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Planejamento, ensaio e otimização in silico de novos protótipos inibidores da enzima acetilcolinesterase / Design, assay and in silico optimization of new prototypes inhibitors of acetylcholinesteraseJonathan Resende de Almeida 26 January 2015 (has links)
A acetilcolinesterase (AChE) é uma enzima essencial que encerra a transmissão colinérgica através de uma rápida hidrólise do neurotransmissor, acetilcolina (ACh). Uma ampla série de evidências mostraram que os inibidores da AChE podem interferir com a progressão da doença de Alzheimer (DA). O desenvolvimento bem sucedido de compostos inibidores da AChE foi baseado na teoria de que o declínio nas funções cognitivas e mentais associadas a DA está relacionado com a perda da neurotransmissão cortical colinérgica, sendo assim, esses compostos podem ser usados para tratar as deficiências colinérgicas. Uma coleção de moléculas orgânicas foi escaneada para ser avaliada a capacidade dessas moléculas em inibir a atividade enzimática da AChE com o objetivo de se encontrar compostos líderes para posteriores otimizações, conduzindo a fármacos com aumento da eficácia e/ou menores efeitos adversos. As estratégias aplicadas incluem o screening ou triagem virtual baseado na estrutura e também no ligante, modelagem farmacofórica, docking molecular e buscas por similaridade (forma e eletrostática). Os estudos foram também concentrados na descoberta de novas classes de inibidores da AChE, tendo como molécula de referência o fármaco donepezil, o qual inaugurou uma nova classe de inibidores da AChE com a ação mais longa e mais seletiva com efeitos adversos manejáveis. Do total de compostos triados, 50 foram selecionados com adequadas propriedades físico-químicas e ADME/Tox. Em geral, esses compostos possuem substancial interação com o sítio periférico aniônico (PAS) da AChE e a maioria deles faz interações adicionais com o sítio catalítico (CAS) e com outros resíduos de aminoácidos importantes ao longo da enzima. Destes 50 compostos, oito foram comercialmente adquiridos e os ensaios enzimáticos revelaram que estes compostos exibem uma alta afinidade pela AChE. Os resultados apontam, ainda, que o composto entitulado ZINC30019441 exibiu a mais potente atividade inibitória para a AChE, com 1,8 micromolar de concentração, e os demais ficaram ainda situados em baixo micromolar, de 2 a 3 micromolar de concentração. Estes resultados, além das modificações químicas ora propostas in silico para estes inibidores protótipos, apontam para o desenvolvimento de uma nova e promissora série de potentes anticolinesterásicos, contendo propriedades de fármacos, as quais são ainda apropriadas para atuarem no Sistema Nervoso Central e interagirem com o peptídeo beta-amiloide, com vistas ao tratamento quimioterápico da doença de Alzheimer. A perspectiva imediata inclui os ensaios de anti-agregação do peptídeo com os oito inibidores já testados com a Acetilcolinesterase. / Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine (ACh). A wide range of evidence shows that AChE inhibitors may interfere with the progression of Alzheimer\'s disease (AD). The successful development of AChE inhibitor compounds was based on the theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission, thus, these compounds can be used for treating cholinergic deficiencies. A collection of organic molecules has been scanned to evaluate the ability of these molecules to inhibit the enzymatic activity of AChE in order to find lead compounds for further optimization, leading to drugs with increased efficacy and/or fewer adverse effects. The strategies applied include structure-based virtual screening and also in ligand-based virtual screening, pharmacophoric modeling, molecular docking and similarity searches (shape and electrostatic). Studies have also focused on the discovery of new classes of AChE inhibitors, having as a reference molecule the drug donepezil, which has opened a new class of AChE inhibitors with longer and more selective action with manageable side effects. 50 of the compounds screened, were selected with appropriate physical and chemical properties and ADME/Tox. In general, these compounds possess substantial interaction with the peripheral anionic site (PAS) of AChE and most of them make further interact with the catalytic site (CAS) and other key amino acid residues throughout the enzyme. Out of these 50 compounds, eight were commercially purchased and the enzyme assays have shown that these compounds exhibit a high affinity for AChE. The results show also that the compound titled ZINC30019441 exhibited the most potent inhibitory activity for AChE, with 1.8 micromolar concentration, and the rest were still located in low micromolar, 2-3 micromolar concentration. These results as well as chemical modifications herein proposed for these prototypes, indicate the development of a new and promising series of potent anticholinesterase containing drug properties, which are still suitable to act on the central nervous system and interact with the ?-amyloid peptide, for chemotherapy treatment of Alzheimer\'s disease. The immediate prospect includes the peptide anti-aggregation assays with the eight inhibitors already tested against acetylcholinesterase
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Passive Immunisierung mit einem N-trunkierten Abetaspezifischen Antikörper - Therapeutisches Potential von NT4X in einem familiären Alzheimer-Mausmodell / Passive immunisation with a N-truncated abeta specific antibody - therapeutic potential of NT4X in a familial Alzheimer mouse modelUeberück, Maximilian 26 March 2019 (has links)
No description available.
