Medicinal chemistry approaches to malaria drug discovery

Tese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2016

High field chemistry with scanning probes

Fabricating Ge and Si integrated structures with nanoscale accuracy is a challenging pursuit essential for novel advances in electronics and photonics. While several scanning probe-based techniques have been proposed, no current technique offers control of nanostructure size, shape, placement, and chemical composition. To this end, atomic force microscope direct write uses a high electric field (> 109 V m-1) to create nanoscale features as fast as 1 cm s-1 by reacting a liquid precursor with a biased AFM tip. In this work, I present the first results on fabricating inorganic nanostructures via AFM direct write. Using diphenylgermane (DPG) and diphenylsilane (DPS), carbon-free germanium and silicon nanostructures (SIMS, x-ray PEEM) are fabricated. For this chemistry, I propose a model that involves electron capture and precursor fragmentation under the high electric field. To verify this model, experimental data and simulations are presented. High field chemistry for DPG and DPS has also been demonstrated for both sequential deposition and the creation of nanoscale heterostuctures, in addition to microscale deposition using a flexible stamp approach. This high field chemistry approach to the deposition of organometallic precursors could offer a low-cost, high throughput alternative for future optical, electronic, and photovoltaic applications.

Laccase bio-grafting a versatile modification tool from green chemistry technologies

Today more than 99% of plastics are petroleum-based because of availability and cost of the raw material. The durability of these disposed plastics contributes to the environmental problems as waste and their persistence in the environment causes deleterious effects on the ecosystem. Environmental pollution awareness and the demand for green technology have drawn considerable attention of both academia and industry into biodegradable polymers. In this regard green chemistry technology has the potential to provide solution to this problematic issue. Laccase bio-grafting has recently been the focus of green chemistry technologies due to the growing environmental concerns, legal restrictions and increasing availability of scientific knowledge. In the last several years, research covering various applications of laccases has been increased rapidly particularly in the field of grafting. In principle, laccase-assisted graft co-polymerization may impart a variety of new functionalities to a polymer. The modified polymers through grafting have a bright future and their development is practically boundless. In present work, novel biodegradable graft copolymers combining the advantages of bacterial cellulose backbone and PHB side chains will be prepared by introducing enzymatic grafting technique. The present research will be a first step in the biopolymer modification. To date no report has been found in literature explaining the enzymatic grafting of PHAs. The technique would also provide an efficient modulation approach to improve the biodegradability and biocompatibility of the graft copolymer. The newly grafted copolymers will exhibit unique functionalities with wider range of potential applications mainly in tissue engineering, biosensors, pharmaceutical industry (drug delivery systems) and bio-plastics.

Experimental and numerical evaluation of composite repairs on wood beams damaged by cross-graining

An experimental and Finite Element study was performed on the bending behaviour of wood beams of the Pinus Pinaster species repaired with adhesively-bonded carbon–epoxy patches, after sustaining damage by cross-grain failure. This damage is characterized by crack growth at a small angle to the beams longitudinal axis, due to misalignment between the wood fibres and the beam axis. Cross-grain failure can occur in large-scale in a wood member when trees that have grown spirally or with a pronounced taper are cut for lumber. Three patch lengths were tested. The simulations include the possibility of cohesive fracture of the adhesive layer, failure within the wood beam in two propagation planes and patch interlaminar failure, by the use of cohesive zone modelling. The respective cohesive properties were estimated either by an inverse method or from the literature. The comparison with the tests allowed the validation of the proposed methodology, opening a good perspective for the reduction of costs in the design stages of these repairs due to extensive experimentation.

Experimental Reinforcement of Wood Beams

Rehabilitation is becoming more and more usual in the construction sector in Portugal. The introduction of newer construction materials and technical know-how of integrating different materials for achieving desired engineering goals is an important step to the development of the sector. Wood industry is also getting more and more adapted to composite technologies with the introduction of the so called “highly engineered wood products” and with the use of modification treatments. This work is an attempt to explain the viability of using stainless steel and glass fibre reinforced polymer (GFRP) as reinforcements in wood beams. This thesis specifically focuses on the flexural behaviour of Portuguese Pine unmodified and modified wood beams. Two types of modification were used: 1,3-dimethylol-4,5- dihydroxyethyleneurea (DMDHEU) resin and amid wax. The behaviour of the material was analysed with a nonlinear model. The latter model simulates the behaviour of the reinforced wood beams under flexural loading. Small-scale beams (1:15) were experimented in flexural bending and the experimental results obtained were compared with the analytical model results. The experiments confirm the viability of the reinforcing schemes and the working procedures. Experimental results showed fair agreement with the nonlinear model. A strength increase between 15% and 80% was achieved. Stiffness increased by 40% to 50% in beams reinforced with steel but no significant increase was achieved with the glass fibre reinforcement.

