Synthesis, In Silico Studies, Antiprotozoal and Cytotoxic Activities of Quinoline‐Biphenyl Hybrids

This is the pre-peer reviewed version of the following article: Synthesis, In Silico Studies, Antiprotozoal and Cytotoxic Activities of Quinoline‐Biphenyl Hybrids, which has been published in final form at https://doi.org/10.1002/slct.201903835. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsThe synthesis, in silico studies, antiprotozoal and cytotoxic activities of eleven quinoline‐biphenyl hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against Plasmodium falciparum, and amastigotes forms both Leishmania (V) panamensis and Trypanosoma cruzi. Cytotoxicity was evaluated against human U‐937 macrophages. 8‐phenylquinoline (4 a) showed similar activity than meglumine antimoniate and 4‐(quinolin‐8‐yl)phenol (4 b) exhibited an activity similar to that of benznidazole. 8‐(3,4‐dimethoxyphenyl) quinoline (4 k) showed the best activity against P. falciparum. Although these compounds were toxic for mammalian U‐937 cells, however they may still have potential to be considered as candidates for drug development because of their antiparasite activity. Molecular docking was used to determine the in silico inhibition of some of the designed compounds against PfLDH and cruzipain, two important pharmacological targets involved in antiparasitic diseases. All hybrids were docked to the three‐dimensional structures of PfLDH and T. cruzi cruzipain as enzymes using AutoDock Vina. Notably, the docking results showed that the most active compounds 4‐(quinolin‐8‐yl)phenol (4 b, CE50: 11.33 μg/mL for T. cruzi) and 8‐(3,4‐dimethoxyphenyl) quinoline (4 k, CE50: 8.84 μg/mL for P. falciparum) exhibited the highest scoring pose (−7.5 and −7.7 kcal/mol, respectively). This result shows a good correlation between the predicted scores with the experimental data profile, suggesting that these ligands could act as competitive inhibitors of PfLDH or T. cruzi cruzipain enzymes, respectively. Finally, in silico ADME studies of the quinoline hybrids showed that these novel compounds have suitable drug‐like properties, making them potentially promising agents for antiprotozoal therapy

Synthesis and in-vitro evaluation of s-allyl cysteine ester-caffeic acid amide hybrids as potential anticancer agents

We have synthesized a series of S-allyl cysteine ester-caffeic acid amide hybrids and evaluated them in order to determine their possible anticancer activity and selectivity in colorectal cancer, which is still one of the leading causes of morbidity and mortality worldwide. All compounds were tested against SW480 human colon adenocarcinoma cells and the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 6e, 9a, 9b, 9c and 9e exhibited the highest effect on viability (IC50 SW480-48h= 0.18, 0.12, 0.12, 0.11 and 0.12 mM, respectively) and selectivity (SI= 10.3, 1.5, >83.33, >90.91 and >83.33, respectively) in a time- and concentration-dependent manner. Besides, our results were even better as regards lead compounds (S-allyl cysteine and caffeic acid) and the standard drug (5-FU). Additionally, these five compounds induced mitochondrial depolarization that could be related with an apoptotic process. Moreover, hybrids 6e, 9a and 9e induced cell cycle arrest in G2/M phase, and compound 9c in S- phase, which suggests that these hybrid compounds could have also a cytostatic effect in SW480 cell line. The SAR analysis showed that hydroxyl groups increased the activity, besides, there was not a clear relationship between the antitumor properties and the length of the alkyl chain. Since hybrid compounds were much more selective than the conventional drug (5-FU), this make them promising candidates for further studies against colorectal cancer

Synthesis and Antiproliferative Activity of 3 and 7-Styrylcoumarins

A series of styrylcoumarins were obtained via Mizoroki-Heck reactions between 3-bromo-4-methyl7-(octyloxy)-2H-chromen-2-one or 2-oxo-2H-chromen-7-yl trifluoromethanesulfonate and functionalized styrenes. The structures of the products were elucidated by spectroscopic analysis. All compounds were evaluated against SW480 and CHO-K1 cell lines. A number of hybrids showed good antiproliferative activity. Among the tested compounds, hybrids 6e, 10c and 10d, exhibited the highest activity (IC50- SW480/48h = 6,92; 1,01 and 5,33 µM, respectively) and selectivity (IS48h = >400; 67,8 and 7,2, respectively). In addition, these compounds were able to preserve their activities over time. The results achieved by these hybrids were even better than the lead compounds (coumarin and resveratrol) and the standard drug (5-FU). As regards structure-activity relationship it seems that the location of the styryl group on the coumarin structure and the presence of the hydroxyl group on the phenyl ring were determinant for the activity

