Synthesis and characterization of copper(II) complexes of pyridine-2-carboxamidrazones as potent antimalarial agents

Copper(II) complexes of some pyridine-2-carboxamidrazones have been prepared and characterized. The crystal structures of the copper complex cis-[dichloro(N1-2-acetylthiophene-pyridine-2-carboxamidrazone) copper(II)] 8a and one of the free ligands, viz. {(p-chloro-2-thioloxy-benzylidine-pyridine-2-carboxamidrazone)} 6, have been determined. The former shows a highly distorted square planar geometry around copper, with weak intermolecular coordination from the thiophenyl sulfur resulting in a stacking arrangement in the crystal lattice. The in vitro activities of the synthesized compounds against the malarial parasite Plasmodium falciparum are reported for the first time, which clearly shows the advantage of copper complexation and the requirement of four coordinate geometry around copper as some of the key structural features for designing such metal-based antimalarials. © 2003 Elsevier Science B.V. All rights reserved.

Selectivity of response in fluorescent polymers imprinted with N1-benzylidene pyridine-2-carboxamidrazones

Fluorescent polymers imprinted with various N1-benzylidene pyridine-2-carboxamidrazones were evaluated for their recognition of the original template and cross-reactivity to similar molecules. Dramatic quenching of fluorescence approaching background levels was observed for most cases where the "empty" MIP was re-exposed to its template. Molecules too large to enter the imprinted cavities gave no reduction of fluorescence. Other compounds were found to quench the fluorescence and are assumed to have entered the imprinted cavities. There is also evidence for partial responses which may give some measure of partial binding. The fluorescence response profiles of substrates containing polycyclic aromatics were found to be quite different from those containing flexible substituents. In order to make this approach more suitable for high-throughput screening a method has been validated wherein the extent of substrate-induced fluorescence quenching may be obtained without having to know how much polymer is present. © 2001 Elsevier Science B.V. All rights reserved.

Studies on the thermal decomposition behaviour, kinetics and electrical conductivity of the non-isothermal decomposition of pyridine mono carboxylic acids and some of their transition metal complexes

The thesis is divided into four chapters. They are: introduction, experimental, results and discussion about the free ligands and results and discussion about the complexes. The First Chapter, the introductory chapter, is a general introduction to the study of solid state reactions. The Second Chapter is devoted to the materials and experimental methods that have been used for carrying out tile experiments. TIle Third Chapter is concerned with the characterisations of free ligands (Picolinic acid, nicotinic acid, and isonicotinic acid) by using elemental analysis, IR spectra, X-ray diffraction, and mass spectra. Additionally, the thermal behaviour of free ligands in air has been studied by means of thermogravimetry (TG), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC) measurements. The behaviour of thermal decomposition of the three free ligands was not identical Finally, a computer program has been used for kinetic evaluation of non-isothermal differential scanning calorimetry data according to a composite and single heating rate methods in comparison with the methods due to Ozawa and Kissinger methods. The most probable reaction mechanism for the free ligands was the Avrami-Erofeev equation (A) that described the solid-state nucleation-growth mechanism. The activation parameters of the decomposition reaction for free ligands were calculated and the results of different methods of data analysis were compared and discussed. The Fourth Chapter, the final chapter, deals with the preparation of cobalt, nickel, and copper with mono-pyridine carboxylic acids in aqueous solution. The prepared complexes have been characterised by analyses, IR spectra, X-ray diffraction, magnetic moments, and electronic spectra. The stoichiometry of these compounds was ML2x(H20), (where M = metal ion, L = organic ligand and x = water molecule). The environments of cobalt, nickel, and copper nicotinates and the environments of cobalt and nickel picolinates were octahedral, whereas the environment of copper picolinate [Cu(PA)2] was tetragonal. However, the environments of cobalt, nickel, and copper isonicotinates were polymeric octahedral structures. The morphological changes that occurred throughout the decomposition were followed by SEM observation. TG, DTG, and DSC measurements have studied the thermal behaviour of the prepared complexes in air. During the degradation processes of the hydrated complexes, the crystallisation water molecules were lost in one or two steps. This was also followed by loss of organic ligands and the metal oxides remained. Comparison between the DTG temperatures of the first and second steps of the dehydration suggested that the water of crystallisation was more strongly bonded with anion in Ni(II) complexes than in the complexes of Co(II) and Cu(II). The intermediate products of decomposition were not identified. The most probable reaction mechanism for the prepared complexes was also Avrami-Erofeev equation (A) characteristic of solid-state nucleation-growth mechanism. The tempemture dependence of conductivity using direct current was determined for cobalt, nickel, Cl.nd copper isonicotinates. An activation energy (ΔΕ), the activation energy (ΔΕ ) were calculated.The ternperature and frequency dependence of conductivity, the frequency dependence of dielectric constant, and the dielectric loss for nickel isonicotinate were determined by using altemating current. The value of s paralneter and the value of'density of state [N(Ef)] were calculated. Keyword Thermal decomposition, kinetic, electrical conduclion, pyridine rnono~ carboxylic acid, cOlnplex, transition metal compJex.

