Síntese, avaliação biológica e modelagem molecular de arilfuranos como inibidores da enzima tripanotiona redutase

Oliveira, Renata Barbosa de; Zani, Carlos L.; Ferreira, Rafaela Salgado; Leite, Rodrigo Souza; Alves, Tânia Maria de Almeida; Silva, Thaís H. A. da; Romanha, Álvaro J.

doi:10.1590/s0100-40422008000200013

Cited by 20 publications

(11 citation statements)

References 16 publications

(25 reference statements)

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“…Reactions were monitored by TLC using silica gel coated plates and different solvents solutions as the mobile phase. The synthesis of the compounds 1a and 1c (Rajak et al, 2011), 1b (Tenório, Carvalho, Pessanha, 2005), 1d (Grammaticakis, Sorbonne, 1959), 1e (Behnisch, Mietzsch, Schmidt, 1955), 1f (Oliveira et al, 2008b), 2a and 2c (Shih, Su, Wu, 2007), 2b (Maccioni et al, 2003) and 2e (Bilinski, Tyburczyk, Urban, 1961) was previously reported in the literature.…”

Section: General Proceduresmentioning

confidence: 90%

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

Braga

Fonseca

Ramos

et al. 2016

Braz. J. Pharm. Sci.

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The aims of this study were to synthesize a series of thiosemicarbazones and their thiazole derivatives, to investigate their cytotoxic activity against three human cancers and normal (Vero cells) cell lines, and to evaluate the pro-apoptotic potential of the most active compounds. Materials and Methods: The thiosemicarbazones were obtained by reacting an aromatic aldehyde with thiosemicarbazide (yield 71-96%), which were subjected to a cyclization with α-bromoacetophenone to yield the required thiazole heterocycles (yield 63-100%). All the synthesized compounds were screened at 50 µM concentration against three cell lines representing HL60 (promyelocytic leukemia), Jurkat (acute lymphoblastic leukemia), and MCF-7 (breast cancer). The pro-apoptotic effect was measured by flow cytometry as the percentage of cells with hypodiploid DNA. Results: Three thiazole compounds showed activity against at least one tumor cell line (IC 50 = 43-76 µM) and low cytotoxicity against Vero cells (IC 50 > 100 µM). The most active compound of this series induced 91% and 51% DNA fragmentation in HL60 and MCF-7 cell lines, respectively, suggesting that this compound triggered apoptosis in these cells. Conclusion: Among the synthesized compounds, one in particular was found to exert antiproliferative and pro-apoptotic activity on tumor cells and can be considered promising as a lead molecule for the design of new analogues with improved activity.Uniterms: Thiosemicarbazones/synthesis. Thiosemicarbazones/cytotoxic activity. Thiazoles/derivatives/ synthesis. Thiazoles/derivatives/cytotoxic activity. O estudo teve como objetivo a síntese de uma série de tiossemicarbazonas e seus derivados tiazólicos e a avaliação da atividade citotóxica contra três linhagens de células tumorais humanas e células normais (Vero), a fim de se avaliar o potencial pró-apoptótico dos compostos mais ativos. As tiossemicarbazonas foram obtidas por reação entre um aldeído aromático e tiossemicarbazida (rend. 71-96%), as quais foram submetidas à ciclização com α-bromoacetofenona, fornecendo os heterociclos tiazólicos desejados (rend. 63-100%). Todos os compostos sintetizados foram testados na concentração de 50 µM contra três linhagens de células tumorais: HL60 (leucemia promielocítica), Jurkat (leucemia linfoblástica aguda) e MCF-7 (câncer de mama). O efeito pró-apoptótico foi avaliado por citometria de fluxo como porcentagem de células com DNA hipodiplóide. Três compostos tiazólicos foram ativos contra, pelo menos, uma linhagem tumoral (CI 50 =43-76 µM), com baixa citotoxicidade contra células Vero (CI 50 > 100 µM). O composto mais ativo dessa série induziu fragmentação do DNA de 91% e 51% nas linhagens HL60 e MCF-7, respectivamente, sugerindo que este composto ativou a apoptose nessas células. Dentre os compostos sintetizados, um em particular apresentou atividade antiproliferativa e pró-apoptótica em células tumorais e pode ser considerado composto protótipo promissor na busca por novos análogos com atividade melhorada.

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Section: General Proceduresmentioning

confidence: 90%

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

Braga

Fonseca

Ramos

et al. 2016

Braz. J. Pharm. Sci.