Enhancement of ultrafiltration process by pretreatment in recovery of hemicelluloses from wood extracts

Hemicelluloses are potential raw material for several items produced in future wood-based biorefineries. One possible method for recovering hemicelluloses from wood extracts is ultrafiltration (UF). However, low filtration capacities and severe fouling restrict the use of tight UF membranes in the treatment of wood extracts. The lack of suitable commercial membranes creates a need for pretreatment which would decrease fouling and increase the filtration capacity. This thesis focuses on the evaluation of the possibility to improve the filtration capacity and decrease fouling with the pretreatment of wood extracts. Methods which remove harmful compounds and methods which degrade them are studied, as well as combinations of the methods. The tested pretreatments have an influence on both the concentration of different compounds and the molecular mass distribution of the compounds in the extract. This study revealed that in addition to which kind of compounds were removed, also the change in molecular size distribution affected the filtration capacity significantly. It was shown that the most harmful compounds for the filtration capacity of the hydrophobic 5 kDa membrane were the ones capable of permeating the membrane and fouling also the inner membrane structure. Naturally, the size of the most harmful compounds depends on the used UF membrane and is thus case-specific. However, in the choice of the pretreatment method, the focus should be on the removal of harmful compound sizes rather than merely on the total amount of removed foulants. The results proved that filtration capacity can be increased with both adsorptive and oxidative pretreatments even by hundreds of per cents. For instance, the use of XAD7 and XAD16 adsorbents increased the average flux in the UF of a birch extract from nearly zero to 107 kg/(m2h) and 175 kg/(m2h), respectively. In the treatment of a spruce extract, oxidation by pulsed corona discharge (PCD) increased the flux in UF from 46 kg/(m2h) to 158 kg/(m2h). Moreover, when a birch extract batch was treated with laccase enzyme, the flux in UF increased from 15 kg/(m2h) to 36 kg/(m2h). However, fouling was decreased only by adsorptive pretreatment while oxidative methods had a negligible or even negative impact on it. This demonstrates that filtration capacity and fouling are affected by different compounds and mechanisms. The results of this thesis show that filtration capacity can be improved and fouling decreased through appropriate pretreatment. However, the choice of the best possible pretreatment is case-specific and depends on the wood extract and the membrane used. Finding the best option requires information on the extract content and membrane characteristics as well as on the filtration performance of the membrane in the prevailing conditions and a multivariate approach. On the basis of this study, it can be roughly concluded that adsorptive pretreatment improves the filtration capacity and decreases fouling rather reliably, but it may lead to significant hemicellulose losses. Oxidation reduces the loss of valuable hemicelluloses and could improve the filtration capacity, but fouling challenges may remain. Combining oxidation with adsorptive pretreatment was not a solution for avoiding hemicellulose losses in the tested cases.

The efficacy of anti-predator behaviour in the wood fog tadpole (Rana sylvatica) /

Activity has been suggested as an important behaviour that is tightly linked with predator avoidance in tadpoles. In this thesis I examine predator-prey relationships using wood frog tadpoles {Rana sylvaticd) as prey and dragonfly larvae {AnaxJunius) and backswimmers {Notonecta undulatd) as predators. I explore the role of prey activity in predator attack rates, prey response to single and multiple predator introductions, and prey survivorship. The data suggest that Anax is the more successful predator, able to capture both active and inactive tadpoles. In contrast, Notonecta strike at inactive prey less frequently and are seldom successftil when they do. A mesocosm study revealed that the presence of any predator resulted in reduced activity level of tadpoles. Each predator species alone had similar effects on tadpole activity, as did the combined predator treatment. Tadpole survivorship, however, differed significantly among both predator treatments and prey populations. Tadpwles in the combined predator treatment had enhanced risk; survivorship was lower than that expected if the two predators had additive effects. Differences in survivorship among wood frog populations showed that tadpoles from a lake habitat had the lowest survivorship, those from a shallow pond habitat had an intermediate survivorship, and tadpoles from a marsh habitat had the highest survivorship. The frequency of interactions with predators in the native habitat may be driving the population differences observed. In conclusion, results from this study show that complex interactions exist between predators, prey, and the environment, with activity playing a key role in the survival of tadpoles.