Studies of recognition and selectivity by fluorescent polymers imprinted with N1-benzylidene pyridine-2-carboxamidrazones

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Preparation of 9-substituted pyridine-stretched adenines and hypoxanthines

9-Methylsulfanyl pyridine-stretched adenine and hypoxanthine derivatives have been prepared via regioselective reaction of a 5-aminoimidazole with 2-(bis-methylsulfanylmethylene)malononitrile [(NC)C=C(SMe) ]. The 9-methylsulfanyl substituent can be replaced by sequential oxidation and substitution by nucleophiles including amines.

Synthesis of a new pyridine-stretched nucleoside

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The performance of poly(styrene)-block-poly(2-vinyl pyridine)-block- poly(styrene) triblock copolymers as pH-driven actuators

Poly(styrene)-block-poly(2-vinyl pyridine)-block-poly(styrene) (PS-b-P2VP-b-PS) triblock copolymers were synthesised by anionic polymerisation. Thick films were cast from solution and their structure analysed by small angle X-ray scattering (SAXS). Longer annealing times led to more ordered structures whereas short evaporation times effectively "lock" the polymer chains in a disordered state by vitrification. Well-ordered structures not only provide an isotropic network, which reduces localised stress within the material, but are also essential for fundamental studies of soft matter because their activity on the molecular scale must be analysed and understood prior to their use in technological applications. Well-characterised PS-b-P2VP-b-PS materials have been coupled to a pH-oscillating reaction and their potential application as responsive actuators is discussed. This journal is © The Royal Society of Chemistry.

Synthesis of pyridine-stretched 2′-deoxynucleosides

Synthesis of novel pyridine-stretched nucleoside (PSN) analogues of adenine (strA) (1), 2,6-diaminopurine (strD) (15) and hypoxanthine (strH) (17) from 4(5)-nitroimidazole has been achieved. Glycosylation of 4(5)-nitroimidazole was optimized to give consistently good yields (>70%) of the desired analytically pure 5-nitro-1′-β isomer 8 which on hydrogenation, C-addition of ethoxymethylene malononitrile (EMMN) and cyclisation provides the key intermediate 14 for PSN synthesis.

Living cationic polymerization of isobutene

The polymerization of isobutene initiated by 1-chloro-1-phenylethane has been investigated, and molecular weight studies conducted using size exclusion chromatography. Polymerizations carried out in a 40/60 (v/v) mixture of dichloromethaneIcyclohexane, using titanium (IV) chloride as a catalyst in the presence of pyridine at -30 °C were found to be controlled and living. The number average molecular weights of the polymers increased linearly with monomer conversion, and the molecular weight distributions were between 1.15 and 1.20. Efficiencies of initiation were between 80 and 100%, and evidence was found to suggest that backbiting to the initiator had occurred, resulting in the formation of cyclic oligomers during the early stages of polymerization. The kinetics of polymerization can be explained in terms of active species in. equilibrium with dormant species. The effects of temperature. and dielectric constant on this equilibrium were studied and a model based upon the Fuoss equation was developed. Pyridine was found to behave as proton trap in the system, and when it was used in excess the rate of polymerization was retarded. By assuming that the catalyst and pyridine formed a one to one complex, it was possible to show that the reaction was second order with respect to the catalyst. The synthesis of low molecular weight polyisobutenes was studied. When the concentration of initiator was increased relative to that of the isobutene, such that the theoretical degree of polymerization was 20 or less, the rate of initiation was slow compared to propagation. The efficiency of initiation in these polymerizations was typically between 30 and 40 %. Optimal conditions of temperature. and.catalyst concentration were established, leading to a 60 % efficiency of initiation. A one-pot synthesis of phenol end-capped polyisobutene was attempted by adding phenol at the end of a living polymerization. Evidence to substantiate the existence of capped polymer chains in the resultant product was inconclusive. Block copolymerizations of oxetane and isobutene were conducted using 1-chloro-1phenylethane/TiCl4, but no copolymer or oxetane homopolymer could be isolated.

