Pharmaceutical Chemistry Journal (v.49, #8)

Hypoglycemic Potential of Benzimidazole Derivatives by A. A. Spasov; K. V. Lenskaya; P. M. Vasil’ev (495-500).
Benzimidazole derivatives exhibiting hypoglycemic and antidiabetic properties were reviewed. Activities of compounds from 22 classes of substituted benzimidazoles and their tricyclic condensed analogs were presented. The structures of compounds acting on various diabetic targets were discussed with respect to antidiabetic activity. Information of potential use for the synthesis and discovery of new targeted antidiabetic drugs was provided.
Keywords: benzimidazole derivatives; tricyclic benzimidazole derivatives; hypoglycemic activity; antidiabetic activity

Synthesis of New 1,3,4-Thiadiazines Capable of Inhibiting Nonenzymatic Glycosylation of Proteins by L. P. Sidorova; T. A. Tseitler; N. M. Perova; V. V. Emel’yanov; E. A. Savateeva; N. E. Maksimova; N. N. Mochul’skaya; V. A. Chereshnev; O. N. Chupakhin (501-505).
A series of new 1,3,4-thiadiazines with cycloalkylamino (cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino) groups were synthesized via cyclocondensation of α-haloacetophenones with thiosemicarbazides containing 4-cycloalkyl groups. Five of the synthesized compounds showed the capability to inhibit nonenzymatic glycosylation of proteins in vitro in a model system. The obtained test results allowed compounds containing cyclopropylamino residues (LT-1a and LT-1d) to be recommended for further in vivo testing.
Keywords: 1,3,4-thiadiazine; cyclocondensation; α-haloacetophenones; thiosemicarbazides; nonenzymatic glycosylation of proteins

Methyl 1-bromocyclohexanecarboxylate reacted with zinc and 2-oxochromene- or 6-bromo-2-oxochromene-3-carboxylic acids to form 4-(1-methoxycarbonylcyclohexyl)- or 6-bromo-4-(1-methoxycarbonylcyclohexyl)-2-oxochromane-3-carboxylic acid derivatives possessing antinociceptive activity.
Keywords: oxochromane carboxylates; Reformatsky reaction; antinociceptive activity

6-Aryl-3,4-dimethyl-N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides were synthesized by three-component reactions of acetoacetanilide, aromatic aldehydes, and N-methylurea. The structures of the compounds were confirmed by IR and PMR spectroscopy and mass spectrometry. The antifungal activity of the synthesized compounds was studied.
Keywords: three-component synthesis; 3,4-dimethyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide derivatives; antifungal activity

N,5-Diaryl-7-methyl-3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide hydrochlorides were synthesized via the reaction of N,6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides with ethyl chloroacetate. Some of the synthesized compounds exhibited antimicrobial activity.
Keywords: N,6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides; ethyl chloroacetate; 5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxyamides; antimicrobial activity

Methyl-3-{[2-(dimethylamino)propyl]amino}acrylate reacted with α-chloro-3-bromobenzylisocyanate to synthesize 4-(3-bromophenyl)-5-methoxycarbonyl-1-(N,N-dimethylaminopropyl)-3,4-dihydropyrimidin-2(1H)-one hydrochloride, alkylation of which by chloroacetate esters yielded a series of quaternary ammonium salts. The structures of the compounds were confirmed by IR and PMR spectroscopy and mass spectrometry. Some of the synthesized compounds exhibited high inhibitory activity with respect to the superoxide-generating ability of mitochondria in both the liver and transformed tissue of tumor-bearing rats.
Keywords: 3,4-dihydropyrimidin-2-ones; quaternization; ammonium salts; antioxidant activity; superoxide anion-radical; superoxide-generating activity; Guerin carcinoma

An x-ray crystal structure analysis found that the bromination of methyl 1-allyl-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate by Br2 in glacial HOAc involved not heterocyclization but classical addition of Br2 to the unsaturated allyl bond, in contrast with structurally similar alkyl 1-allyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates. Pharmacological tests showed that removal of the double bond from the 1-N-alkyl moiety in the esters was associated with a decrease of analgesic activity.
Keywords: bromination; 4-hydroxy-2,1-benzothiazines; synthesis; analgesic activity

