Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2017. / Crystal engineering principles were used to cocrystallize sulfa drugs, sulfapyridine (SFP) and sulfadiazine (SFD) with aromatic acids and an amine via solution crystallization. Sulfapyridine formed cocrystals with 3-nitrobenzoic acid (SFP∙3NBA), 5-bromosalicylic acid (SFP∙5BSA), 4-dimethylaminopyridine (SFP∙4DMAP) and salts with 4-nitrobenzoic acid [SFP+][4NBA-], 3,5-dinitrosalicylic acid [SFP+][DNSA-] and 3,5-dibromosalicylic acid [SFP+][DBSA-], while sulfadiazine formed a salt with 3,5-dinitrosalicylic acid [SFD+][DNSA-]. The newly formed complexes were analyzed by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), fourier transform infrared spectroscopy (FTIR), single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD) and nuclear magnetic resonance spectroscopy (1H and 13C NMR). The hydrogen bonding and crystal packing of the new solid forms were analyzed with the aid of Mercury and CrystalExplorer. The SFP and SFD compounds exhibit tautomerism. In this work it was investigated how the introduction of coformers with varying acidity provides the possibility to form a variety of synthons, and therefore disrupt the common preferred interactions within the sulfonamides. Using selected acids as coformers, the effect on crystal packing of the coformer’s substituent position was examined by using the isomers 3NBA and 4NBA. 5BSA and DBSA were employed to analyse the effect of the number of substituents on hydrogen bond formation and crystal packing. In addition, it was investigated how small structural changes in the pharmaceutical compound influences the crystal packing by cocrystallising structurally similar SFP and SFD with the same coformer. Evaluation of the change in coformer acidity was studied by using a pyridine coformer, 4DMAP, and its crystal packing was analyzed and compared to structures formed with carboxylic acid coformers. Finally, we examined how inter-conversion of tautomers promotes crystal formation by conforming to the geometric demands of the different coformers. / National Research Foundation(NRF)

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Tuberculosis (TB) has become a global health epidemic affecting millions of people worldwide with a high incidence in third-world countries. The emergence of multi-drug and extremely-drug resistant M. tuberculosis strains together with the HIV/AIDS pandemic warrants the need for new drugs or new drug combinations. The folic acid synthesis pathway is one of the key pathways that are essential for the survival of bacteria in general. Sulfonamides are a group of compounds that target folic acid synthesis, particularly dihydropteroate synthetase, the first enzyme in the folate pathway. Some of these sulfonamides were used during the introduction of chemotherapy for the treatment of TB in the 1930s, but had toxic side effects. Newer derivatives became safer, but were not employed again for TB treatment. In a recent case study it was reported that the combination of trimethoprim-sulfamethoxazole (Bactrim), which is used to treat various bacterial infections, such as urinary tract infections, had activity against M. tuberculosis. In light of this and the fact that trimethoprim-sulfamethoxazole is well tolerated by humans, we have investigated their antimycobacterial activity with particular interest in the combinational effect of sulfamethoxazole and trimethoprim with the first-line anti-TB drugs, Isoniazid, Rifampicin and Ethambutol against M. tuberculosis. Since sulfonamides are known to produce oxidative stress, we also investigated the contribution of this factor to the efficacy of sulfamethoxazole using a mycothiol deficient strain of M. tuberculosis, ΔmshA. Though trimethoprim-sulfamethoxazole targets the folic acid pathway, we also investigated the possibility that trimethoprim-sulfamethoxazole may have other cellular targets and