Synthesis and study of spirooxindols with anti-HIV activity

INTRODUCERE Conform unui număr mare de publicaţii spirooxindoli au proprietăţi biologice diferite printre care se numără și activitatea anti-HIV [1, 2]. Se știe că unii dintre derivaţii de spirooxindol au o capacitate ridicată de a inhiba transcriptaza inversă HIV. Această capacitate se manifestă la concentraţii apropiate de concentraţiile compușilor active în medicmantele anti-HIV contemporane (EC50 = 50 nM).Totuși, proprietăţile biologice ale acestor derivaţi au fost determinate prin testarea amestecurilor racemice și nu a enantiomerilor individuali. Având în vedere faptul că adesea numai unul dintre enantiomeri este activ, se poate presupune că utilizarea derivaţilor puri din punct de vedere enantiomeric va crește activitatea la jumătate, ceea ce va reduce doza globală și, în consecinţă, va diminua toxicitatea compușilor. SCOPUL LUCRĂRII Dezvoltarea de noi compușicu activitate antivirală, care vor fi mai active și mai puţin toxice decât cele existente. MATERIAL ȘI METODE Au fost utilizaţi reactivi, metode și utilaj uzuali în sinteza organic fină. Pentru identificarea structurii nou-sintetizate a fost folosită spectroscopia de rezonanţă magnetică nucleară (RMN), anliza cu raze X. REZULTATE A fost efectuată sinteza enantioselectivă a spiro[ciclopropan-oxindolilor]. Au fost obţinute valori ridicate ale enantioselectivităţii (mai mult de 95% ee) cu o anumită modificare a structurii substanţei finale, dar aceasta a dus la o pierdere completă a proprietăţilor biologice ale moleculei, ceea ce poate fi explicat prin faptul că dimensiunea moleculei noi nu corespund dimensiunii centrului activ al enzimelor. În scopul obţinerii stereoizomerilor individuali și a creșterii eficacităţii compușilor ţintă, au fost obţinuţi niște derivaţi noi prin introducerea anumitor grupări asimetrice în structura moleculelor iniţiale și separarea ulterioară a diastereomerilor formaţi. CONCLUZII A fost sintetizat un șir de compuși spirooxindolici, care au demonstrat activitatea semnificativă împotriva enzimelor retrovirale – integrază și transcriptaza inversă.INTRODUCTION According to a large number of publications spirooxindoles have different biological properties, including anti-HIV activity [1, 2]. Some spirooxindole derivatives are known to have a high ability to inhibit HIV reverse transcriptase. This ability is manifested at concentrations close to the concentrations of active compounds in contemporary anti-HIV drugs (EC50 = 50 nM). However, the biological properties of these derivatives were determined by testing racemic mixtures and not individual enantiomers. Given that often only one of the enantiomers is active, it can be assumed that the use of enantiomerically pure derivatives will increase activity by half, which will reduce the overall dose and, consequently, decrease the toxicity of the compounds. THE AIM of the paper is to develop new compounds with antiviral activity, which will be more active and less toxic than existing ones. MATERIALS AND METHODS Common reagents, methods and equipment were used in fine organic synthesis. Nuclear magnetic resonance (NMR) spectroscopy, X-ray analysis was used to identify the newly synthesized substances. RESULTS Enantioselective synthesis of spiro [cyclopropane-oxindoles] was performed. High valuesof enantioselectivity (more than 95% ee) were obtained with some modification of the structure of the final substance, but this led to a complete loss of the biological properties, which can be explained by the fact that the size of the new molecule does not correspond to the size of the active center of the enzymes. In order to obtain the individual stereoisomers and to increase the efficacy of the target compounds, some new derivatives were obtained by introducing certain asymmetric groups in the structure of the initial molecules and the subsequent separation of the formed diastereomers. CONCLUSIONS A series of spirooxindole compounds were synthesized, which demonstrated significant activity against retroviral enzymes - integrase and reverse transcriptase

DETERMINATION OF FLUORIDES IN FEEDING PHOSPHATES

Abstract Synek 0., E. Sucman, M. Sucmanova: Determination of Fluorides in Feeding Phosphates. Acta vet. Bmo, 47, 1978: 159-162. A method was elaborated of the determination of fluorides in mineral feeding phosphates using the fluoride ion selective electrode. The following average contents of fluoride were determined using this method: 0.07 -1.80 g kg -1 in dicalciumphosphates, 0.22-2.47 gkg-1 in dinatriumphosphates, 1.97-3.86gkg-1 in pyrophosphates, and 0.21 g kg -1 in ammoniumdihydrogenphosphate. This method of determination is quick, simple and sufficiently accurate. It can be used for controlling the content of fluoride in mineral feeding phosphates. Nutrition of farm animals under conditions of modem agricultural large-scale production has become unthinkable without commercially produced feed mixtures of different kinds. A very important component of these feed mixtures are also mineral feeding phosphates which sometimes represent as much as one tenth of the weight of the mixture. These phosphates are necessary both for supplying the organism of farm animals with a sufficient amount of phosphorus and for the optimization of the phosphorus/calcium ration in the feed ration. Along with the optimum composition of feed mixtures it is important to control the purity of their individual components. In feeding phosphates it is namely the content of fluorides which are a natural component of raw materials used for their production. According to The fluoride ion selective electrode method has much simplified fluoride determination which had always been very time and labour consuming and represents, at the present time, an accessible means for a simple determination of this element. With regard to the fact that mineral feeding phosphates are a permanent component of nutrition of farm animals, they represent a potential source of excessive flow of fluorides into the organism. That is why a method of fluoride determination was elaborated using the ion selective electrode and in. the commonly applied mineral feeding phosphates this method was used for the determination of the fluoride content. Materials and Methods The fluoride content was determined in formulas of dicalciumphosphates imported to Czechoslovakia in the period of 1975-1977 as feeding mineral admixtures. Dinatriumphosphate and pyrophosphate were produced in 1976-1977 in the national enterprise FOSFA in Postoma, ammo