Aseries of biphenyl-2-carbonitile clubbed 1,3,4-oxadiazole derivatives have been synthesized by the condensation of biphenyl-2-carbonitrile with various substituted 2-mercapto-5-aryl-1,3,4-oxadiazoles. Structures of the newly synthesized compounds IVa – IVh were characterized using FTIR, 1H NMR, 13C NMR, mass spectroscopy, and elemental analysis. All the compounds were screened for their antimicrobial properties against a broad spectrum of bacteria and fungi. It was very clearly noted from SAR study that the derivatives bearing electron-withdrawing functional groups (-NO2, -Cl) were more promising than the derivatives with electron-donating group (-CH3) as antimicrobial agents.
Keywords: 1,3,4-oxadiazole; carbonitrile; antimicrobial activity; Minimum Inhibitory Concentration (MIC); Structure Activity Relationship (SAR)

Synthesis and Evaluation of Analgesic and Anti-Inflammatory Properties of Novel Ibuprofen Analogs by Abbas Ahmadi; Mohsen Khalili; Haniyeh Zandieh; Babak Nahri-Niknafs (530-536).
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to ameliorate the symptoms of inflammation and pain, particularly those associated with rheumatoid arthritis. Chronic use of these drugs including ibuprofen may elicit appreciable gastrointestinal (GI) toxicity. In order to synthesize novel analgesic and anti-inflammatory agents with reduced ulcerogenic effects, carboxylic acid of ibuprofen has been modified with respect to various heterocyclic amide groups, which is the most active area of research in this family. In this article, synthesis of a series of hybrid molecules containing important pharmacophore of ibuprofen and substituted benzothiazoles are described. All the synthesized compounds (IV) were tested for their analgesic and anti-inflammatory properties on mice, in comparison to standard (ibuprofen) and control (saline) groups. All the synthesized compounds exhibited significant analgesic and anti-inflammatory activities when compared to both standard drug and control. Findings indicated that addition of substituted amino benzothiazoles (especially methyl, bromine, and nitro groups) to ibuprofen moiety as the main pharmacophore, is a desirable strategy for reduction of pain and inflammation which may lead to the production of new drugs with higher activities compared to ibuprofen.
Keywords: non-steroidal anti-inflammatory drugs; ibuprofen; anti-inflammatory; analgesic; substituted benzothiazoles

Synthesis of New Chloroquine Derivatives as Antimalarial Agents by Rajesh Sharma; Abhishek Tiwari; Anupama Parate (537-542).
A series of hybrid molecules referred to as “reversed chloroquines” (RCQs) were designed, synthesized, and tested against chloroquine resistant strains of Plasmodium falciparum. The designed compounds contain bulky aromatic groups and chloroquine like nucleus linked with each other via two or three carbon alkyl linkers. Five compounds were designed based on the structure – activity relationship. These five compounds have been successfully synthesized, of which three compounds show significant antimalarial activity in vitro. A modification of the reversal agent (RA) like moiety was designed using substituted biphenyl groups. The aminoalkyl substitution of the heterocycle and tertiary aliphatic aminoalkyl nitrogen atom with two- or three-carbon bridges to the heteroaromatic nitrogen is required for potential “resistance reversal activity”. The synthesized compounds were screened for their in vitro antimalarial activity as characterized by the 50% inhibitory concentration (IC50), cytotoxic concentration (CC50), and selectivity index (SI). These compounds did not show any cytotoxic effect. One of these compounds (5), which contains two-carbon linker chain, unsaturation at position 2, and chlorine substituted biphenyls in RA-like moiety, was found to possess appreciable and promising in vitro antimalarial activity against the chloroquine sensitive 3D7 strain of P. falciparum.
Keywords: chloroquine derivatives; reversed chloroquines; synthesis; structure—activity relationship; antimalarial activity; resistant strains; Plasmodium falciparum

Investigation of Chaga Melanin. II. Composition of Hydrocarbon Fraction by S. A. Nikitina; V. R. Khabibrakhmanova; M. A. Sysoeva; F. F. Nosova (543-546).
The composition of the fraction extracted by petroleum ether from chaga melanin was investigated for the first time. Saturated hydrocarbons with normal and iso-branched structures in addition to pristane, phytane, steranes, and terpanes were identified.
Keywords: chaga; melanin; petroleum-ether extract; hydrocarbons; steranes; terpanes

