Submitted by Sandro Camargo (sandro.camargo@unipampa.edu.br) on 2015-05-08T03:06:29Z No. of bitstreams: 1 127110046.pdf: 2895137 bytes, checksum: edf417bbba917e277ef644cfa24efbf9 (MD5) / Made available in DSpace on 2015-05-08T03:06:29Z (GMT). No. of bitstreams: 1 127110046.pdf: 2895137 bytes, checksum: edf417bbba917e277ef644cfa24efbf9 (MD5) Previous issue date: 2014-07-21 / As chalconas são compostos de origem vegetal e apresentam estrutura química simples que é amplamente utilizada como molécula protótipo para a obtenção de novos compostos bioativos através de modificações estruturais nos seus anéis aromáticos. Este fato é importante uma vez que a Sociedade Americana de Doenças Infecciosas lançou a iniciativa “10 x 20”, ou seja, o rápido desenvolvimento de 10 novos antibióticos até o ano de 2020. O objetivo deste estudo é a obtenção e determinação das propriedades físico-químicas e biológicas de chalconas com atividade antibacteriana potencial. As moléculas foram planejadas utilizando-se a metodologia de bioisosterismo clássico de valência, propondo a alteração da hidroxila presente na posição 4 do anel A da Licochalcona pelo grupo amino; no anel B houve a introdução de grupos nas posições para e meta, com graus variáveis de efeito eletrônico, de acordo com o emprego do Diagrama de Craig. As aminochalconas substituídas foram sintetizadas pela reação de Claissen-Schimdt, com quantidades equimolares de 4- aminoacetofenona e benzaldeídos variados e purificadas via cromatografia em coluna ou recristalização para posterior caracterização por espectroscopia de infravermelho e ressonância magnética nuclear. A avaliação da atividade antibacteriana e sinérgica foi realizada através do método de microdiluição em caldo descrito pelo Clinical and Laboratory Standards Institute e Teste de checkerboard frente a cepas referências de bactérias gram- positivas e gram-negativas (Staphylococcus aureus ATCC 29213 e Escherichia coli ATCC 25922), além de uma cepa S. aureus resistente à meticilina (N315). Foi utilizado o programa computacional Spartan ́08 for Windows para determinação da estrutura química em 3D e cálculo dos valores das energias de HOMO e LUMO. O estudo teórico das propriedades físico-químicas foi realizado pelos programas Chem3D Ultra, Molinspiration e MarvinSketch 6.2. Para o estudo teórico da toxicidade e dos perfis de druglikeness e drugscore empregou-se o programa Osiris Property Explorer. Os compostos 1, 3 e 7 apresentaram os menores valores de CIM quando ensaiados frente a ambas cepas de S. aureus, o que sugere que o mecanismo de resistência bacteriana não afeta a atividade desempenhada pelas 4-aminochalconas. Os compostos 5 e 8 foram os mais ativos frente a cepas E. coli. Não houve interação significativa entre as 4-aminochalconas e os antibióticos testados (oxacilina e cloranfenicol). Através da avaliação das relações estrutura-atividade, verificou-se que o composto 8 apresentou vários parâmetros que podem justificar sua ação frente a bactérias gram-negativas, como peso molecular elevado e menores valores de cLogP e LogD 7.4 . Resultados superiores à levofloxacina foram também evidenciados quando calculado seu potencial de druglikeness e de drugscore. Todos os compostos apresentaram alto risco teórico para o efeito mutagênico e baixo perfil toxicológico para o efeito irritante. Em relação aos efeitos no sistema reprodutor, apenas o composto 1 apresentou um risco médio, e para os compostos 2 e 3 foi descrito alto risco para o efeito tumorogênico. Mesmo apresentando uma atividade antibacteriana baixa, estas moléculas podem vir a delinear modificações estruturais com o intuito de aumento da ação biológica, visto que todas enquadram-se dentro dos parâmetros delineados na Regra dos Cinco e, devido a isso, são promissoras a apresentar uma boa biodisponibilidade oral. / Chalcones are vegetal origin compounds and they present a simple chemical structure which is widely used as a molecule prototype in order to obtain new bioactive compounds by structural changes in their aromatic rings. Such fact is important as the American Society of Infectious Diseases has released the “10 x 20” initiative, meaning the fast development of 10 new antibiotics up to 2020. This study aims to obtain and establish chalcone’s physical- chemical and biological properties with potential antibacterial activity. The molecules were designed by the classic bioisosterismo classic methodology, proposing the modification of the hydroxyl existent in licochalcone’s position 4 of ring A in the amino group, in ring B groups were introduced in para and meta positions, with variable degrees of electronical effects, according to the usage of Craig ́s Diagram. The replaced aminochalcones were synthesized by the Claissen-Schimdt reaction with equimolar quantities of 4-aminoacetophenone and varied benzaldehydes and purified by column chromatography or