applied proteomic analysis. We have found that Trimethoprim-Sulfamethoxazole has activity against M. tuberculosis and that Sulfamethoxazole is the active compound. However, our observation was that not all sulfonamides are active against M. tuberculosis. In addition we observed that sulfamethoxazole enhances the activity of Rifampicin against M. tuberculosis in a synergistic way. We also observed that a mycothiol deletion mutant was more susceptible to Sulfamethoxazole compared to the wild type strain CDC 1551. Through global protein expression profiling (Proteomics) we were also able to show that sulfamethoxazole could also kill M. tuberculosis by oxidative stress production as we identified oxidative stress responsive proteins that were differentially regulated upon exposure to sulfamethoxazole. As trimethoprim-sulfamethoxazole is a registered drug combination, inexpensive and widely available, we propose that this regimen could be used in our fight against M. tuberculosis infection. / AFRIKAANSE OPSOMMING: Tuberkulose (TB) is ‘n globale gesondheidsprobleem wat miljoene mense wêreldwyd affekteer met ‘n besoderse hoë voorkoms in die derdewêreld lande. Die voorkoms van multi-middel weerstandige en uitersweerstandige M. tuberculosis stamme, tesame met die HIV/VIGS pandemie, steun die erns vir die ontwikkeling van nuwe middels teen M.tuberculosis . Die foliensuur sintesepad is essensieël tot die oorlewing van bakterieë in die algemeen. Vir daardie rede is daar vele middels ontwerp om hierdie metaboliese pad te teiken. Die sulfonamiedes is ‘n groep antibiotika wat foliensuursintese, spesifiek dihidropteroaatsintese, die eerste ensiem in die foliensuursintese pad, teiken. Van hierdie sulfonamiedes is voorheen in die 1930’s gebruik vir die behandeling van tuberkulose, maar het toksiese newe-effekte getoon. Nuwe, minder toksiese derivate, is later ontwikkel maar is nooit vir TB behandeling weer aangewend nie. In ‘n onlangse gevallestudie is daar gerapporteer dat die kombinasie trimethoprim-sulfamethoxazole (TMP/SMX. Handelsnaam: Bactrim), wat normaalweg gebruik word vir die behandeling van algemene bakteriële infeksies soos blaasinfeksies, aktiwiteit teen M. tuberculosis getoon het. Na aanleiding hiervan en dat Bactrim veilig in mense gebruik kan word, het ons die aktiwiteit van Bactrim komponente teen M. tuberculosis bepaal en in die besonder die aktiwiteite van SMX en TMP in kombinasie met die eerstelinie anti-tuberkulose middels Isoniasied, Rifampisien en Ethambutol. Aangesien sulfonamiedes ook oksidatiewe stres intrasellulêr genereer, het ons ook die bydrae van hiervan tot die doeltreffendheid van SMX bepaal deur gebruik te maak van ‘n mycothiol-gemuteerde M. tuberculosis stam ( mshA). Omdat TMP/SMX die foliensuur-pad hoofsaaklik teiken het ons ook die moontlikheid ondersoek dat SMX ander sellulêre teikens het en het ons proteomiese (Proteomics) tegnieke hiervoor aangewend. Ons het gevind dat TMP/SMX aktiwiteit teen M. tuberculosis toon en dat SMX die aktiewe komponent van Bactrim is teen M. tuberculosis . Ons wys ook dat sulfonamiedes in die algemeen nie noodwendig ook aktiwiteit teen M. tuberculosis toon nie. Ons het ook waargeneem dat SMX die aktiwiteit van rifampisien bevorder en dat die twee middels saamwerk op ‘n sinergistiese wyse. Ons het ook getoon dat oksidatiewe stres ‘n rol speel deurdat‘n mycothiol delesie-mutant meer vatbaar was vir SMX in vergelyking met die wilde-tipe stam van M. tuberculosis (CDC1551). Met globale proteïenkartering (Proteomics) het ons ook getoon dat SMX M. tuberculosis kan doodmaak deur oksidatiewe stres te genereer omdat ons oksidatiewe stres reaktiewe proteïne geïdentifiseer het wat differensieël gereguleer is gedurende blootstelling aan SMX. Aangesien Bactrim ‘n reeds geregistreerde middel is, goedkoop is en geredelik beskikbaar is, stel ons voor dat Bactrim moontlik geïnkorporeer kan word in die huidige behandeling van Tuberkulose.