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“…The residue purified by column chromatography on silica gel using hexane/ethyl acetate 8:2 as eluent. General procedure for the preparation of triazole derivatives (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) To a solution of terminal acetylenes 25a-d (2 mmol, 1.0 equiv) and azides 27a-d (2 mmol, 1.0 equiv) in dichloromethane (2 mL) and water (2 mL), were added CuSO 4 .5H 2 O pentahydrate (0.128 mmol, 0.064 equiv) and sodium ascorbate (0.352 mmol, 0.176 equiv). The reaction mixture was stirred for 24 h. Then was added a saturated solution of NH 4 Cl (30 mL) and the product was extracted with dichloromethane (3 × 20 mL).…”

Section: General Remarksmentioning

confidence: 99%

“…10,12,13 Among natural products, our research group has focused on the tetrahydrofuran neolignans, a class that exhibits a great number of biological activities including antibacterial, antifungal, antitumor, and anti-inflammatory. [14][15][16][17][18][19][20][21][22][23] The neolignans veraguensin 1, grandisin 2, and machilin G 3 ( Figure 1) have shown antitrypanosomal and antileishmanial activities. [14][15][16][17][18][19][20][21][22][23] Studies on the antitrypanosomal activity of compounds 1-3 found maximum inhibitory concentration (IC 50 ) values of 2.3, 3.7 and 2.2 µM, respectively.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antitrypanosomastid Activity of 1,4-Diaryl-1,2,3-triazole Analogues of Neolignans Veraguensin, Grandisin and Machilin G

Cassamale¹,

Costa²,

Carvalho³

et al. 2016

Journal of the Brazilian Chemical Society

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Sixteen 1,4-diaryl-1,2,3-triazole compounds derived from the natural products veraguensin, grandisin and machilin G were synthesized, with yields of 78-92%. Biological activity tests against Leishmania amazonensis promastigotes showed that three of these compounds were the most active, with maximum inhibitory concentration (IC 50 ) values of 1.1, 3.71 and 7.23 µM. One compound was highly active against Leishmania infantum, with an IC 50 value of 5.2 µM, and one derivative showed an IC 50 value of 28.6 µM against Trypanosoma cruzi trypomastigotes. Regarding structureactivity relationship (SAR), hybrid 1,2,3-triazolic compounds containing a methylenedioxy group, showed the best antileishmanial and antitrypanosomal activities.

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“…Tetrahydrofuran neolignans, derived from natural sources, are considered privileged structures as they show several biological activities including antibacterial, antifungal, antitumour and anti‐inflammatory. The tetrahydrofuran neolignans veraguensin ( 1 ), grandisin ( 2 ) and machilin G ( 3 ), for instance (Figure ), have shown antitrypanosomal and antileishmanial activities (Figure ) (Bernardes, Kato, Albuquerque & Carvalho, ; Carvalho et al., ; Da Cruz et al., ; Filho et al., ; Jean‐Moreno, Rojas, Goyeneche, Coombs & Walker, ; Lopes, Chicaro, Albuquerque, Yoshida & Kato, ; Oliveira et al., , ; Schmidt et al., ; Silva Filho et al., ; Verza et al., ).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and antitrypanosomatid activities of 3,5‐diaryl‐isoxazole analogues based on neolignans veraguensin, grandisin and machilin G

et al. 2018

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Using bioisosterism as a medicinal chemistry tool, 16 3,5-diaryl-isoxazole analogues of the tetrahydrofuran neolignans veraguensin, grandisin and machilin G were synthesized via 1,3-dipolar cycloaddition reactions, with yields from 43% to 90%. Antitrypanosomatid activities were evaluated against Trypanosoma cruzi, Leishmania (L.) amazonensis and Leishmania (V.) braziliensis. All compounds were selective for the Leishmania genus and inactive against T. cruzi. Isoxazole analogues showed a standard activity on both promastigotes of L. amazonensis and L. braziliensis. The most active compounds were 15, 16 and 19 with IC 50 values of 2.0, 3.3 and 9.5 μM against L. amazonensis and IC 50 values of 1.2, 2.1 and 6.4 μM on L. braziliensis, respectively. All compounds were noncytotoxic, showing lower cytotoxicity (>250 μM) than pentamidine (78.9 μM). Regarding the structure-activity relationship (SAR), the methylenedioxy group was essential to antileishmanial activity against promastigotes. Replacement of the tetrahydrofuran nucleus by an isoxazole core improved the antileishmanial activity. K E Y W O R D S bioisosterism, cycloaddition [3+2], isoxazole, neolignans 314 | TREFZGER ET al.

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Síntese, avaliação biológica e modelagem molecular de arilfuranos como inibidores da enzima tripanotiona redutase

Cited by 20 publications

References 16 publications

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

Synthesis and Antitrypanosomastid Activity of 1,4-Diaryl-1,2,3-triazole Analogues of Neolignans Veraguensin, Grandisin and Machilin G

Design, synthesis and antitrypanosomatid activities of 3,5‐diaryl‐isoxazole analogues based on neolignans veraguensin, grandisin and machilin G

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