Pharmaceutical Chemistry Journal (v.50, #3)

The influence of the melatonin-correcting drugs melaxen and Valdoxan on the gene-transcription level of superoxide dismutase (SOD, EC and catalase (EC in liver and heart of rats with hyperthyroidism has been investigated. Administration of these drugs to rats with model pathology leads to changes in SOD and catalase expression in their tissues toward the control values.
Keywords: gene-transcription level; melaxen; Valdoxan; superoxide dismutase; catalase

Improving Pharmaceutical Characteristics of Curcumin by Alginate/Pectin Microparticles by N. Sattarahmady; A. A. Moosavi-Movahedi; P. Bazzi; H. Heli; S. Pourtakdoust (131-136).
This study was aimed at the preparation of curcumin-loaded alginate/pectin microparticles (beads) in order to enhance the pharmaceutical effect of curcumin as a drug for colon related diseases. For this purpose, three types of curcumin-loaded beads were prepared with different alginate/pectin ratios (100/0, 75/25 and 50/50) and studied in various experiments including the release of curcumin from beads and swelling of beads in buffer solutions of simulated gastric, intestinal, and colon fluids. The results of curcumin releasing experiments under conditions mimicking stomach to colon transit showed that the beads with higher content of pectin exhibit stronger curcumin entrapment, slower release rate, and lower swelling. Thus, 50/50 alginate/pectin composition has minimum release in the upper parts of gastrointestinal tract (stomach and intestine). However, when these beads reached colonic buffer medium, the curcumin release suddenly increased. Therefore, beads with 50/50 alginate/pectin compositions could be useful as a suitable carrier for curcumin delivery to colon. Moreover, the stability and chemical protection of curcumin encapsulated in these beads was confirmed by high performance liquid chromatography measurements after a period of six months.
Keywords: curcumin; delivery system; pectin; alginate, bead microparticles

Molecular docking and molecular dynamics (MD) simulations were used for determining the binding positions of 2-aroylbenzofuran-3-ols, which positions cannot be attained from experimental studies. MD simulation was performed for all initial structures docked within 15000 ps. RMSD and potential energy analysis showed that all simulations reach equilibrium after 3000 ps. Analysis of the simulation trajectories showed that the structures of initial docked complexes and equilibrium structures in MD are identical. Moreover, a direct relation between steric hindrance of R2 substituent group and binding mode on DNA structure was found. The MM/GBSA analysis showed that the van der Waals (vdW) energy term is the most important energy term in binding process. It has been also found that the vdW and non-polar energy terms (∆G sur) are favorable for binding. At the same time, the polar groove-binding energy term (∆G GB) is an unfavorable term in the predicted binding free energy (∆G binding).
Keywords: benzofuran; docking; molecular dynamics; calf-thymus DNA

Synthesis and Antifungal and Antiviral Activity of N-Benzyl Derivatives of the Tetraene Macrolide Antibiotic Lucensomycin by V. V. Belakhov; A. V. Garabadzhiu; V. A. Kolodyaznaya; O. V. Topkova (143-151).
Reductive amination of the tetraene macrolide antibiotic lucensomycin by para-substituted benzaldehydes and cyanoborohydride formed its N-benzyl derivatives. The physicochemical, medical, and biological properties of the obtained pimaricin derivatives were studied. Biological tests showed that the N-benzyl lucensomycin derivatives possessed high antifungal and antiviral activity. Pharmacological tests showed that the acute toxicity (LD50) of the synthesized lucensomycin derivatives was six times less than that of the starting antibiotic.
Keywords: polyene macrolide antibiotic; lucensomycin; chemical modification; N-benzyl derivatives; toxicity; antifungal activity; antiviral activity

Experimental Study of the Biocompatibility of Soft Tissues and a Finely Dispersed Sorbent Containing Silver by T. V. Popova; T. G. Tolstikova; A. Yu. Letyagin; L. N. Rachkovskaya; V. A. Burmistrov (152-155).
The physicochemical and biological properties of a new finely dispersed Si- and Al-containing sorbent are presented. Its modification using silver nanoclusters immobilized on the sorbent-particle surface is described. The parameters of the sorbent porous structure, its sorption activity, and the rate of silver release from the sorbent surface in contact with a liquid medium are determined. Both the sorbent matrix and the original silver-modified sorbent are well tolerated by experimental animals upon intramuscular administration and cause no changes in the behavior, weight, and appearance of the animals. Results from studies of the leukocyte, platelet, and red-blood-cell pools of peripheral blood also confirm that the sorbents are biocompatible with body tissues.
Keywords: silver-containing sorbents; silver nanoclusters; biocompatibility