Living cationic polymerization of styrene monomers

This thesis describes an experimental investigation of synthesis of polystyrene under various polymerization conditions such as solvent polarity, temperature, initial concentrations of initiator, catalyst, monomer and added salts or co-catalyst, which was achieved using the living cationic polymerization technology in conjunction with gel permeation chromatography (GPC) and NMR spectroscopy. Polymerizations of styrene were conducted using 1-phenyl ethylchloride (1-PEC) as an initiator and tin tetrachloride (SnCI4) as a catalyst in the presence of tetra-n-Butylammonium chloride (nBu4NCI). Effects of solvent polarity varied by mixing dichloromethane (DCM) and less polar cyclohexane (C.hex), temperature, initial concentrations of SnC14, 1-PEC and nBu4NCI on the polymerizations were examined, and the conditions under which a living polymerization can be obtained were optimised as: [styrene]o ~ 0.75 - 2 M; [1-PEC]o ~ 0.005 - 0.05 M; [SnCI4Jo ~ 0.05 - 0.4 M; [nBu4NCIJo ~ 0.001 - 0.1 M; DCM/C.hex ~ 50/0 - 20/30 v/v; T ~ 0 to -45°C. Kinetic studies of styrene polymerization using the Omnifit sampling method showed that the number average molecular weight (Mn) of the polymers obtained increased in direct proportion to monomer conversion and agreed well with the theoretical Mn expected from the concentration ratios of monomer to initiator. The linearities of both the 1n([MJoI[M]) vs. time plot and the Mn vs. monomer conversion plot, and the narrow molecular weight distribution (MWD) measured using GPC demonstrated the livingness of the polymerizations, indicating the absence of irreversible termination and transfer within the lifetimes of the polymerizations. The proposed 'two species' propagation mechanism was found to apply for the styrene polymerization with 1-PEC/SnCI4 in the presence of nBu4NCl. The further kinetic experiments showed that living styrene polymerizations were achieved using the 1-PEC/SnCI4 initiating system in mixtures of DCM/C.hex 30/20 v/v at -15°C in the presence of various bromide salts, tetra-n-butylammonium bromide, tetra-n-pentylammonium bromide, tetra-n-heptylammonium bromide, and tetra-n-octylammonium bromide, respectively. The types of the bromide salts were found to have no significant effect on monomer conversion, Mn, polydispersity and initiation efficiency. Living polymerizations of styrene were also achieved using titanium tetrachloride (TiCI4) as a catalyst and 1-PEC as an initiator in the presence of a small amount of 2,6-di-tert-butylpyridine or pyridine instead of nBu4NCl. GPC analysis showed that the polymers obtained had narrow polydispersities (P.D. < 1.3), and the linearities of both the In([MJo/[MJ) vs. time plot and the Mn vs. monomer conversion plot demonstrated that the polymerizations are living, when the ratio of DCM and C.hex was less than 40 : 10 and the reaction temperature was not lower than -15°C. The reaction orders relative to TiCl4 and 1-PEC were estimated from the investigations into the rate of polymerization to be 2.56 and 1.0 respectively. lH and 13C NMR analysis of the resultant polystyrene would suggest the end-functionality of the product polymers is chlorine for all living polymerizations.

