No / A series of 19 huprines has been evaluated for their activity against cultured bloodstream forms of Trypanosoma brucei and Plasmodium falciparum. Moreover, cytotoxicity against rat myoblast L6 cells was assessed for selected huprines. All the tested huprines are moderately potent and selective trypanocidal agents, exhibiting IC50 values against T. brucei in the submicromolar to low micromolar range and selectivity indices for T. brucei over L6 cells of approximately 15, thus constituting interesting trypanocidal lead compounds. Two of these huprines were also found to be active against a chloroquine-resistant strain of P. falciparum, thus emerging as interesting trypanocidal–antiplasmodial dual acting compounds, but they exhibited little selectivity for P. falciparum over L6 cells.

Submitted by Irene Nascimento (irene.kessia@ufpe.br) on 2017-05-04T18:15:26Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação-Final (5).pdf: 1546136 bytes, checksum: 53adafdfff412dd5657ebbb3bab08a78 (MD5) / Made available in DSpace on 2017-05-04T18:15:26Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação-Final (5).pdf: 1546136 bytes, checksum: 53adafdfff412dd5657ebbb3bab08a78 (MD5) Previous issue date: 2016-02-24 / O benznidazol (BNZ) é um derivado de 2-nitroimidazol com largo espectro de atividade farmacológica antiparasitária. Um dos grandes problemas deste fármaco são as grandes doses administradas, tratamentos prolongados, bem como a alta incidência de reações adversas, o que, provavelmente, estão relacionados com a sua baixa solubilidade. Parte destes problemas pode ser reduzidos com associação do fármaco a uma estrutura que aumente a sua solubilidade e modifique a liberação do mesmo, modulando-a e prolongando a sua dissolução. Assim, esse trabalho objetivou obter e caracterizar sistemas microparticulados do BNZ a uma estrutura organometálica - Metal Organic Framework (MOF) chamada Zeolitic Imidazolate Framework (ZIF-8), a fim deser utilizada nos estudos de pré-formulação de forma farmacêutica de liberação prolongada para o tratamento alternativo da doença de Chagas. Os sistemas foram obtidos após agitação do fármaco e da ZIF-8 em diferentes solventes (água e acetona) para que fosse escolhido o melhor método, seguindo a obtenção com a secagem. Quanto às caracterizações, estas foram realizadas através de diferentes técnicas analíticas (espectroscopia de absorção na região do ultravioleta-visível, análise térmica, espectroscopia de absorção na região do infravermelho com transformada de Fourier, difratometria de raios-x, microscopia eletrônica de varredura, microscopia de luz polarizada, tamanho de partícula por granulometria à laser, análise de área superficial e tamanho e volume de poros) para garantir a obtenção do sistema, prosseguindo com os ensaios de dissolução que evidenciaram o comportamento de liberação do BNZ em diferentes pH’s quando associado aos materiais organometálicos. Os perfis de dissolução foram analisados através da área sob a curva (AUC), eficiência de dissolução (ED%) e ajuste de seus resultados quanto aos modelos cinéticos. Por meio dos métodos desenvolvidos o escolhido para obtenção foi o realizado com a acetona como solvente, onde foi possível conseguir um valor de 38% de incorporação do fármaco à ZIF-8. Através das análises térmicas, ficou comprovada a obtenção do sistema, indicando que o mesmo também pode influenciar positivamente a estabilidade térmica do fármaco. Já os espectros de FT-IR, difratogramas de DR-X e demais análises realizadas corroboraram os resultados, confirmando a formação do sistema microparticulado BNZ:ZIF-8. Com o estudo de dissolução, verificou-se que houve modulação da liberação do fármaco de acordo com o pH utilizado, onde em pH 4,5 o sistema liberou uma grande quantidade de fármaco em um curto intervalo de tempo, atingindo 80% de liberação em 2h, já em pH 7,6 houve uma liberação gradual atingindo essa mesma porcentagem em 7h, além dessa modulação o sistema apresentou incremento de solubilidade quando comparado ao BNZ isolado. O presente trabalho trouxe informações relevantes para o desenvolvimento de formas farmacêuticas de liberação prolongada que utilize o BNZ como insumo farmacêutico ativo. / The benznidazole (BNZ) is a 2-nitroimidazole derived with broad-spectrum antiparasitic drug activity. Among the problems with this drug are: large doses, long term treatment and the high incidence of adverse reactions, which are probably related to its low solubility. Many of these problems can be reduced associating the drug with a structure that increases the its solubility and modulates its release. Thus, this study aimed to obtain and characterize the BNZ microparticulate systems with a Metal Organic Framework (MOF) called Zeolitic Imidazolate Framework (ZIF-8), to be used in pre-formulation studies of extended release dosage form, as an alternative treatment of Chagas' disease. The systems were obtained after stirring the drug and ZIF-8 in different solvents (water and acetone), followed by drying, in order to choose the best method of obtaining. The characterizations were performed using different techniques (absorption spectroscopy in the ultraviolet region, thermal analysis, absorption spectroscopy in the infrared with Fourier transform, x-ray diffractometry, scanning electron microscopy, polarized light microscopy, particle size by laser granulometry, surface area nalysis and size and pore volume) to ensure the achievement of the system. Then they were carried out dissolution tests, which showed the BNZ release behavior at different pH’s when associated with organometallic materials. The dissolution profiles were analyzed by area under the curve (AUC), dissolution efficiency (DE%) and release kinetic models. The method using acetone to obtain the system reach a value of 38% of drug incorporation on ZIF-8 and it was determined as the standard obtaining method. Thermal analysis, FTIR, XRD and other analyses corroborate the results that confirms the formation of BNZ:ZIF-8 microparticulate system. With dissolution study it was found that there was modulation of drug release according to the pH used. At pH 4.5 the system released a large amount of drug in a short period of time, up to 80% release in 2 hours. At pH 7.6 there was a gradual release over time until it reaches the same percentage in 7 hours. In addition to this modulation, the system showed increased solubility when compared to the isolated BNZ. This study brought relevant information for the development of extendedrelease dosage forms using the BNZ as an active pharmaceutical ingredient.

Yes / Dual submicromolar trypanocidal–antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.

We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypanocidal/anticholinesterase activity ratio.