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Gamma-AApeptides as a New Class of Peptidomimetics: Synthesis, Structures, and FunctionsWu, Haifan 15 February 2015 (has links)
Peptidomimetics are synthetic oligomers that resemble the activities of peptides. Their advantages over peptides include high stability towards proteolysis and enormous chemical diversity. Over the past two decades, there have been extensive efforts to develop peptide mimics, such as beta-peptides, peptoids, D-peptides, etc. The research on peptidomimetics have led to many important applications in both medicinal and material science. In order to explore new functions, the discovery of peptidomimetics with novel frameworks is essential. We reported the synthesis and evaluation of a new class of peptidomimetics, termed as gamma-AApeptides. Previous studies of gamma-AApeptides have revealed that gamma-AApeptides are highly resistant to proteolysis, and are highly amendable to chemical diversification. However, new biological activities and folding properties of gamma-AApeptides still need to be explored. In order to expand the potential of gamma-AApeptides in chemical biology and medicinal chemistry, I have been focusing on the development of new methods to synthesize linear and cyclic gamma-AApeptides, development of one-bead-one-compound (OBOC) gamma-AApeptide libraries for the discovery of inhibitors against beta-amyloid aggregation, exploring new helical foldamers for the rational design of protein-protein interaction (PPI) inhibitors, and studying cyclic gamma-AApeptides for antimicrobial development.
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Nanofluidic biosensing for beta-amyloid detectionChou, I-Hsien 15 May 2009 (has links)
A nanofluidic biosensor using surface-enhanced Raman scattering (SERS) was
developed to detect the β-amyloid (Aβ) protein, one of the biomarkers of Alzheimer’s
disease (AD). Recent studies have indicated that investigating changes in relative
concentrations of structure specific Aβ oligomers in cerebral spinal fluid (CSF) during the
progression of AD could be important indicators for diagnosing AD pre-mortem. However,
there is no definitive pre-mortem diagnosis of AD thus far because of the lack of technology
available for sensitive Aβ detection. Hence, the development of a system for detecting the
structure specific Aβ oligomers, along with the concentrations of these oligomers in CSF,
would be useful in the investigation of the molecular mechanisms of Aβ cytotoxicity
associated with AD.
In this thesis, a nanofluidic trapping device trapping system for detecting
biomolecules at sub-picomolar concentrations was developed for using SERS. The device,
with a microchannel leading to a nanochannel, carries out dual functions: encouraging sizedependent
trapping of gold nanoparticles (60nm) at the entrance of the nanochannel as well as restricting the target molecules between the gaps created by the aggregated nanoparticles.
Initially, the trapping capability of the nanofluidic device was tested using fluorescent
polystyrene and gold nanoparticles. UV-vis absorption spectroscopy was used to characterize
the gold nanoparticle clusters at the entrance to the nanochannel. The device established
controlled, reproducible, SERS active sites within the interstices of gold nanoparticle clusters
and shifted the plasmon resonance to the near infrared, in resonance with incident laser light.
Two strongly Raman active molecules, adenine and Congo red, were used to test the
feasibility of the SERS nanofluidic device as a platform for the detection of multiple
analytes. The results showed that strong SERS signals were obtained from the nanoparticle
clusters at the nanochannel entrance.
Once the feasibility of the approach was determined with strong Raman molecules,
Aβ was detected using this nanofluidic SERS platform. Distinct surface-enhanced Raman
spectra of Aβ was observed in different conformational states as a function of concentration
and structure (monomer versus oligomer form) due to Aβ refolding from α-helical to a
predominantly β-pleated sheet form. The sensor was also shown to potentially distinguish Aβ
from insulin and albumin, confounder proteins in cerebral spinal fluid. Thus, a novel
platform was developed to detect picomoler levels of Aβ with the ultimate goal of facilitating
the diagnosis and understanding of Alzheimer’s disease by means of detecting structure
specific oligomers of Aβ.