An analysis of the photoelectron and Rydberg states of formaldehyde /|nby Carol R. Lessard. -- 260 St. Catharines [Ont.] : Dept. of Chemistry, Brock University,

Although it is generally accepted that Rydberg orbitals are very large and diffuse, and that electron promotion to a Rydberg orbital is not too different from ionization of the molecule, analysis of the two types of transitions proves otherwise. The photoelectron spectrum of the 2B2 (n) ion has very little vibrational structure attached to the origin band; on the other hand, several of the Rydberg transitions which involve the promotion of the n(bZ) electron exhibit a great deal of vibrational activity. In particular, the members of the n=3 Rydberg\ series interact with and perturb each other through pseudo-Jahn-Teller vibronic coupling. The vacuum ultraviolet spectrum contains a number of features which are difficult to explain, and two unusually sharp bands can only be identified as representing some form of electron promotion in formaldehyde.

A study of thermal decompositions of an allylic hydroperoxide /|nby Thomas A. McCarrick. -- 260 St. Catharines [Ont.] : Dept. of Chemistry, Brock University,

The thermal decomposition of 2,3-di~ethy l - J-hydr operox y- 1 - butene , p r epared f rol") singl e t oxygen, has been studied i n three solvents over the tempe r a ture r ange from 1500e to l o00e and t!1e i 111 t ial ~oncentrfttl nn r Ange from O. 01 M to 0.2 M. Analys i s of the kine tic data ind ica te s i nduced homolysis as the n ost probRble mode of d e composition, g iving rise to a 3/2 f S order dependence upon hy d.roperoxide concent :r8.tl on . Experimental activation e nergies for the decomposition were f ound to be between 29.5 kcsl./raole and 30.0 k cal./mole .• \,iith log A factors between 11 . 3 and 12.3. Product studies were conducted in R variety of solvents a s well as in the pr esence of a variety of free r adical initiators . Investigation of the kinetic ch a in length indicated a chain length of about fifty. A degenerat i ve chain branching mechanism 1s proposed which predicts the multi t ude of products which Rre observed e xperimentally as well as giving activation energies and log A factors si~il a r to those found experimentally .

Reduced local energy calculations on X¹Sigmaâ ½gHâ and 1¹S He /|nGerald F. Thomas. -- 260 St. Catharines [Ont.] : Dept. of Chemistry, Brock University,

The one-electron reduced local energy function, t ~ , is introduced and has the property < tL)=(~>. It is suggested that the accuracy of SL reflects the local accuracy of an approximate wavefunction. We establish that <~~>~ <~2,> and present a bound formula, E~ , which is such that where Ew is Weinstein's lower bound formula to the ground state. The nature of the bound is not guaranteed but for sufficiently accurate wavefunctions it will yield a lower bound. ,-+ 1'S I I Applications to X LW Hz. and ne are presented.

Some aspects of the chemistry of Reissert compounds / |nDurga Prasad Aysola. -- 260 St. Catharines [Ont. : s. n.],

1-(0- and m-Ohlorobenzoyl)isoquinolines have been synthesized by two routes involving Reissert compounds. One route involves condensation of 2-benzoyl-l,2-dihydroisoquinaldonitrile with the appropriate chlorobenzaldehyde and the second involves rearrangement of the appropriate Z-(chlorobenzoyl)-l,Z-dihydroisoquinaldonitrile under basic conditions. The action of potassamide in anhydrous liquid ammonia on both ketones gave unexpectedly N-(l-isoquinolyl)benzamide (67) as the major product and the use of dibenzo-18-crown-6-ether 98% substantially improved the yd..e.ld in the case of l-chloroketone. This amide (67) exhibits unusual hydrogen bonding. 1-(o-chlorobenzoyl)-6,7-dimethoxyisoquinoline (79) was prepared in very s,amll quantities by the route involving condensation of 2-benzoyll, Z-dihydro-6,7-dimethoxyisoquinaldonitrile with o-chlorobenzaldehyde. The poor yields are due to the instability of the anion of 2-benzoyl1, Z-dihydro-6,7-dimethoxyisoquinaldonitrile. Attempted preparation of the ketone (79) by rearrangement of 2-(o-chlorobenzoyl)-l,2-dihydro6,7- dimethoxyisoquinaldonitrile under basic conditions yielded the start~ng material (Reissert compound) and 6,7-dimethoxyisoquinoline. The action of potassamide in anhydrous liquid ammonia on l-(o-bromo-4,5-dimethoxybenzoyl)isoquinoline (85), which was prepared by the route involving the condensation of 2-benzoyl-l,4-dihydroisoquinaldonitrile with o-bromo-4,5-dimethoxybenzaldehyde, gave two products, which have not yet been identified. The ketone (85) and its precursors are interest~ng in that their 20 eV and 70 eV mass spectra do not show molecular ions.