Synthesis and Antiviral Activity of Hydroxy-Substituted Benzaldehydes and Related Compounds by O. I. Shadyro; V. L. Sorokin; G. A. Ksendzova; O. V. Savinova; S. N. Samovich; N. I. Pavlova; G. I. Polozov; E. I. Boreko (156-158).
A series of hydroxy-substituted benzaldehydes and related compounds were synthesized and studied in cell culture against herpes simplex type I (HSV-1) and influenza A (H7N1) viruses. It was found that salicylaldehyde, 2,3-dihydroxybenzaldehyde, and gossypol could suppress HSV-1 replication. The structure–activity relationship of the series of hydroxylated benzaldehydes was analyzed.
Keywords: benzaldehyde; gossypol; ionol; antiviral activity; synthesis

Ionization constants (pKa and pKb) of N-substituted mono(di)halo(H)anthranilic acids and their amides and hydrazides were studied as functions of their quantum-chemical parameters. The predicted pKa and pKb values calculated for 10 new compounds of this series were confirmed experimentally. An analysis of the ionization constants predicted using the proposed equations showed them to be advantageous over other computer programs.
Keywords: N-substituted mono(di)halo(H)anthranilic acids and their amides and hydrazides; ionization constant; pKa ; pKb ; quantum-chemical parameters; prediction

Synthesis and Evaluation of the Hypoglycemic and Hypolipidemic Activity of Novel Arylidene Thiazolidinedione Analogson a Type 2 Diabetes Model by Abbas Ahmadi; Mohsen Khalili; Simin Samavat; Elnaz Shahbazi; Babak Nahri-Niknafs (165-171).
Thiazolidinediones (TZDs) represent a new class of antidiabetic drugs having an insulin sensitizing effect in patients with type2 diabetes. This article reports synthesis and evaluation of two novel derivatives of rosiglitazone (an effective drug of 5-arylidene-2,4-thiazolidinedione family) containing chlorophenyl instead of phenyl, s-triazine-morpholine instead of pyridine, and a double bond adjacent to the TZD ring (compounds V and VI).The new chemical entities were tested for antihyperglycemic and antihyperlipidemic activity on the alloxan-induced diabetic rat model. Results indicated that both new drugs showed hypoglycemic and hypolipidemic activity comparable to the control group, but compound V exhibited more significant blood lipid lowering activity as compared to other groups. Moreover, the new drugs displayed high efficiency in increasing HDL level and also HDL/LDL ratio, as good lipid profiles compared to others, which provide useful results for the interpretation of hypolipidemic activity of 2,4-thiazolidinedionedrugs.
Keywords: 5-arylidene-2,4-thiazolidinediones; glitazone; antihyperglycemic activity; antihyperlipidemic activity; alloxan-induced diabetic rat model

Novel Armed Pyrazolobenzothiazine Derivatives: Synthesis, X-Ray Crystal Structure and POM analyses of Biological Activity Against Drug Resistant Clinical Isolate of Staphylococcus aureus by Zara Sajid; Matloob Ahmad; Sana Aslam; Usman Ali Ashfaq; Ameer Fawad Zahoor; Furqan Ahmad Saddique; Masood Parvez; Abdul Hameed; Sadia Sultan; Hsaine Zgou; Taibi Ben Hadda (172-180).
Novel structural hybrids of pyrazolobenzothiazine and triazole ring systems have been prepared to observe a synergistic effect of the two ring systems. The methodology involves condensation of pyrazolobenzothiazine rings with methyl chloroacetate, followed by hydrazide formation. The hydrazides were converted to triazoles through the formation of intermediate potassium salts of dithiocarbazate. The final compounds as well as intermediates were screened for their antibacterial activity against a multidrug resistant strain of Staphylococcus aureus. It was interesting to observe that dithiocarbazates (7a, 7b) and target triazoles (8a, 8b) exhibited antibacterial activity.
Keywords: pyrazolobenzothiazine dioxides; triazole; antibacterial pharmacophore site; Petra/Osiris/Molinspiration (POM) analyses