Made available in DSpace on 2014-06-11T19:23:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-05-11Bitstream added on 2014-06-13T20:10:54Z : No. of bitstreams: 1 nicoleti_nh_me_bauru.pdf: 1244120 bytes, checksum: 82b0fc15919f6c3214248fe48efec3e6 (MD5) / Neste trabalho estudamos dois grupos de moléculas: as anilinoquinolinas e as sulfonamidas, inibidores do Plasmodium causador da malária, com o objetivo de correlacionar a estrutura eletrônica com a atividade antimalarial. Em nossas buscas utilizamos métodos empíricos e semi-empíricos para o estudo conformacional e obtenção dos descritores eletrônicos. Também aplicamos vários métodos estatísticos como: Regressão Linear Simples e Múltipla, Análise de Componentes Principais (PCA) e Análise Discriminante Linear (LDA), para verificar uma possível correlação estrutura-atividade dessas moléculas. Os resultados apontaram os descritores eletrônicos mais relevantes na classificação das moléculas antimalariais. / In this work we study two groups of antimalarial compounds: the anilinoquinolines and sulfonamides, aiming the correlation of the electronic structure with the antimalarial activity. In our studies we employ empirical and semi empirical quantum chemistry methods for the geometry optimization and calculation of the electronic descriptors. Also we employed the statistical methods Simple and Multiple Linear Regression, Principal Component Analysis (PCA) and Linear Discriminating Analysis (LDA), to verify the existence of a possible structure-activity correlation for these compounds. The results of this work have pointed out the best electronic descriptors in the classification of the active compounds.

Orientador: Raquel Nogueira Fernandes Pupo / Banca: Clóvis Augusto Ribeiro / Banca: Renato Sanches Freire / Resumo: Este trabalho tem como objetivo avaliar a atividade catalítica de um rejeito de mineração de ferro para a degradação de micropoluentes presentes no meio aquático em processo foto-Fenton heterogêneo. Como poluentes alvos, foram estudados os fármacos: sulfatiazol (STZ) e sulfametazina (SMZ), fármacos de uso estendido no tratamento humano e veterinário. Esses fármacos têm sido detectados em concentrações de ng L-1 a μg L-1 em águas superficiais, subterrâneas, águas de abastecimento, além de Estações de Tratamento de Esgoto (ETE) onde por processos convencionais não conseguem ser eliminados devido à baixa biodegradabilidade ambiental. Foi realizado um planejamento fatorial 24 para determinar os efeitos dos parâmetros reacionais ̶ pH, concentração de peróxido de hidrogênio, dose de rejeito e tamanho de partícula ̶ sendo a variável resposta a porcentagem de degradação do fármaco quantificado por Cromatografia Liquida de Alta Eficiência (HPLC-DAD) com Limites de Detecção (LD) e de Quantificação (LQ) de 6 μg L-1 e 20 μg L-1, respectivamente. O rejeito de minério foi caracterizado por Difração de Raios- X (DRX), Microscopia Eletrônica de Varredura de Alta Resolução (MEV-FEG), Espectroscopia de fotoelétrons excitados por raios- X (XPS) e Área Superficial Específica (BET). O rejeito foi caracterizado separando-se em duas faixas de tamanho de partícula <180 e ≥180 μm, além do rejeito bruto (sem separar). O resíduo apresentou entre seus principais minerais Fe2O3, SiO2, P2O5, CeO2, TiO2,... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: This work aims to evaluate the catalytic activity of a residue from iron mining on the degradation of micropolluants present in the aquatic environment, by using the heterogeneous photo-Fenton process. The target pollutants studied was: sulfathiazole (STZ) and sulfamethazine (SMZ), drugs that are used in human and animal treatments, which has been detected in concentrations of ng.L-1 and ug.L-1 in superficial and underground water, human water supply and sewage treatment station where by conventional processes can't be eliminated due to the low environmental biodegradability. A factorial design was performed 24 to determine the effects of the reaction parameters (pH, hydrogen peroxide