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Molecular dynamics simulation of complex molecules at interfaces: dendritic surfactants in clay and amyloid peptides near lipid bilayersHan, Kunwoo 02 June 2009 (has links)
We apply a molecular dynamics (MD) simulation technique to complex molecules at
interfaces. Partitioning of dendritic surfactants into clay gallery and Ab protein behavior
near hydrated lipids are chosen for the purpose. Using a full atomistic model of dendritic
surfactants, the confinement force profiles featuring oscillatory fashion at moderate layer
separation of 10 to 25 Å were observed. Integration of the confinement forces led to free
energy profiles, which, in turn, were used to determine the final morphology of the
nanocomposite. From the free energy profiles, smaller and linear surfactants (G1 and
G2L) are expected to intercalate into the clay comfortably, while larger surfactants (G2
and G3) are expected to form frustrated intercalated structures due to the location and
depth of the free energy minima. This would agree with the previous observations.
As primary steps to understand the Ab protein behavior under biological conditions,
simulations of bulk water and hydrated lipids were performed and the results were
compared with the literature. Hydrated lipids were simulated using a full atomistic
model of lipids (dipalmitoylphosphatidylcholine) and water with a cvff force-field and it
was found that structural properties such as the molecular head group area and
membrane thickness were accurately produced with MD simulation. Systems of the
protein Ab(1-42) in bulk water were simulated and some secondary structural change,
with loss of part of the a-helical structure, occurred during the 1 ns of simulation time at
323K. The fragment Ab(31-42) with b-sheet conformation was also simulated in bulk
water, and the extended b-sheet structure became a bent structure. Simulations of Ab(1-
42) or Ab(31-42) near lipid bilayers have been performed to investigate the structural property changes under biological conditions. The different nature of structural change
was observed from the simulations of the protein or fragment in water and near lipid
bilayers due to the different solvent environment. The protein has close contacts with the
membrane surface. It was impossible to observe the conformational change to b-sheet
and protein entrance into the lipid bilayer within 1 ns simulations.
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The use of Surface Enhanced Raman Spectroscopy (SERS) for biomedical applicationsChowdhury, Mustafa Habib 25 April 2007 (has links)
Recent advances in nanotechnology and the biotechnology revolution have
created an immense opportunity for the use of noble metal nanoparticles as Surface
Enhanced Raman Spectroscopy (SERS) substrates for biological sensing and diagnostics.
This is because SERS enhances the intensity of the Raman scattered signal from an
analyte by orders of 106 or more. This dissertation deals with the different aspects
involved in the application of SERS for biosensing. It discusses initial studies performed
using traditional chemically reduced silver colloidal nanoparticles for the SERS
detection of a myriad of proteins and nucleic acids. It examines ways to circumvent the
inherent aggregation problems associated with colloidal nanoparticles that frequently
lead to poor data reproducibility. The different methods examined to create robust SERS
substrates include the creation of thermally evaporated silver island films on microscope
glass slides, using the technique of Nanosphere Lithography (NSL) to create
hexagonally close packed periodic particle arrays of silver nanoparticles on glass
substrates as well as the use of optically tunable gold nanoshell films on glass substrates. The three different types of SERS surfaces are characterized using UV-Vis absorption
spectroscopy, Electron Microscopy (EM), Atomic Force Microscopy (AFM) as well as
SERS using the model Raman active molecule trans-1,2-bis(4-pyridyl)ethylene (BPE).
Also discussed is ongoing work in the initial stages of the development of a SERS based
biosensor using gold nanoshell films for the direct detection of b-amyloid, the causative
agent for Alzheimer's disease. Lastly, the use of gold nanoshells as SERS substrates for
the intracellular detection of various biomolecules within mouse fibroblast cells in cell
culture is discussed. The dissertation puts into perspective how this study can represent
the first steps in the development of a robust gold nanoshell based SERS biosensor that
can improve the ability to monitor biological processes in real time, thus providing new
avenues for designing systems for the early diagnosis of diseases.