Study of antituberculosis activity of the cyclodextrins particles loaded with Juglone

Laboratorul Sinteză Organică, Institutul de Chimie, Chișinău, Republica Moldova, Centrul Știinţific al Medicamentului, Universitatea de Stat de Medicină și Farmacie „Nicolae Testemiţanu” din Republica Moldova, Laboratorul Microbiologia și Morfologia tuberculozei, IMSP Institutul de Ftiziopneumopogie „Chiril Draganiuc”, Chișinău, Republica MoldovaRezumat. Această lucrare este dedicată obţinerii particulelor de ciclodextrine încărcate cu Juglonă în calitate de compus antimicobacterian. Au fost descrise metoda de preparare și morfologia particulelor obţinute. Sunt prezentate datele privind activitatea antimicobacteriană a sistemelor obţinute. S-a detectat, că sistemele de particule de ciclodextrine încărcate cu Juglonă sunt la fel de eficiente ca Juglona pură aplicată în doze mai mari.Abstract. This paper is dedicated to obtaining of cyclodextrins particles loaded with Juglone as antimycobacterial compound. Method of preparation and morphology of the obtained particles have been described. The antimycobacterial activity data of the obtained systems is presented. It has been detected that cyclodextrins particulate systems loaded with Juglone are as effective as pure Juglone applied in higher dosages

Moznosti vyuziti iontove selektivnich elektrod v hodnoceni kvality a nezavadnosti potravin.

This report presents the description of a new method of chloride extraction from a thin slice of a sample, using an ultrasonic bath. The sample matrices chosen for this extraction were various meat products. The chloride content was determined by the potentiometric titration using AgNO_3. The measurement was carried out using silver ion-selective electrode.Summary in EnglishAvailable from STL, Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Fish – Useful Bio-Indicators For Evaluation Of Contamination In Water Ecosystems

Fish is one of the animal species used as an environmental bio-indicator. Fish were taken during the years 2002 – 2004 from the water reservoirs Smradavka and Korycany located in the South-east part of the Czech Republic. Seven fish species were monitored. Fish tissues were analyzed for both heavy metals and PCBs indicator congeners. Atomic absorption spectroscopy was used for heavy metals determination, high resolution gas chromatography was used for PCBs determination. The levels of particular trace elements ranged as follows (μg /kg fresh tissue): As 21.6–48.0, Cu 126–612, Ni 45–125, Pb 12.4–28.7 and Zn 3700–12500. Concentrations of cadmium were below the limit of determination (0.2 μg /kg) in all samples. The highest values (in μg /kg fresh tissue) were found for the PCB 153 congener in bream, eel and pike 12.5-22.5. The lowest concentration in all fish species was found for the PCB 52 congener 0.12-1.30. The sum of PCB indicator congeners ranged from 9.10 - roach to 53.9 - bream. All data are. The overall level of contamination in fish is low and the current limit for residues that is valid in the Czech Republic was not exceeded in any case

