Pharmaceutical Chemistry Journal (v.48, #9)

We report here a comparative study of the effects of Russian-produced derivatives of 3-hydroxypyridine and succinic acid (emoxypine, Reamberin, and Mexidol) on the resistance of mice to acute adrenaline intoxication and formalin edema. The corresponding effects of α-lipoic acid (α-LA) were also studied - this has previously been used as a reference agent in assessments of the antihypoxic activity of 3-hydroxypyridine and succinic acid derivatives. Single doses of emoxypine, Reamberin, Mexidol, and α-LA at the optimum doses, corresponding to the therapeutic range for humans, were found to increase the duration of life in mice dying from acute adrenaline intoxication. α-LA was found to decrease formalin edema, while emoxypine and Mexidol increased its severity. The protective effects of all compounds tested against adrenalin intoxication were found to increase in direct proportion to their ability to increase formalin edema.
Keywords: 3-hydroxypyridine and succinic acid derivatives; adrenaline intoxication; formalin edema; Reamberin

Synthesis and Antiviral Activity of Substituted 2,4-bis-aminomethyl-5-hydroxy-1H-indole-3-carboxylic Acid Ethyl Esters and their Derivatives by A. V. Ivashchenko; P. M. Yamanushkin; O. D. Mit’kin; V. M. Kisil’; O. M. Korzinov; V. Yu. Vedenskii; I. A. Leneva; E. A. Bulanova; V. V. Bychko; I. M. Okun’; A. A. Ivashchenko; Ya. A. Ivanenkov (569-581).
New substituted ethyl esters of 2,4-bis-aminomethyl-5-hydroxy-1H-indole-3-carboxylic acids, 8-aminomethyl-2-methyl-2,3-dihydro-1H,7H-[1,3]-oxazino-[5,6-e]indole-9-carboxylic acids, and members of the previously unknown 4,5-dihydro-1H-pyrrolo[4,3,2-de]isoquinolin-3-ones of 1,4-dihydropyrrolo[4,3,2-de]isoquinolin-3,6-diones were synthesized. Their cytotoxicities and antiviral activities against bovine viral diarrhea virus (BVDV), hepatitis C virus (HCV), and A/Aichi/2/69 (H3N2) were studied in vitro. These compounds were found not to be active against these viruses. The only exceptions were the hydrochlorides of the ethyl esters of 5-hydroxy-2-(dimethylaminomethyl)-1-methyl-6-pyridine-3-yl- and 5-hydroxy-2-(dimethylaminomethyl)-1-methyl-6-fluoro-1H-indole-3-carboxylic acids, which at micromolar concentrations not only produced effective suppression of influenza A/Aichi/2/69 (H3N2) virus replication in cell cultures, but also showed high in vivo efficacy in a model of influenza pneumonia in mice infected with influenza A/Aichi/2/69 (H3N2) virus at a dose of 25 mg/kg/day.
Keywords: 2-aminomethyl-5-hydroxy-1H-indole-3-carboxylic acids, 8-aminomethyl-2-methyl-1,2,3,7-tetrahydro[1,3]oxazino[5,6-e]indole-9-carboxylic acids; 4,5-dihydro-1H-pyrrolo[4,3,2-de]isoquinolin-3-ones; 1,4-dihydro-pyrrolo-[4,3,2-de]isoquinolin-3,6-diones; hepatotoxicity; antiviral activity; antiinfluenza activity; influenza A/Aichi/2/69 (H3N2) virus; BVDV; HCV

Computerized Prediction, Synthesis, and Antimicrobial Activity of New Amino-Acid Derivatives of 2-Chloro-N-(9,10-Dioxo-9,10-Dihydroanthracen-1-Yl)Acetamide by V. I. Zvarich; M. V. Stasevich; O. V. Stan’ko; E. Z. Komarovskaya-Porokhnyavets; V. V. Poroikov; A. V. Rudik; A. A. Lagunin; M. V. Vovk; V. P. Novikov (582-586).
Interaction of 2-chloro-N-(9,10-dioxo-9,10-dihydroanthracen-1-yl)acetamide with α-, β- and ω-amino acids was used to synthesize new amino-acid derivatives of 9,10-anthraquinone. Experimental testing of the antimicrobial actions of the compounds synthesized demonstrated antibacterial activity against Mycobacterium luteum and antifungal activity against Aspergillus niger and Candida tenuis. These results from experimental testing of biological activity are consistent with results obtained by predictions using the computer program PASS. The prediction identified the need for further study of the antitumor and antioxidant actions of the newly synthesized amino acid derivatives.
Keywords: amino acids; 9,10-anthraquinone; in silico prediction; in vitro studies; antimicrobial activity

This review presents data on the high efficacy of acqua di Fiuggi water in the treatment and prophylaxis of urinary stone disease. Acqua di Fiuggi is a natural oligomineral water with a strong diuretic effect. Its contents include the humic substances with which the soil of the Anticolana valley is enriched. Humous substances, which are natural macromolecules with complex, disordered moleculare structures, include humic acids and fulvic acids, which are key components of acqua di Fiuggi. These acids can disorder the crystal lattices of calcium salts (oxalates, phosphates, etc.) in kidney stones, forming soluble calcium complexes. The result is that stones dissolve and are eliminated from the human body via the natural pathway.
Keywords: Humous acids; humic acids; fulvic acids; urinary stone disease; acqua di Fiuggi mineral water

