers 1 (3.07%) and 2 (1.61%), 1,8-cineol (1.61%), spathulenol (1.73%), caryophyllene oxide (1.65%), and caryophyllene (1.01%), which accounted for 67.09% of the oil composition. It was established that thyme, tansy, and absinthe contributed most significantly to the total antioxidant activity of the herbal mix.
Keywords: hepatoprotective herbal mix; thyme; tansy; absinthe; antioxidant activity

Use of Protease Inhibitors in Composite Polyelectrolyte Microparticles in Order to Increase the Bioavailability of Perorally Administered Encapsulated Proteins by M. A. Pechenkin; N. G. Balabushevich; I. N. Zorov; V. A. Izumrudov; N. L. Klyachko; A. V. Kabanov; N. I. Larionova (62-69).
Protein protease inhibitors (aprotinin, soybean Bowman–Birk inhibitor, and Kunitz soybean trypsin inhibitor) possessing different specificity with respect to trypsin, chymotrypsin, and elastase were encapsulated together with a cargo protein in polyelectrolyte microparticles using layer-by-layer (LbL) deposition techniques. The most efficient inclusion of the inhibitors occurred at the formation stage of the insoluble protein complex with the polyanion. Simultaneous immobilization of the inhibitor and protein did not influence the physicochemical properties of the microparticles, specifically their pH-sensitive behavior under conditions modeling the passage through various parts of the human gastrointestinal tract after peroral administration. The most effective protection against the action of proteolytic enzymes of pancreatic juice and the small intestine was achieved for simultaneous release of cargo protein and inhibitor from the microparticles. Soybean Bowman–Birk inhibitor, which is most similar to insulin with respect to physicochemical properties, in addition to the soybean extract enriched with protease inhibitors were the most suitable agents for protection of human insulin or its rapidly acting analogs (lispro and aspart). These findings suggested that simultaneous microencapsulation of both protein and protein protease inhibitor was a promising way to increase the protein bioavailability upon peroral administration of polyelectrolyte microparticles.
Keywords: microparticles; layer-by-layer deposition of polyelectrolytes; protein protease inhibitors; insulin; peroral administration of proteins