DETERMINATION OF LEAD, MERCURY AND ARSENIC IN FEEDING PHOSPHATES

Abstract Synek 0., S. Zima, M. Sucmanova, E. Sucman: Determination of Lead, Mercury and Arsenic in Feeding Phosphates. Acta vet. Bmo, 47, 1978: 153-158. Elaborated was the method of determination of lead, mercury and arsenic in feeding phosphates by means of atomic absorption spectrophotometry. Five different types of foreign and Czechoslovak phosphates commonly used for the preparation of feed mixtures were analyzed. The content of lead, mercury and arsenic ranged from 0.72 to 6.89 mg kg-I, 0.09 to 0.37 mg kg-l and from 0.75 to 69.77 mg kg-I, respectively. With regard to the content of all the three elements studies it was found that the relatively purest was dinatriumphosphate (Fosfa, n. p.), while the highest amount of admixtures was found in monocalciumphosphate (Reymeshoim) and dicalciumphosphate (CKF). Microelements, atomic absorption spectrophotometry, feed mixtures. The ever increasing industrialization and intensification of agricultural large-scale production necessitates investigations of new aspects in the nutrition of farm animals, aspects that had not been important before. One of the problems discussed has recently become the content of some microelements in feeds and feed mixtures; the intense development of instrumentation techniques over the past years has enabled these investigations to be carried out. The most important of these microelements are lead, cadmium, mercury and arsenic, indicated as "toxical civilization elements". The importance of uptake of these elements by farm animals should be judged from two aspects. i. e. from the point of view of the health condition of animals (possible intoxication, etc.), and because feed is the first link of the food chain which ends in man. Whereas the final links of this chain (raw materials for the preparation of foodstuffs, finished products, etc.) have already been studied, are being discussed, or there already exist standards for the admissible contents, in the field of feeds not many studies of this kind exist. These studies are aimed namely at lead of which namely the increased content in conventional feeds is closely associated with civilization. The intoxication of farm animals with lead in the industrial regions and in the vicinity of main roads with heavy traffic is becoming an ever increasing problem The most important mineral components of feed mixtures include various types of phosphates, representing 1-10 % of the total composition of feed mixtures. With regard to the initial raw materials and the industrial character of the production of these substances the present study deals with the determination of lead, mercury and arsenic in the most frequently used types of feeding phosphates of both foreign and Czechoslovak origin. Materials and Methods Samples of dicalcium phosphate (DCP) and monocaIciumphosphate (MCP) imported to Czechoslovakia in 1975Czechoslovakia in -1977 as mineral feed admixtures were analyzed as for the content of lead, mercury and arsenic. The other phosphates studied (dinatriumphosphate, pyrophosphate and hexametaphosphate) were produced in Fosfa n. p. in Postorna. Determination of the content of lead, mercury and arsenic in phosphates was performed using the method of atomic absorption spectrophotometry (AAS) with the Varian Techtron Mode

Facile and Convenient One-Pot Process for the Synthesis of Spirooxindole Derivatives in High Optical Purity Using (−)-(S)-Brevicolline as an Organocatalyst

The paper presents an application of the asymmetry approach to spirooxindoles via Brevicolline, Cinchonidine or Cinchonine catalyzed one-pot multicomponent synthesis. Brevicolline, in comparison with Cinchonidine or Cinchonine, catalyzes the reaction of isatins, acetylacetone/ethyl 3-oxobutanoate and malononitrile, with the formation of spiro[oxindole-3,4'-4'H-pirane] derivatives in an optically active form in very good to excellent yields

SYNTHESIS AND ANTIVIRAL ACTIVITY OF NEW THIAZOLE, 1,2,4-TRIAZOL AND OXINDOLE DERIVATIVES

The synthesis and antiviral activity evaluation of new derivatives of 2-aminothiazole, 1,2,4-triazole, as well as oxindoles has been realized. The synthesized compounds exhibited different cytotoxicity, in particular, oxindols 4 , 5 , 7 , 8 , 9, 10, 11, 12, 13, 58 as well as thiazole/triazole 73 and 75 turned out to be the most cytotoxic for MT-4 cell lines. The compounds 11, 12, 73, and 75 are more toxic than reference compound Efavirenz. As far as the antiviral activity is concerned, none of the title compounds turned out active against Reo-1, Sb-1, VSV, RSV, YFV and VV viruses. The results obtained against Bovine Viral Diarrhoea Virus (BVDV) showed that nine compounds (six from oxindol’s seria 6, 12, 13, 52, 56, 58 and three 73, 75, 77 of triazole homologues) resulted moderate active. Among all of them, the most potent compound was 52, with EC50 of 6.6 μM. Studies of effect of synthesized compounds against Coxsakie Virus (CVB-2) revealed that only two compounds, 13 and 73 exhibit moderate activity (EC50 >40 and >18 μM, respectively). It should be noticed that eleven compounds, 4, 5, 7, 8, 9, 10, 11, 12, 13, 58, and 75 showed moderate activity against HIV-1 (EC50 >16 – m >59μM)

NEW CATALYTIC SYSTEM FOR PREPARATION OF METHYL 2-(3-HYDROXY-2-OXO-2,3-DIHYDRO-1H-3- INDOLYL)ACRYLATES

A novel catalyst derived from the nitrile functionalized ionic liquids and DMAP promoted the MoritaBaylis-Hillman reaction of N-substituted isatines and the methyl acrylate with moderate up to high yields

THE SYNTHESIS OF NEW SPIROLACTONES FROM SUBSTITUTED ISATINS

Interaction of N-ethyl isatin 3 with dimethyl acetylenedicarboxylate in the presence triphenylphosphine has led to good selectivity of methyl 1'-ethyl-4-methoxy-2',5-dioxo-5H-spiro[furan-2,3'-indoline]-3-carboxylate 4 formation. Similar yields of spirolactones 6,8 were obtained by addition of dimethyl acetylenedicarboxylate to 5-bromo functionalized isatins 5,7. However, reaction of N-butyl isatin 9 resulted in formation of an inseparable mixture of compounds. Treatment of N-benzyl isatin 10 and dimethyl acetylenedicarboxylate with triphenylphosphine proceeded with reduced selectivity of the spirooxindole 11 formation