The microbiological destruction of thiocyanate in activated sludge plants treating coke oven effluent

The treatment of effluents produced during the manufacture of metallurgical coke is normally carried out using the activated sludge process. The efficiency of activated sludges in purifying coke oven effluent depends largely on the maintenance of species of micro-organisms which destroy thiocyanate. The composition, production, toxicity and treatment of coke oven effluent at Corby steelworks are described. A review is presented which follows the progress made towards identifying and monitoring the species of bacteria which destroy thiocyanate in biological treatment plants purifying coke oven effluents. In the present study a search for bacteria capable of destroying thiocyanate led to the isolation of a species of bacteria, identified as Pseudomonas putida, which destroyed thiocyanate in the presence of succinate; this species had not previously been reported to use thiocyanate. Washed cell suspensions of P. putida destroyed phenol and thiocyanate simultaneously and thiocyanate destruction was not suppressed by pyridine, aniline or catechol at the highest concentrations normally encountered in coke oven effluent. The isolate has been included, as N.C.I.B. 11198, in the National Collection of Industrial Bacteria, Torrey Research Station, Aberdeen. Three other isolates, identified as Achromobacter sp., Thiobacillus thioparus and T. denitrificans, were also confirmed to destroy thi.ocyanate. A technique has been developed for monitoring populations of different species of bacteria in activated sludges. Application of this technique to laboratory scale and full scale treatment plants at Corby showed that thiobacilli were usually not detected; thiobacilli were el~inated during the commissioning period of the full scale plant. However experiments using a laboratory scale plant indicated that during a period of three weeks an increase in the numbers of thiobacilli might have contributed to an improvement in plant performance. Factors which might have facilitated the development of thiobacilli are discussed. Large numbers of fluorescent pseudomonads capable of using thiocyanate were sometimes detected in the laboratory scale plant. The possibility is considered that catechol or other organic compounds in the feed-liquor might have stimulated fluorescent pseudmonads. Experiments using the laboratory scale plant confirmed that deteriorations in the efficiency of thiocyanate destruction were sometimes caused by bulking sludges, due to the excessive growth of fungal floes. Increased dilution of the coke oven effluent was a successful remedy to this difficulty. The optimum operating conditions recommended by the manufacturer of the full scale activated sludge plant at Corby are assessed and the role of bacterial monitoring in a programme of regular monitoring tests is discussed in relation to the operation of activated sludge plants treating coke oven effluents.

Design and synthesis of potential antimicrobial agents

Tuberculosis is one of the most devastating diseases in the world primarily due to several decades of neglect and an emergence of multidrug-resitance strains (MDR) of M. tuberculosis together with the increased incidence of disseminated infections produced by other mycobacterium in AIDS patients. This has prompted the search for new antimycobacterial drugs. A series of pyridine-2-, pyridine-3-, pyridine-4-, pyrazine and quinoline-2-carboxamidrazone derivatives and new classes of carboxamidrazone were prepared in an automated fashion and by traditional synthesis. Over nine hundred synthesized compounds were screened for their anti mycobacterial activity against M. fortutium (NGTG 10394) as a surrogate for M. tuberculosis. The new classes of amidrazones were also screened against tuberculosis H37 Rv and antimicrobial activities against various bacteria. Fifteen tested compounds were found to provide 90-100% inhibition of mycobacterium growth of M. tuberculosis H37 Rv in the primary screen at 6.25 μg mL-1. The most active compound in the carboxamidrazone amide series had an MIG value of 0.1-2 μg mL-1 against M. fortutium. The enzyme dihydrofolate reductase (DHFR) has been a drug-design target for decades. Blocking of the enzymatic activity of DHFR is a key element in the treatment of many diseases, including cancer, bacterial and protozoal infection. The x-ray structure of DHFR from M. tuberculosis and human DHFR were found to have differences in substrate binding site. The presence of glycerol molecule in the Xray structure from M. tuberculosis DHFR provided opportunity to design new antifolates. The new antifolates described herein were designed to retain the pharmcophore of pyrimethamine (2,4- diamino-5(4-chlorophenyl)-6-ethylpyrimidine), but encompassing a range of polar groups that might interact with the M. tuberculosis DHFR glycerol binding pockets. Finally, the research described in this thesis contributes to the preparation of molecularly imprinted polymers for the recognition of 2,4-diaminopyrimidine for the binding the target. The formation of hydrogen bonding between the model functional monomer 5-(4-tert-butyl-benzylidene)-pyrimidine-2,4,6-trione and 2,4-diaminopyrimidine in the pre-polymerisation stage was verified by 1H-NMR studies. Having proven that 2,4-diaminopyrimidine interacts strongly with the model 5-(4-tert-butylbenzylidene)- pyrimidine-2,4,6-trione, 2,4-diaminopyrimidine-imprinted polymers were prepared using a novel cyclobarbital derived functional monomer, acrylic acid 4-(2,4,6-trioxo-tetrahydro-pyrimidin-5- ylidenemethyl)phenyl ester, capable of multiple hydrogen bond formation with the 2,4- diaminopyrimidine. The recognition property of the respective polymers toward the template and other test compounds was evaluated by fluorescence. The results demonstrate that the polymers showed dose dependent enhancement of fluorescence emissions. In addition, the results also indicate that synthesized MIPs have higher 2,4-diaminopyrimidine binding ability as compared with corresponding non-imprinting polymers.

