Síntese e caracterização de chalonas derivadas da 3,4,5- trimetoxiacetofenona com potencial atividade antileucêmica.

TCC (graduação) - Universidade Federal de Santa Catarina, Centro de Ciências Físicas e Matemáticas, Curso de Química.As neoplasias malignas representam atualmente a segunda maior causa de mortes no Brasil. Dentre essas enfermidades, os casos de câncer, em especial de leucemia, vem aumentando ano após ano. Desta maneira, o uso de uma ferramenta química que possibilite a busca por novos tratamentos é necessária. Uma classe de compostos que vem recebendo grande atenção dos grupos de pesquisa são as trimetoxichalconas, em especial as 3’,4’,5’-trimetoxichalconas. Neste trabalho foram sintetizadas 18 chalconas derivadas da 3,4,5-trimetoxiacetofenona com diferentes substituintes no anel B, através da condensação de Claisen-Schmidt. Dos compostos obtidos, 17 foram avaliados quanto à sua citotoxicidade frente a células de leucemia linfoblástica aguda da linhagem L1210, pelo método do MTT. As chalconas M5, M6, M24 e M33 apresentaram IC50 inferiores a 45μmol.L-1, sendo consideradas promissoras. Os resultados possibilitaram a discussão entre a estrutura química e a atividade biológica dos compostos, observando-se que a atividade não está vinculada apenas a efeitos eletrônicos, uma vez que entre os compostos com melhores resultados aparecem três com grupos doadores (cloro na posição 4 do anel B) e um composto com o anel B trissubstítuido por metoxilas (retirador de elétrons)

Síntese, caracterização e avaliação da atividade biológica de nitrichalconas e de chalconas derivadas da 6-acetil-2h-1,4-benzoxazin-3(4H)-ona

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciencias Fisicas e Matemáticas, Programa de Pós-Graduação em Química, Florianópolis, 2013.Este trabalho teve como objetivo a síntese e caracterização de duas séries de chalconas, uma derivada da CH8 (previamente patenteada pelo grupo), contendo o grupo nitro na posição 3 ou 3' (série ML) e a outra derivada da 6-acetil-2H-1,4-benzoxazin-3(4H)-ona (série MN), bem como a posterior avaliação biológica de todos os compostos obtidos. Os compostos da série ML foram avaliados como inibidores das proteínas tirosina fosfatase PtpA e PtpB de Mycobacterium tuberculosis, e não apresentaram atividades significativas. Foram também avaliados como agentes anti-leishmania, e de modo geral observou-se que apresentaram inibição superior a 60% para as formas amastigotas de Leishmania amazonensis, sendo (2E)-1-(4-metoxifenil)-3-(2-nitrofenil)prop-2-en-1-ona (ML3) o mais promissor, devido ao seu elevado índice de seletividade quando comparado aos outros compostos do estudo (IS = 15,58). A avaliação dos compostos da série MN revelou 3 chalconas com promissora atividade inibitória das proteínas PtpA e PtpB de Mycobacterium tuberculosis, para os quais foram determinados os valores de IC50: (2E)-6-(3-(3,4-diclorofenil)acriloil)-2H-benzo[b][1,4]oxazin-3(4H)-ona (MN1) (IC50 = 18,44 ± 4,71 para PtpB e IC50 = 28,11 ± 0,33 para PtpA), (2E)-6-(3-(4-bromofenil)acriloil)-2H-benzo[b][1,4]oxazin-3(4H)-ona (MN5) (IC50 = 16,71 ± 0,29 para PtpA) e (2E)-6-(3-(3nitrofenil)acriloil)-2H-benzo[b][1,4]oxazin-3(4H)-ona (MN10) ( IC50=12,04 ± 1,90 para PtpB). O composto com melhor atividade frente a PtpB foi MN10 e frente a PtpA foi MN5.Abstract : This work aimed to objective the synthesis and characterization of two series of chalcones, a derivative of CH8 (previously patented by the group ), containing the nitro group in position 3 or 3' (ML series) and the other derived from 6-acetyl-2H-1,4-benzoxazin-3(4H )-one (MN series), as well as subsequent biological evaluation of all the compounds obtained. The compounds of ML series were evaluated as inhibitors of proteins tyrosine phosphatase PtpA and PtpB of Mycobacterium tuberculosis, and no present significant activities. Also were evaluated as anti-leishmania agents and in general was observed that they presented 60% inhibition superior to amastigote forms of L. amazonensis, being (2E)-1-(4-methoxyphenyl)-3-(2-nitrophenyl)prop-2-en-1-one (ML3) most promising due to their high selectivity index as compared to the other compounds of the study (IS=15.58). The evaluation of the compounds of MN series showed 3 chalcones with promising inhibitory activity of the proteins PtpA and PtpB of Mycobacterium tuberculosis, for which were determined IC50 values: (2E)-6-(3-(3,4-dichlorophenyl)acryloyl)-2H- benzo [b][1,4]oxazin- 3(4H) -one (MN1) (IC50= 18.44 ± 4.71 for PtpB and IC50= 28.11 ± 0.33 for PtpA), (2E)-6-(3-(4-bromophenyl)acryloyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (MN5) (IC50= 16.71 ± 0.29 PtpA) and (2E)-6-(3-(3nitrophenyl)acryloyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (MN10) (IC50= 12.04 ± 1.90 for PtpB). The compound with better activity in relation to PtpB was MN10 and in relation to PtpA was MN5

Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum

Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkyl-esters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC50 values (8.5±0.8μM, 9.5±0.2μM and 4.9±1.3μM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.Fil: Bertoldo, Jean Borges. Universidade Federal de Santa Catarina; BrasilFil: Chiaradia Delatorre, Louise Domeneghini. Universidade Federal de Santa Catarina; BrasilFil: Mascarello, Alessandra. Universidade Federal de Santa Catarina; BrasilFil: Leal, Paulo César. Universidade Federal de Santa Catarina; BrasilFil: Sechini Cordeiro, Marlon Norberto. Universidade Federal de Santa Catarina; BrasilFil: Nunes, Ricardo José. Universidade Federal de Santa Catarina; BrasilFil: Salas Sarduy, Emir. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de La Habana; CubaFil: Rosenthal, Philip Jon. University of California; Estados UnidosFil: Terenzi, Hernán. Universidade Federal de Santa Catarina; Brasi

Synthesis, Biological Evaluation, And Molecular Modeling of Chalcone Derivatives As Potent Inhibitors of Mycobacterium tuberculosis Protein Tyrosine Phosphatases (PtpA and PtpB)

Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure-activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC50 values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs.CNPqCNPqCAPESCAPESFAPESPFAPESPMCTMCTFAPESCFAPESCFINEPFINE

Sulfonyl-hydrazones of cyclic imides derivatives as potent inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase B (PtpB)

Searching lead compounds for new antituberculosis drugs, the activity of synthetic sulfonamides and sulfonyl-hydrazones were assayed for their potential inhibitory activity towards a protein tyrosine phosphatase from Mycobacterium tuberculosis - PtpB. Four sulfonyl-hydrazones N-phenylmaleimide derivatives were active (compounds 14, 15, 19 and 21), and the inhibition of PtpB was found to be competitive with respect to the substrate p-nitrophenyl phosphate. Structure-based molecular docking simulations were performed and indicated that the new inhibitor candidates showed similar binding modes, filling the hydrophobic pocket of the protein by the establishment of van der Waals contacts, thereby contributing significantly to the complex stability.CNPqCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)MCT Ministério de Ciência e TecnologiaFINEPFAPES