Synthesis, Leishmanicidal and Cytotoxic Activity of Triclosan-Chalcone, Triclosan-Chromone and Triclosan-Coumarin Hybrids

Twelve hybrids derived from triclosan were obtained via Williamson etherification of O-triclosan alkyl bromide plus chalcone and O-coumarin or O-chromone alkyl bromide plus triclosan, respectively. Structures of the products were elucidated by spectroscopic analysis. The synthesized compounds were evaluated for antileishmanial activity against L. (V) panamensis amastigotes. Cytotoxic activity was also evaluated against mammalian U-937 cells. Compounds 7–9 and 17, were active against Leishmania parasites (EC50 = 9.4; 10.2; 13.5 and 27.5 µg/mL, respectively) and showed no toxicity toward mammalian cells (>200 µg/mL). They are potential candidates for antileishmanial drug development. Compounds 25–27, were active and cytotoxic. Further studies using other cell types are needed in order to discriminate whether the toxicity shown by these compounds is against tumor or non-tumor cells. The results indicate that compounds containing small alkyl chains show better selectivity indices. Moreover, Michael acceptor moieties may modify both the leishmanicidal activity and cytotoxicity. Further studies are required to evaluate if the in vitro activity against Leishmania panamensis demonstrated here is also observed in vivo.The authors thank COLCIENCIAS (contract No. 0333-2013, code: 111556933423) and the Universidad de Antioquia (Estrategia de Sostenibilidad 2013–2014 and CIDEPRO) for financial support

Synthesis and leishmanicidal activity of cinnamic acid esters: structure–activity relationship

Several cinnamic acid esters were obtained via Fischer esterification of cinnamic acids derivatives with aliphatic alcohols. Structures of the products were elucidated by spectroscopic analysis. The synthesized compounds were evaluated for antileishmanial activity against L. (V) panamensis amastigotes and cytotoxic activity was evaluated against mammalian U-937 cells. The compounds 11, 15–17, and 23, were active against Leishmania parasite and although toxic for mammalian cells, they still are potential candidates for antileishmanial drug development. A SAR analysis indicates that first, while smaller alkyl chains lead to higher selectivity indices (10, 11 vs. 12–17); second, the degree of oxygenation is essential for activity, primarily in positions 3 and 4 (17 vs. 18–20 and 22); and third, hydroxyl groups increase both activity and cytotoxicity (14 vs. 23). On the other hand, the presence of a double bond in the side chain is crucial for cytotoxicity and leishmanicidal activity (12 vs. 21). However, further studies are required to optimize the structure of the promising molecules and to validate the in vitro activity against Leishmania demonstrated here with in vivo studies.The authors thank Dr. Javier Garcés for his help in this study. We acknowledge the support by the Universidad de Antioquia (Estrategia de Sostenibilidad 2013–2014 and CIDEPRO) and Colciencias (contract No. 357-2011)

Síntesis de pironas con posible actividad leishmanicida

Las passifloricinas son pironas naturales con una alta actividad leishmanicida; de ellas se han preparado varios análogos estructurales con el fin de mejorar su perfil farmacológico, En este trabajo se describe la secuencia sintética conducente a otros derivados. Estos posteriormente serán evaluadas contra amastigotes de Leishmania panamensis

Aprendizagem organização: uma pesquisa empírica sobre o contexto de suporte à aprendizagem contínua