A spectroscope study of some semiquinone radical ions

The effect of substituents on the value of the oxidation potential of quinones is reviewed and attempts to prepare substituted diphenoquinones with high oxidation potentials are reported. Attempts to characterise the mechanism of addition and substitution in diphenoquinones by identifying the products of the Thiele acetylation of diphenoquinone are reported. The reaction proved most efficient when the incoming acetylinium ion is directed by substituents in the diphenoquinone. A 1,8-addition to diphenoquinone is reported and characterised by isolating the products of the reaction between acetyl chloride and diphenoquinone, with perchloric acid as catalyst. The alternating linewidth effects observed in e.s.r.spectra are discussed and applied to account for such effects observed in the e.s.r.spectra of diphenosemiquinone anion and cation radicals. The spectra are analysed and the intramolecular processes producing these effects are discussed. A dianion diradical where intramolecular rotation about the 1 - 1' bond is restricted is produced by the oxidation of 2,2' ,4,4' -tetra hydroxybiphenyl. Previous studies of diphenosemiquinone anions are reviewed and alkylated diphenosemiquinone anion are produced by the reduction of the parent quinone with potassium hydroxide solution, the resulting radical being stabilised by the presence of pyridine. A qualitative interpretation of the solvent-ion effect in alkylated diphenosemiquinone anions is given. Diphanosemiquinone cation radicals are reviewed and previous studies are re-examined.

The toxic effects of anticholinesterases on muscle

It has been shown that acute administration of ecothiopate iodine in vivo caused an approximate 80% depression of acetylcholinesterase activity in the diaphragms of mice. Inhibition of acetylcholinesterase was accompanied by an influx of calcium at the junctional region of the diaphragm, which continued during subsequent progressive development of a severe myopathy located in the same region. Myopathy was accompanied by loss of creatine kinase from the muscle and was represented, at the light microscope level, by hypercontraction, Procion Yellow staining and loss of cross striations within the muscle fibres. It appeared to reach a point of maximum severity approximately 3-6 hours after ecothiopate administration and then, by means of some repair/regeneration process, regained an apparently normal morphology within 72 hours of the intoxication. At the ultrastructural level, ecothiopate-induced myopathy was recognised by loss of Z-lines, swelling and vacuolation of mitochondria and sarcoplasmic reticulum, dissarray of myofilaments, crystal formation, and sometimes, by the complete obliteration of sarcomeric structure. The development of myopathy in vitro was shown to be nerve-mediated and to require a functional acetylcholine receptor for its development It was successfully treated therapeutically in vivo by pyridine-2-aldoxime methiodide and prophylactically by pyridostigmine bromide. However, the use of a range of membrane-on channel blockers, and of leupeptin, an inhibitor of calcium-activated-neutral-protease, have been unsuccessful in the prevention of ecothiopate-induced myopathy.