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Dissecting out the contribution of cognitive, social, and physical activities to environmental enrichment's ability to protect Alzheimer's mice against cognitive impairmentCracchiolo, Jennifer R 01 June 2005 (has links)
Retrospective studies suggest that lifestyle activities may provide protection against Alzheimer s Disease (AD). However, such studies can be inaccurate and prospective longitudinal studies investigating lifestyle protection against AD are both impractical and impossible to control for. Transgenic (Tg+) AD mice offer a model in a well controlled environment for testing the potential for environmental factors to impact AD development. In an initial study, Tg+ and non-transgenic (Tg-) mice were housed in either environmentally enriched (EE) or standard housing (SH) from 2-6 months of age, with a behavioral battery given during the last 5 weeks of housing. In the Morris maze, platform recognition, and radial arm water maze tasks, Tg+/EE mice were completely protected from cognitive impairment present in Tg+/SH mice and comparable to control Tg-/SH mice in cognitive performance. The current study utilized the same cognitive-based behavioral battery and multimetric statis
statistical analysis to investigate the protective effects of "complete" environment enrichment (EE) versus several of its components (physical activity, social interactions) in AD transgenic mice. The AD transgenic mice utilized develop beta-amyloid (AB) deposition and cognitive impairment by 6-7 months of age. Similar to our initial study, results show that "complete" EE (physical, social, and cognitive activities) from 2 to 8 months of age completely protected AD transgenic mice from cognitive impairment in tasks representing different cognitive domains - working memory, reference learning, and search/recognition. In strong contrast, Tg+ mice reared in environments that included physical activity and social interaction, or only social interaction, were not protected from cognitive impairment in adulthood --
enhanced cognitive activity was required over and above that present in these other environments. Through use of discriminant function analysis, EE and/or NT mice were consistently discriminated from the poorer performing other housing groups. The cognitive benefits observed in EE-housed Tg+ mice occurred without significant changes in cortical AB levels, plasma cytokine levels, or plasma corticosterone levels, suggesting involvement of mechanisms independent of these endpoints. However, EE-housed Tg+ mice did have decreased dendritic length of neurons in the parietal cortex (but not hippocampus). Noteworthy is that plasma cytokine levels and hippocampal dendritic length consistently correlated with cognitive measures, suggesting their involvement in underlying mechanisms of cognitive performance. The present work provides the first evidence that "complete" EE (including enhanced cognitive activity) is needed to provide cognitive protection against AD in a Tg+ model of the disease,
while the physical and social activity components of EE do not alone lead to protection. These results suggest that humans desiring to gain maximal environmental protection against AD should live a lifestyle high in cognitive, social, and physical activities together.
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ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR REGULATION IN EXPERIMENTAL NEURODEGENERATIVE DISEASECharriez, Christina Margaret 01 January 2010 (has links)
The α7 nicotinic acetylcholine receptor (nAChR) is involved in learning and memory, synaptic plasticity, neuroprotection, inflammation, and presynaptic regulation of neurotransmitter release. Alzheimer’s disease (AD), a neurodegenerative disease characterized by diminished cognitive abilities, memory loss, and neuropsychiatric disturbances, is associated with a loss of nAChRs. Similarly, traumatic brain injury (TBI) may result in long term neurobehavioral changes exemplified by cognitive dysfunction. Deficits in α7 nAChR expression have previously been shown in experimental TBI and may be related to cognitive impairment experienced in patients following TBI.
The purpose of this dissertation was to investigate changes in α7 nAChR expression in models of neurodegeneration and determine if allosteric modulation of the nAChR facilitates functional recovery following experimental TBI through changes in nAChRs. Experimental models employed include a transgenic mouse model of AD that overexpresses the amyloid precursor protein (APPswe mice) and the controlled cortical impact injury model of TBI in rats. Quantitative receptor autoradiography using α-[125I]-bungarotoxin and [125I]-epibatidine and in situ hybridization were used to investigate changes in nAChR density and mRNA expression, respectively.
In the first study, the effects of aging and β-amyloid on α7 nAChR expression were evaluated in APPswe mice. Hippocampal α7 nAChR density was significantly upregulated in APPswe mice compared to wild-type mice. It is postulated that elevated Aβ levels bind to the α7 nAChR resulting in upregulation. In a second study, galantamine, a medication used in the treatment of AD, was administered subchronically following experimental TBI to determine if treatment could facilitate cognitive recovery and affect nAChR expression. Interestingly, the results indicate TBI interferes with agonist mediated upregulation of nAChRs, and galantamine did not improve function in a behavioral task of learning a memory. In a third study, the regulation of TBI related deficits in α7 nAChRs was examined 48 hours following injury. α7 nAChR deficits occurred with a reduction in α7 mRNA in several hippocampal regions and non-α7 nAChR deficits occurred with a reduction in α4 mRNA in the metathalamus. The results of these studies suggest AD and TBI may involve complex but parallel processes contributing to the regulation of α7 nAChRs.