Analysis of Factors Influencing the Interchangeability of Antiepileptic Drugs by R. N. Alyautdin; B. K. Romanov; E. Yu. Pasternak; N. D. Bunyatyan; V. A. Merkulov (181-184).
The presence of several generics on the pharmaceutical market makes it possible to create a competitive environment and helps to reduce the costs of drug therapy. RF Government Decree No. 1154 of October 28, 2015, “On the procedure for determining the interchangeability of drugs for medical use” determines largely the fate of generics in Russia. Quality assurance of generics and the creation of a competitive environment for the procurement of pharmaceutical products by regional public health institutions in order to reduce costs were the primary drivers of this decree. However, results from substitution of antiepileptic drugs indicate a number of problems in this field. The present review is devoted to an analysis of the interchangeability problems of antiepileptic drugs.
Keywords: antiepileptic drugs; interchangeability; generic drugs; bioequivalence

Oxidative Bromination of O-Xylene by P. V. Kazakov; S. V. Gorelenko; O. T. Morozova; I. D. Derevyagina; O. I. Lukashov; N. S. Mirzabekova (185-187).
Oxidative bromination of o-xylene with liquid bromine or hydrobromic acid in aqueous solution in the presence of an alkali-metal bromate as the oxidizing agent was studied. The proposed method allowed the amount of wastes to be reduced while maintaining a high yield of bromo-o-xylene, which is used in the synthesis of vitamin B2.
Keywords: bromine; xylene; oxidative bromination; alkali-metal bromate

The biological properties of low-molecular-mass polypeptides isolated from the extracellular matrix of bone tissues were studied using healing of a fractured rat tibia as a model. It was found that a single injection of the test fraction near the fracture caused glycogen to accumulate and the sarcoplasmic protein content to increase in skeletal muscle of the traumatized extremity section. The healing time of the experimental fracture in rats was shortened. The results justify the creation of complex preparations designed to promote regeneration of support tissues that are composed of low-molecular-mass derivatives of collagen + growth factors.
Keywords: bone proteins; chromatography; skeletal muscles; bone fracture

An effective four-step synthesis of the tripeptide H-Pyr-His-Trp-OH that is used to produce synthetic gonadoliberin agonists was developed. The synthesis was carried out without adding and removing protecting groups and could produce the target compound with >98% purity.
Keywords: gonadoliberin; synthetic agonists; peptide synthesis; production

Determination of Cycloserine in Blood Plasma by HPLC/MS: Application to Bioequivalence Studies by E. S. Stepanova; M. V. Ovcharov; S. S. Barsegyan; V. V. Chistyakov (195-199).
A selective and specific quantitative assay with HPLC/MS determination of the broad-spectrum antituberculosis antibiotic cycloserine in blood plasma with reserpine internal standard was developed and validated. It was shown that the method was accurate and precise and linear in the range 0.5 – 20.0 μg/mL. A calibration curve obeyed the equation Y = aX + b, where a = 0.0893 and b = –0.0134 with a correlation coefficient of 0.9994. The cycloserine limit of detection was 0.1 μg/mL; the limit of quantitation, 0.5 μg/mL. The recoveries of cycloserine from the matrix at low (0.5 μg/mL) and high (20.0 μg/mL) drug concentrations were 41.7 and 62.4%, respectively, with matrix factors of 0.28 and 0.34, respectively, normalized to the internal standard.
Keywords: antituberculosis drug; cycloserine; HPLC/MS; validation; pharmacokinetics; bioequivalence

Development and Validation of a Gas Chromatography Method for Quantitative Determination of Lavendar Oil in Lavaflam Preparation by M. A. Aslanyan; L. A. Bobritskaya; E. S. Nazarova; T. A. Mirnaya; T. V. Zborovskaya (200-204).
A gas chromatography method for quantitative determination of lavender oil in a combined tablet dosage form was developed. Validation studies using acceptability criteria for contents variations of ±10% confirmed that the proposed method was specific, linear, precise (convergent), and accurate in the applicable range.
Keywords: lavender oil; gas chromatography; tablets; flamin

Solid-State Ion-Selective Electrode with an Ion – Electron Transducer for Doxycycline Determination by S. S. Ryasenskii; M. A. Feofanova; D. V. Vasil’eva; G. I. Mantrov (205-208).
A solid-state ion-selective electrode (ISE) for doxycycline hydrochloride determination is proposed. A construction feature is a plasticized membrane ion—electron transducer containing polyaniline. The transducer is situated between the current conductor and ion-selective membrane. The main metrological characteristics of the electrode are determined. It is established that the transducer increases the stability of the electrode potential during the measurements. It is demonstrated that the ISE can be used in practice for quantitative determination of doxycycline hydrochloride in dosage forms.
Keywords: ion-selective electrode, polyaniline, ion; electron transducer