recrystallization for further characterization by infrared spectroscopy and nuclear magnetic resonance. The evaluation of the antibacterial and synergic activity was made through Microdilution Methods described by the Clinical and Laboratory Standards Institute and checkerboard test against reference strains of gram-positive and gram-negative (Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922), plus S. aureus meticillin resistant (N315). Spartan’08 for Windows was the computational program used to establish the 3D chemical structure and the HOMO’s and LUMO’s energy amount figures. The theoretical study of Physical-chemical properties was accomplished by Chem3D Ultra, Molinspiration and MarvinSketch 6.2 programs. In order to theoretically study both toxicity and profile of druglikeness and drugscore, Osiris Property Explorer program was used. The compounds 1, 3 and 7 showed the smallest CIM values when against both S. aureus strains, which suggests that the bacterial resistance mechanism doesn’t affect the 4-aminochalcones activity. Compounds 5 and 8 were more actives against strains E. coli. There was no significant interaction among the 4- aminochalconas and the antibiotics tested (oxacilin and chloramphenicol). Throughout the structural-activity relation evaluation, it was verified that compound 8 presented several parameters that may justify its action facing Gram-negative bacteria, such as the growth of its molecular weight and decreased values of cLogP and LogD7,4 . Levofloxacin superior results were also certified when its potential of druglikeness and drugscore were figured. All the compounds have presented a high theoretical risk to the mutagenic effect and low toxicological profile to the irritant effect. Relating to the effects in the reproductive system, only compound 1 has presented a mid-risk and compound 2 and 3 high risk to tumorigenic effect. Even though these molecules have showed low antibacterial activity, they might outline changes in their structure aiming the biological action growth as they all fit the Rule of Five parameters and as a result, they tend toward a good oral bioavailability.

The 2-aryl-2,3-dihydroquinolin-4(1H)-ones were prepared via acid-catalyzed cyclization of the corresponding 2-aminochalcones, which were in turn, prepared by base-promoted Claisen-Schmidt aldol condensation of 2-aminoacetophenone and benzaldehyde derivatives. The 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones were prepared by reacting 2-aryl-2,3-dihydroquinolin-4(1H)-ones with N-bromosuccinimide (NBS) in carbon tetrachloride-chloroform mixture at room temperature. The 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones were subjected to palladium-catalyzed Suzuki-Miyaura cross-coupling reaction with arylboronic acid using dichlorobis(triphenylphosphine)palladium(II)-tricycohexylphosphine as catalyst mixture and potassium carbonate as a base in dioxane-water under reflux to afford the corresponding novel 2,6,8-triaryl-2,3-dihydroquinolin-4(1H)-ones in a single-pot operation. The latter were subjected to thallium(III) p-tolylsulfonate in dimethoxyethane under reflux to yield the 2,6,8-triarylquinolin-4(1H)-ones. The 2,6,8-triaryl-2,3-dihydroquinolin-4(1H)-ones were treated with molecular iodine in refluxing methanol to afford the corresponding 2,6,8-triaryl-4-methoxyquinolines. All the new compounds were characterized using a combination of 1H NMR & 13C NMR spectroscopy, IR and mass spectroscopic techniques. / Chemistry / M.Sc. (Chemistry)

The 2-aryl-2,3-dihydroquinolin-4(1H)-ones were prepared via acid-catalyzed cyclization of the corresponding 2-aminochalcones, which were in turn, prepared by base-promoted Claisen-Schmidt aldol condensation of 2-aminoacetophenone and benzaldehyde derivatives. The 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones were prepared by reacting 2-aryl-2,3-dihydroquinolin-4(1H)-ones with N-bromosuccinimide (NBS) in carbon tetrachloride-chloroform mixture at room temperature. The 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones were subjected to palladium-catalyzed Suzuki-Miyaura cross-coupling reaction with arylboronic acid using dichlorobis(triphenylphosphine)palladium(II)-tricycohexylphosphine as catalyst mixture and potassium carbonate as a base in dioxane-water under reflux to afford the corresponding novel 2,6,8-triaryl-2,3-dihydroquinolin-4(1H)-ones in a single-pot operation. The latter were subjected to thallium(III) p-tolylsulfonate in dimethoxyethane under reflux to yield the 2,6,8-triarylquinolin-4(1H)-ones. The 2,6,8-triaryl-2,3-dihydroquinolin-4(1H)-ones were treated with molecular iodine in refluxing methanol to afford the corresponding 2,6,8-triaryl-4-methoxyquinolines. All the new compounds were characterized using a combination of 1H NMR & 13C NMR spectroscopy, IR and mass spectroscopic techniques. / Chemistry / M.Sc. (Chemistry)