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Beta amiloido sąveika su žiurkės neuroninėmis ir mikroglijos ląstelėmis: eksperimentiniai tyrimai in vitro / Interaction of beta amyloid with rat neuronal and microglial cells: experimental investigations in vitroČižas, Paulius 18 September 2012 (has links)
Tikslas.
Ištirti įvairaus oligomerizacijos laipsnio Aβ1-40 ir Aβ1-42 peptidų agregatų poveikį smegenėlių ląstelėms ir išaiškinti toksinio veikimo mechanizmus.
Uždaviniai:
1.Įvertinti Aβ1-40 ir Aβ1-42 monomerų, oligomerų ir fibrilių poveikį neuronų-glijos ląstelių kultūros gyvybingumui.
2.Nustatyti ryšį tarp Aβ1-42 oligomerų toksiškumo ir dydžio.
3.Ištirti Aβ1-42 oligomerų poveikį neuronų ir mikroglijos ląstelių plazminės membranos įtampos pokyčiams ir įvertinti, kokią reikšmę Aβ1-42 oligomerų sukeltoje neuronų žūtyje turi išorinio kalcio koncentracija, NMDA receptorių ir endocitozės aktyvumas.
4.Nustatyti Aβ1-42 oligomerų poveikį smegenėlių kultūrai, papildytai J774 makrofagais
5.Nustatyti Aβ1-42 oligomerų poveikį mitochondrijų oksidacinio fosforilinimo sistemai.
Mokslinis naujumas
Šiame darbe nustatytas ryšys tarp Aβ1-42 oligomerų dydžio ir toksiškumo neuronams. Pirmą kartą parodyta, kad maži (toksiški) Aβ1-42 oligomerai (1–2 nm), koncentracijose, kurios gali susidaryti smegenyse patologinėmis sąlygomis, yra toksiški ląstelių kultūroje esantiems neuronams, tačiau nekeičia kitų, ląstelių kultūroje esančių, ląstelių gyvybingumo (mikroglijos ir astrocitų).
Pirmieji išsiaiškinome, kad maži ir dideli Aβ1-42 oligomerai gali sukelti neuronų žūtį skirtingais mechanizmais: maži tiesiogiai veikdami neuronus, o dideli veikdami per glijos ląsteles.
Mūsų tyrimai atskleidė iki šiol neaprašytą reiškinį, kad maži Aβ1-42 oligomerai gali sąlygoti ne tik neuroninių ląstelių žūtį, bet ir jų... [toliau žr. visą tekstą] / Objective and tasks.
The aim of this study is to investigate the effects of Aβ1-40 and Aβ1-42 peptide aggregates at various degrees of oligomerization on cultivated neurons of brain cells and their toxic mechanisms.
1.To investigate the effect of various Aβ1–40 and Aβ1-42 aggregates on the viability of neuronal-glial cell cultures.
2.To determine the relationship between the toxicity of Aβ1-42 oli-gomers and their size.
3.To analyze the effect of Aβ1-42 oligomers on membrane potential of neuronal and glial cells. To assess the effect of extracellular Ca2+ concentration, NMDA receptors and activity of endocytosis on neu¬ronal death caused by Aβ1-42 oligomers.
4.To determine the effect of Aβ1-42 oligomers (4–6 nm in size) on neurons in CGC cultures with added macrophages J774 cells.
5.To determine the effect of Aβ1-42oligomers on respiration of isolated brain mitochondria.
Scientific novelty
This study determined the relationship between size of amyloid and its toxicity to neurons. For the first time it was shown that small Aβ1-42 oligomers of the size 1–3 nm were toxic to neurons in cell cultures at the concentrations which occur in brain under pathological conditions. However, they did not affect the viability of other cells (microglia and astrocytes) present in the cell cultures.