O presente artigo é uma contribuição à área de pesquisa empírica no âmbito de aprendizagem organizacional, com base na revisão de literatura da área. Especificamente, analisa-se o suporte do contexto organizacional voltado à aprendizagem contínua percebida pelos funcionários de uma empresa privada de jornalismo em Brasília. O estudo tem como objetivo analisar a percepção do suporte à aprendizagem contínua no trabalho desta empresa. Para alcançar o objetivo, buscou-se seguir o caminho da conceituação e análise da aprendizagem organizacional e não da empresa no qual o questionário foi aplicado. Primeiramente, fez-se um levantamento teórico sobre os temas percepção, aprendizagem sobponto de vista individual e organizacional e aprendizagem contínua e suporte à aprendizagem contínua. Na pesquisa de campo quantitativa, fez-se a aplicação do questionário elaborado pela Drª Maria Julia Pantoja (2004) em todos os funcionários da empresa. Assim sendo a diferenciação demográfica foi feita apenas durante a análise dos resultados e considerações, não para delimitar a amostra de pesquisa. Como principais resultados, foi observado que a confiança e layout da empresa são percebidos como fatores que favorecem a aprendizagem organizacional. Porém, o conhecimento da atividade e função dos colegas do grupo de trabalho, assim como o incentivo a compartilhamento de experiência entre setores obtiveram um baixo resultado. Juntamente com a teoria de base e análise qualitativa, o artigo agrega valor empírico ao crescente tema de aprendizagem organizacional

Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities

The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosan-caffeic acid hybrids are described herein. The structure of the synthesized products was elucidated by a com- bination of spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis , which is the most prevalent Leishmania species in Colombia, and against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against hu- man U-937 macrophages. Eight compounds were active against L. (V) panamensis ( 18 e 23, 26 and 30 ) and eight of them against T. cruzi ( 19 e 22 , 24 and 28 e 30 ) with EC 50 values lower than 40 m M. Compounds 19 e 22 , 24 and 28 e 30 showed higher activities than benznidazole (BNZ). Esters 19 and 21 were the most active compounds for both L. (V) panamensis and T. cruzi with 3.82 and 11.65 m M and 8.25 and 8.69 m M, respectively. Compounds 19 e 22 , 24 and 28 e 30 showed higher activities than benznidazole (BNZ). Most of the compounds showed antiprotozoal activity and with exception of 18 , 26 and 28 , the remaining compounds were toxic for mammalian cells, yet they have potential to be considered as candidates for anti-trypanosomal and anti-leishmanial drug development. The activity is dependent on the length of the alkyl linker with compound 19 , bearing a four-carbon alkyl chain, the most performing hybrid. In general, hydroxyl groups increase both activity and cytotoxicity and the presence of the double bond in the side chain is not decisive for cytotoxicity and anti-protozoal activity

Synthesis, leishmanicidal, trypanocidal and cytotoxic activities of quinoline-chalcone and quinoline-chromone hybrids

We report herein the synthesis and biological activities (cytotoxicity, leishmanicidal and trypanocidal) of six quinoline-chalcone and five quinoline-chromone hybrids. The synthesized compounds were evaluated against amastigotes forms of Leishmania (V) panamensis, which is the most prevalent Leishmania species in Colombia and Trypanosoma cruzi, which is the major pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Compounds 8–12, 20, 23 and 24 showed activity against Leishmania (V) panamensis, while compounds 9, 10, 12, 20 and 23 had activity against Trypanosoma cruzi with EC50 values lower than 18 mg mL−1. 20 was the most active compound for both Leishmania (V) panamensis and Trypanosoma cruzi with EC50 of 6.11 ± 0.26 μg mL−1 (16.91 μM) and 4.09 ± 0.24 (11.32 μM), respectively. All hybrids compounds showed better activity than the anti-leishmanial drug meglumine antimoniate. Compounds 20 and 23 showed higher activity than benznidazole, the current anti-trypanosomal drug. Although these compounds showed toxicity for mammalian U-937 cells,they still have the potential to be considered as candidates to antileishmanial or trypanocydal drug development

Furanchalcone–biphenyl hybrids: synthesis, in silico studies, antitrypanosomal and cytotoxic activities

The synthesis, antitrypanosomal, and cytotoxic activities of 17 furanchalcone derivatives are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Eleven compounds were active against amastigotes of T. cruzi with EC50 values lower than 40 µM. Hybrids 7b–7d and 8a–8g showed better activity than benznidazole. Structure activity relationship (SAR) showed that the presence of electron withdrawing groups, such as nitro or fluorine, increased the activity and that the degree of oxygenation is essential for activity. In addition, molecular docking was used to identify a possible protein target for the designed compounds. A spearman correlation of 0.608 between the predicted scores and the experimental data profile the enzyme cruzipain as a potential candidate. Finally, in silico ADMET studies of the arylfuranchalcones showed that these novel compounds have suitable drug-like properties, making them potentially promising agents for antichagasic therapy