Biochemical Features of Common Cocklebur (Xanthium strumarium L.) by G. I. Klimakhin; V. S. Fonin; V. Yu. Maslyakov; N. B. Fadeev; V. V. Semikin; L. A. Pel’gunova (547-550).
Biochemical features of wild common cocklebur (Xanthium strumarium L.) were studied in order to assess its possible cultivation. Analyses showed high contents of fatty oil in seeds (up to 40%) and fruit (up to 12%) that consisted of unsaturated (palmitic, stearic) and more valuable polyunsaturated (linoleic, linolenic) acids. Oils extracted from seeds and whole fruit had practically identical chemical compositions. The results indicated that free iodide ion was absent in the plant and that the contents of organically bound iodine in oils from the fruit (385 mg/L) and fruit pulp after pressing (215 mg/kg) were elevated.
Keywords: common cocklebur; Xanthium strumarium L; fatty oil; saturated and unsaturated fatty acids; organic iodine compounds

Development and Evaluation of Standards for Assessing the Biological Activity of Allergens by L. V. Nevskaya; S. F. Radunskaya; E. I. Lavrenchik; V. K. Kapitanova; M. Yu. Korotkova (551-553).
The guidelines for construction and approval of international standards and reference reagents of biological substances according to which allergens, like all immunobiological drugs, should be standardized were described. The units of biological (allergic) activity for the first batch of standard are determined in vivo (provocative tests, intradermal tests, skin-prick test, etc.) in sensitized persons. The activity of the first batch of the standard is also studied in parallel by immunoassay methods using inhibition of serum containing allergen-specific IgE. The standard should also be characterized with respect to content of main (major) allergenic proteins, protein profile, and protein structure. Modern requirements for allergen preparations were introduced for the first time in the XIIIth Edition of the State Pharmacopoeia of the Russian Federation.
Keywords: allergens; main allergens; biological standardization; units of biological (allergenic) activity; skin tests; immunoassay

Synthesis and Molecular-Weight Characteristics of N-Oxidized Copolymers of N-Vinylpyrrolidone and 2-Methyl-5-Vinylpyridine by E. V. Vorfolomeeva; S. A. Kedik; A. V. Panov; E. S. Zhavoronok; Yu. S. Efimov; M. S. Starchenkova; D. V. Vasil’eva; G. V. Zatonskii (554-558).
Aseries of N-oxides of N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymers with various degrees of oxidation were prepared via oxidation of the copolymers by peracetic acid. The N-oxidation kinetic rate constants were calculated using UV spectrophotometry. The temperature dependence of the limiting N-oxidation was determined. The molecular-weight characteristics of the N-oxidized copolymers were established using 13C NMR methods. An approach based on direct UV spectrophotometry was proposed for practical monitoring of the reaction completion (degree of conversion).
Keywords: N-vinylpyrrolidone; 2-methyl-5-vinylpyridine; copolymer; N-oxidation; UV spectroscopy; 13C NMR spectroscopy

Modification of PMR Spectroscopy Technique for Determination of the Molar Substitution in Hydroxyethyl Starch by N. E. Kuz’mina; S. V. Moiseev; V. I. Krylov; O. V. Knyaz’kina; V. A. Yashkir; V. A. Merkulov (559-563).
The PMR spectroscopy technique for determining the molar substitution (MS) in hydroxyethyl starch (HES) was modified. It was shown that allowance for integrated intensities of resonances for anomeric H(1) protons of terminal and branching substituted and unsubstituted α-D-glucopyranose residues in HES decreased the calculated MS values and eliminated differences in the MS values obtained by PMR spectroscopy and gas chromatography.
Keywords: hydroxyethyl starch; molar substitution; molar substitution determination technique

Zolpidem was determined quantitatively in blood using a GC/MS method with an internal standard of imipramine hydrochloride. The multiple regression coefficient for the obtained calibration curve was r = 0.999. Metrological assessment of the method used eight statistical parameters. The extraction efficiencies of zolpidem at three concentrations were determined in model blood. Yields of 96 – 99% of the test compound were observed. The method was validated for specificity, detection limit (DL), limit of quantitation (LOQ), linearity, analytical range, accuracy, and precision (repeatability and intralaboratory precision). Statistically processed results were within acceptance limits. The DL for zolpidem in blood was 24 ng/mL; LOQ, 72.7 ng/mL
Keywords: zolpidem; quantitative determination; validation

Hydrolytic Stability of Albicar by A. S. Berlyand; N. V. Kostebelov; A. A. Prokopov (570-571).
Albicar underwent noticeable hydrolytic cleavage only under forcing conditions (high temperature, strong acid). Albicar in solutions for injection was shown to be highly stable under sterilizing conditions.
Keywords: Albicar; hydrolytic stability; hydrolysis constant