Some aspects of the chemistry of 1, 3, 4 - Thiadiazolium salts and related compounds

The work described in this thesis has been divided into seven sections. The first section involves the preparation of N'-acyl-N'-arylN- benzothiohydrazides by the acylation of N'-aryl-N-benzothiohydrazides and is followed by a brief discussion of their possible conformation in solution. The second section deals with the preparation of 1,3,4-thiadiazolium salts by the action of perchloric acid/acetic anhydride on N'-acylN'- aryl-N-benzothiohydrazides and also by the reaction of N'-arylN- benzothiohydrazides with nitriles in an acidic medium. The preparation of 2-methylthio-I,3,4-thiadiazolium methosulfate by methylating the corresponding thione is also described. The third section deals with the reaction of 2-phenyl- and 2-methyl-I,3,4-thiadiazolium salts with alcohols in the presence of base. The stability and spectra of these compounds are discussed. Treatment of the 2-methyl-I,3,4-thiadiazolium salt with base was found to give rise to a dimeric anhydrobase and evidence supporting its structure is given. The anhydrobase could be trapped by a variety of acylating and thioacylating agents before dimerization occurred. In the fourth section, the reaction of N'-acyl-N'-aryl-N-benzothiohydrazides with a variety of acid anhydrides is described. These compounds were found to be identical with those obtained by acylating the anhydrobase. The mass spectral fragmentation of these compounds is described and the anomolous product obtained upon thiobenzoylation of 3-methyl-l-phenyl-pyrazal-5-one is also discussed. The fifth section deals with thioacyl derivatives of the anhydrobase which were prepared by the action of phosphorus pentasulfide upon the oxygen analogues and also obtained as the major product of the reaction of thioacetic acid with compounds related to N'-aryl-N-benzothiohydrazides. The mass spectra and p.m.r. spectra of these compounds are discussed. In the sixth section, the reaction of the 2-methylthio-l,3,4- thiadiazolium salt with active methylene compounds to give acyl and diacyl derivatives of the anhydrobase is described. Some aspects of these compounds are discussed. The seventh section describes the synthesis of ncyanine~' type dyes incorporating the l,3,4-thiadiazole ring and their spectra are briefly discussed.

The chemistry of heterocyclic methine bases and of their acyl and thioacyl derivatives

The work described in this thesis has been dtvided into six sections . The first section involves the reaction of 3,5-diphenyl-2-methyl-l,3,4-oxadiazolium perchlorate with acetic and benzoic anhydrides. The second section deals with the preparation and reactions of 1,3,4-thia diazolium salts. Some monomeric 1,3,4-thiadiazoline methine bases have also been prepared by reacting 1,3,4-thia d iaz ol ium s al t s with concen trated ammonium hydroxide solution. Variable temperature p.m.r. of 2-(3-acetylacetonylidene)-3,5-diphenyl-A4 -1,3,4-thiadiazoline has also been described. The third section deals with prepar a tion and reactions of some compounds in benzoxazole series. The fourth section deals with the prep a ration and reactions of N-alkyl-2-methylbenzothi azolium salts with base , a nd with some a cetylating and thioacetylating agents. Treatment of 2,3-dimethylbenzothiazolium iodide and of 3-ethyl-2-methylbenzothia zolium iodide with base wa s found to give the corresponding dimeric methine b a ses and evidence supporting their structure is also given. Thiol acetic acid was found to exchange 0 for S in its reactions with 2-acetonylidene-3-methylbenzothiazoline and 2-acetophenonylidene-3-methylbenzothi a zoline. (ii) In th e fifth section, the r eactions of 2,3-dimethylbenzselenazolium iodide with a variety of ac e tylating and thioacetylating agents has been described. The treatment of 2,3-dimethylbenzselenazolium iodide with base was found to give rise to a dimeric methine base and evidence supporting its structure is also given. The reactions of this dimeric methine b a se with benzoic anhydride and phenylisothiocyanate have also been described. The sixth section deals with the preparation and reactions of l-alkyl-2-methylquinolinium salts. Treatment of 1,2-dimethylquinolinium iodide and l-ethyl-2-methylquinolinium iodide was found to give the corresponding monomeric methine bases and evidence supporting their structure is also given. The E-type geometry of the olefinic bond in 2-acetonylidene-l-methylquinoline has been established on the basis of an N.O.E. experiment.