For the first time it has been shown that small and large Aβ1-42 oligo-mers can cause neuronal death by different mechanisms: small oligomers by affecting neurons directly, and large oligomers... [to full text]
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Avaliação do efeito de agentes antimicrobianos na inibição da agregação do peptídeo beta-amilóide / Evaluation of the effect of antimicrobial agents on the inhibition of aggregation of beta amyloid peptideHuber, Paula Cristina, 1983- 21 August 2018 (has links)
Orientador: Wanda Pereira Almeida / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-21T15:17:44Z (GMT). No. of bitstreams: 1
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Previous issue date: 2012 / Resumo: A Doença de Alzheimer é um processo neurodegenerativo associado ao envelhecimento. Seu arsenal terapêutico é muito pobre. Dentre as características fisiopatológicas desta doença, destaca-se a formação de placas senis constituídas de fibrilas do peptídeo b-amilóide, principalmente do Ab42. Neste trabalho, avaliou-se o efeito de agentes antimicrobianos na inibição da agregação do peptídeo Ab42. Considerando a importância crescente do reposicionamento de fármacos, foram selecionados alguns antimicrobianos, que estão no mercado farmacêutico e tem o seu perfil farmacológico bastante conhecido, a fim de suprimir algumas etapas clínicas no caso destas substâncias apresentarem atividade anti-fibrilogênica. Levofloxacino e ciprofloxacino foram as fluorquinolonas selecionadas. Levofloxacino inibiu in vitro a agregação do peptideo Ab42 quando submetido a condições de fibrilogênese. As metodologias empregadas foram o ensaio de fluorescência da tioflavina-T, microscopia de força atômica e eletroforese em gel de poliacrilamida. Os resultados promissores obtidos nos motivaram a buscar o grupo farmacofórico responsável pela atividade observada. Para tanto, sintetizamos a 3-carboetoxi-4-quinolona, correspondente a porção quinolônica mais simples e planar do levofloxacino. Os ensaios indicaram que esta substância e ainda mais eficaz do que o levofloxacino. Sabendo que in vivo o processo de agregação e metal dependente (zinco e cobre divalentes), fizemos um estudo comparativo das propriedades geométricas destas substâncias com as de conhecidos agentes complexantes de metais. De acordo com a literatura, fluorquinolonas apresentam interações medicamentosas com antiácidos que apresentam em sua formulação cátions divalentes. Então, realizamos um estudo de formação de complexos de cobre e zinco tendo como ligantes as substâncias estudadas. Estes complexos foram obtidos e caracterizados, e, um estudo de propriedades importantes foi realizado, incluindo a solubilidade em água e coeficiente de partição. A atividade antimicrobiana e citotóxica dos complexos também foi determinada, o que e de extrema importância para o caso destes serem formados in vivo / Abstract: Alzheimer's disease is a neurodegenerative pathology associated with aging. The therapeutic arsenal to treat it is very poor. Among the main pathophysiological characteristics of this disease, there is the formation of senile plaques composed of fibrils of b-amyloid peptide, mainly of Ab42. This study assessed the effects of antimicrobial quinolones on peptide Ab42 aggregation inhibition. Considering the growing importance of drug repositioning, some antimicrobial agents available in the pharmaceutical market with a well known pharmacological profile were selected, in order to eliminate some Clinical Study steps in case they present anti-fibrilogenic activity. Levofloxacin and ciprofloxacin were the selected fluoroquinolones. Levofloxacin inhibited in vitro aggregation of the peptide Ab42 when subjected to fibrillogenesis conditions. The methods used were thioflavin T fluorescence, atomic force microscopy and polyacrylamide gel electrophoresis. The promising results obtained motivated us to seek the pharmacophore group responsible for the observed activity. For this purpose, we synthesized the 3-carboethoxy-4-quinolone, quinolone portion corresponding to the planar portion of levofloxacin. The tests indicated that this substance is more effective than levofloxacin. Knowing that in vivo aggregation process is metal dependent (divalent zinc and copper), we made a comparative study of the geometric properties of these substances with known metal complexing agents. According to the literature, fluoroquinolones have drug interactions with antacids that contain divalent cations in its formulation. So, we conducted a study of complex formation with copper and zinc using the studied substances as ligands. These complexes were obtained and characterized, and a study of important properties was conducted, including water solubility and partition coefficient. The antimicrobial and cytotoxic activities of the complexes were also determined, which is extremely important in case these are formed in vivo / Mestrado / Quimica Organica / Mestra em Química
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