concentration, residue dose and particle size). The response variable was the percentage of degradation of the drug, quantified by High Performance Liquid Chromatography (HPLC- DAD) with Detection Limits (DL) and Quantification (QL) of 6 μg L-1 and 20 μg L-1, respectively. Iron mining was characterized by X-ray diffraction (XRD), high resolution scanning electron microscopy (SEM), X-ray photoelectron Spectroscopy (XPS) and surface-specific spectroscopy (BET) spectroscopy. The reject was characterized by separating into two particles size < 180 and ≥ 180 μm in addition to the crude (unseparated) reject. The residue presented among its main minerals Fe2O3, SiO2, P2O5, CeO2, TiO2, ZnO, MgO in addition to other traces, and it does not present significant differences in the composition in the two different particle fractions. The optimum degradation condition was at pH 2.5 with 1 mmol L-1 of hydrogen peroxide, waste dose of 0.3 g L-1 and using the crude waste as catalyst. Both the dark and irradiated degradation experiments showed good percentages of degradation for the two drugs studied, with percentages above 50% in the dark and above 80% under irradiation, with pseudo first order kinetics follow... / Mestre

Made available in DSpace on 2014-06-11T19:29:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-06-20Bitstream added on 2014-06-13T20:59:14Z : No. of bitstreams: 1 fernandes_fcb_me_araiq.pdf: 1102858 bytes, checksum: 4c88e34a40933cd981ce043c3b791166 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Neste trabalho foram desenvolvidos dois métodos ambientalmente mais amigáveis para screening e determinação de sulfonamidas em matrizes diversas. O primeiro método desenvolvido foi o de análise por injeção em fluxo (FIA) com detecção espectrofotométrica, o qual se baseia na reação entre sulfonamidas e o reagente cromogênico p-dimetilaminobenzaldeído (p-DAB - 1,34 x 10-2 mol L-1 ou 0,2 % m/v) em meio ácido (HCl - 2,05 x 10-1 mol L-1) com adição de dodecil sulfato de sódio (SDS - 3,0 x 10-2 mol L-1), o que aumentou significativamente a sensibilidade da reação a qual produz um produto amarelo com λmáx = 465 nm. A configuração escolhida para o sistema FIA foi a de zonas coalescentes empregando um injetor comutador de três peças. Neste caso, são adicionados a reação, volumes fixos da solução contendo o analito e da solução contendo o reagente, sendo estes de 502 e 150 μL, respectivamente, transportados por uma solução carregadora de HCl 5,0 x 10-2 mol L-1 até a confluência. A faixa linear estudada variou entre 0,2 mg L-1 a 5,0 mg L-1 (0,2 - 5,0ppm). Os limites de detecção (LOD) e de quantificação (LOQ) calculados foram entre 0,040 - 0,050 mg L-1 e 0,130 - 0,160 mg L-1, respectivamente. A freqüência analítica obtida foi de 60 análises por hora. O segundo método desenvolvido foi o de espectroscopia de reflectância difusa utilizando spot test. O método é baseado na reação entre sulfonamidas e o reagente cromogênico p-dimetilaminocinamaldeído (2,4 x 10-3 mol L-1 ou 0,042 % m/v) em meio ácido (HCl - 2,0 x 10-2 mol L-1) e SDS (3,5 x 10-2 mol L-1), sobre a superfície de um papel de filtro, produzindo um complexo colorido (λmáx = 560 nm) estável. Para a reação apenas 20 μL de cada solução foi utilizada, sendo um procedimento limpo, pois gera pouco resíduo ao meio ambiente. A faixa linear de... / In this work were developed two environmentally friendly analytical methods for screening and determination of sulfonamides in several matrices. The first method developed was flow injection analysis (FIA) using spectrophotometric determination, which is based on the reaction between sulfonamide and coupling reagent p-dimethylaminobenzaldehyde (1.34 x 10-2 mol L-1 or 0.2 % m/v) in acid medium (HCl - 2.05 x 10-1 mol L-1) with the addition of sodium dodecyl sulfate (SDS - 3.0 x 10-2 mol L-1) what significantly increased the sensitivity of the reaction which yield a yellow product with λmáx = 465 nm. Merging zone configuration employing a three-piece manual injector-commutator was chosen for