With the aim of identifying new biologically active substances with antihypoxic actions, the methyl ester of 4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid was reacted with dialkylaminoalkylamines for the targeted synthesis of a series of corresponding N-R-amides, obtained as hydrochlorides with good solubility in water. Primary pharmacological screening demonstrated structural-biological relationships of importance for future testing. As essentially nontoxic substances, several of the resulting amides showed high antihypoxic effects. One of these compounds, 3-(morpholin-4-yl)-propylamide 4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid hydrochloride, is suitable for further pharmacological testing as a potential antioxidant.
Keywords: 4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide; synthesis; amidation; structure; antihypoxic activity

Cytotoxic and Antimicrobial Compounds from Cinnamomum cebuense Kosterm. (Lauraceae) by Dinah L. Espineli; Esperanza Maribel G. Agoo; Ramon S. del Fierro; Chien-Chang Shen; Consolacion Y. Ragasa (598-602).
The dichloromethane extract of Cinnamomum cebuense afforded α-terpineol (1), 4-allyl-2-methoxyphenol or eugenol (2), humulene (3), 4-hydroxy-3-methoxycinnamaldehyde (4) and a monoterpene (5) which were evaluated for cytotoxicity against colon carcinoma (HCT 116). Compound 4 showed moderate cytotoxicity against this cell line with an IC50 value of 18.8004 μg/mL, while 3 and 5 exhibited slight cytotoxicity. Compounds 35 were further tested for cytotoxicity against non-small cell lung adenocarcinoma (A549) and non-cancer Chinese hamster ovary cells (AA8). Sesquiterpene 3 exhibited moderate cytotoxicity against A549 with an IC50 value of 23.1964 μg/mL, 4 indicated slight cytotoxicity, while 5 was non-toxic against this cell line. Compound 4 showed moderate cytotoxicity against AA8 with an IC50 value of 20.4837 μg/mL, while 3 and 5 exhibited slight cytotoxicity. Compounds 1, 2 and 3 were active against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis and fungi Candida albicans and Trichophyton mentagrophytes, but were found inactive against Aspergillus niger. Sesquiterpene 3 was the most active against E. coli, P. aeruginosa, S. aureus, C. albicans and T. mentagrophytes, while 1 exhibited the highest activity against B. subtilis, even surpassing the activity of the standard antibiotic chloramphenicol.
Keywords: Cinnamomum cebuense ; Lauraceae; cytotoxicity; antimicrobial activity

Synthesis and Biological Evaluation of a New Series of Pyrazolines as New Anticandidal Agents by Ahmet Özdemir; Mehlika Dilek Altıntop; Zafer Asım Kaplancıklı; Gülhan Turan-Zitouni; Gülşen Akalın Çiftçi; Fatih Demirci (603-612).
New pyrazoline derivatives bearing an oxadiazole moiety were synthesized via the reaction of 1-(chloroacetyl)-3-(2-furyl/thienyl)-5-aryl-2-pyrazolines with 5-substituted-1,3,4-oxadiazole-2(3H)-thiones in the presence of potassium carbonate. Compounds 1 – 32 were screened for their antifungal activity against various Candida species and compared with ketoconazole. Among these compounds, the most effective derivatives were evaluated for their cytotoxicity against NIH/3T3 cells. 2-({2-[5-(4-Bromophenyl)-3-(2-furyl)-4,5-dihydro-1H-pyrazol-1-yl]-2-oxoethyl}thio)-5-(2-cyclopentylethyl)-1,3,4-oxadiazole (23) can be identified as the most potent antifungal agent against C. tropicalis due to its inhibitory effect on C. tropicalis and low toxicity to NIH/3T3 cells.
Keywords: anticandidal activity; cytotoxicity; oxadiazole; pyrazoline

Natural polyacetylenes are compounds whose structures contain two or more triple bonds. More than 1100 different acetylenes and biogenetically related substances have been identified in plants of the Asteraceae family. The various tribes of this family are characterized by individual sets of acetylene metabolites, allowing these compounds to be regarded as important chemotaxonomic markers. Polyacetylene compounds of the Asteraceae family have cytotoxic, antimicrobial, anti-inflammatory, neurotoxic, phototoxic, and several other types of activity. Information on this class of natural compounds is limited, especially in the Russian scientific literature. The aim of the present review is to fill this gap in our knowledge of the polyacetylenes of the Asteraceae family.
Keywords: polyacetylenes; Asteraceae ; biological activity; chemotaxonomy

We describe here the development of the immunomodulatory agent timofer, which is a 0.0148% aqueous solution of coordination compounds of the dipeptide isoleucyl-tryptophan and iron (II) sulfate; the synthesis of the free dipeptide and the medicinal formulation timofer and its production technology are described. Interactions were studied and the composition of the coordination compounds of the isoleucyl-tryptophan dipeptide with the iron (II) ion was identified. Interaction of the peptide and a metal ion in aqueous solution was shown to result in the formation of several complex forms, due to a stepwise complex formation process.
Keywords: immunomodulator drug; peptides; coordination compounds; timofer