system FIA. In this case, are added to the reaction, fixed volumes of solution containing the analyte and the solution containing the reagent, the latter being of 502 and 150 μL, respectively, loaded via the porter (5.0 x 10-2 mol L-1) until confluent point. The linear range was 0.2 mg L-1 a 5.0 mg L-1 (0.2 - 5.0 ppm). The limits of detection LOD) and quantification (LOQ) estimated were 0.040 - 0.050 mg L-1 and 0.130 - 0.160 mg L-1, respectively. The average sample rate of 60 determinations per hour. The second method developed was diffuse reflectance spectroscopy using spot test analysis. The method is based on the reaction between sulfonamides and coupling reagent p-dimethylaminocinnamaldeyde (2.4 x 10-3 mol L-1 or 0.042% m/v) in acid medium (HCl - 2.0 x 10-2 mol L-1) and SDS (3.5 x 10-2 mol L-1), on the surface of filter paper, yielding a stable colored product (λ = 560 nm). For the reaction only 20 μL of reagent was applied, it’s a clear procedure, yielding a little quantity of residues. The linear range was 1.0-10.0 mg L-1 (1 - 10 ppm). The limits of detection (LOD) and quantification (LOQ) estimated were 0.140 a 0.200 mg L-1 and... (Complete abstract click electronic access below)

Orientadores: José Roberto Guimarães, Edson Aparecido Abdul Nour / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Civil, Arquitetura e Urbanismo / Made available in DSpace on 2018-08-25T08:51:38Z (GMT). No. of bitstreams: 1 Candello_FernandoPena_M.pdf: 1963368 bytes, checksum: 78504c5406b503757532a0a28430340c (MD5) Previous issue date: 2014 / Resumo: Os fármacos veterinários utilizados para aumentar a produtividade agropecuária podem atingir o solo, via excreção animal, e causar impactos sobre os ecossistemas aquáticos e terrestres. Nesse trabalho, implantou-se o recente ensaio padronizado pela ABNT de comportamento de fuga com minhocas Eisenia andrei (representantes da macrofauna terrestre) para avaliar o efeito subletal do antimicrobiano sulfadiazina (fármaco sintético da classe das sulfonamidas), utilizada de forma extensiva na produção animal. Dessa forma, desenvolveu-se metodologia alternativa de cultivo dessa espécie de minhoca conhecida como vermelha-da-califórnia a partir de restos vegetais domésticos, visando à obtenção de organismos viáveis para os testes. Validou-se o ensaio com uma substância de referência, obtendo-se uma CE50-48h de 819 mg H3BO3 kg-1 (intervalo a 95%: 628 a 1066 mg kg-1), caracterizando-o como uma ferramenta padronizada para avaliação ecotoxicológica rápida de solos contaminados. Também foram executados ensaios com a substância-teste sulfadiazina em solo artificial tropical, obtendo-se baixas respostas de fuga (máxima: 30%), afastando-se da curva concentração-resposta linear, mas permitindo uma discussão acerca dos efeitos assimétricos dos xenobióticos no ambiente / Abstract: Veterinary pharmaceuticals used to increase agricultural productivity can reach soil via animal excretions, and cause impacts on aquatic and terrestrial ecosystems. In this work, the recent standardized ABNT avoidance behavior test was implanted using earthworms Eisenia andrei (terrestrial macrofauna representatives) to assess the sublethal effects of antimicrobial sulfadiazine (a sulfonamide synthetic drug), extensively used in animal production. It was developed an alternative cultivation method of this red worms species made of household vegetable wastes, in order to obtain viable organisms for testing. The escape essay was validated with reference substance, resulting a EC50-48h of 819 mg H3BO3 kg-1 (95% confidence interval: 628-1066 mg kg-1), characterizing it as a standardized tool for rapid ecotoxicological screening of contaminated soil. Some essays were performed with the test-substance sulfadiazine in tropical artificial soil, resulting in low response avoidance (maximum 30 %), away from the linear concentration-response curve, but allowing a discussion on the xenobiotics asymmetric effects over the environment / Mestrado / Saneamento e Ambiente / Mestre em Engenharia Civil