RESUMO
BACKGROUND: Quinoline and its derivatives have been shown to display a wide spectrum of biological properties, especially anticancer activity. Particularly, diverse potent anticancer drugs are based on the 4-phenoxyquinoline skeleton, acting as small-molecules VEGR2 and/or c-Met kinase inhibitors. However, the design of new drugs based on these quinoline derivatives remains a challenge. Up till now, all approaches to 4-phenoxyquinoline skeleton construction do not obey any green chemistry principles. AIMS AND OBJECTIVES: Developing a new, and efficient protocol for the synthesis of potentially bioactive 4-phenoxyquinoline derivatives and benzazole-quinoline-quinoline hybrids from commercially available 4,7-dichloroquinoline and phenol derivatives using microwave energy (MW) in the presence of 1-methyl 3-butylimidazolium hexafluorophosphate. METHODS: Neweco-efficient protocol for valuable 7-chloro-4-phenoxyquinolines and their hybrids, which is based on SNAr reaction of 4,7-dichloroquinoline with respective simple phenols and hydroxyaryl- benzazoles under MWenergy in green reaction media, is studied for the first time. RESULTS: We found that among various solvents tested, the ionic liquid 1-methyl 3-butylimidazolium hexafluorophosphate ([bmim][PF6]) favored the SNAr reaction affording phenoxyquinolines in excellent yields (72-82%) in 10 min. The developed protocol allowed to obtain quickly in good yields (48-60%) new diverse benzazole-quinoline hybrids, which are expected to be pharmacologically active. According to the calculated bioactivity scores, new hybrids are potential kinase inhibitors that could be useful in anticancer drug research. CONCLUSION: We developed for the first time a new green, efficient method to prepare potentially bioactive functionalized 7-chloro-4-phenoxyquinolines and benzazole-quinoline molecules. Good to excellent yields of the quinoline products, use of MW irradiation in ([bmim] [PF6] as a green solvent, and short times of reactions are some of the main advantages of this new protocol.
RESUMO
A rapid, efficient, and original synthesis of novel pyrido[3,2,1-de]phenanthridin-6-ones is reported. First, the key cinnamamide intermediates 8a-f were easily prepared from commercial substituted anilines, cinnamic acid, and 2-bromobenzylbromide in a tandem amidation and N-alkylation protocol. Then, these N-aryl-N-(2-bromobenzyl) cinnamamides 8a-f were subjected to a TFA-mediated intramolecular Friedel-Crafts alkylation followed by a Pd-catalyzed direct C-H arylation to obtain a series of potentially bioactive 4-phenyl-4,5-dihydro-6H,8H-pyrido[3,2,1-de]phenanthridin-6-one derivatives 4a-f in good yields. Finally, the toxicological profile of the prepared final compounds, including their corresponding intermediates, was explored through in silico computational methods, while the acute toxicity toward zebrafish embryos (96 hpf-LC50, 50% lethal concentration) was also determined in the present study.
Assuntos
Peixe-Zebra , Animais , Alquilação , CiclizaçãoRESUMO
Abstract Tetrahydroquinoline derivatives are interesting structures exhibiting a wide range of biological activities, including antitumor effects. In this investigation, the effect of the synthesized tetrahydroquinolines JS-56 and JS-92 on apoptosis, intracellular Ca2+ concentration ([Ca2+]i), and the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity was determined on MCF-7 breast cancer cells. Colorimetric assays were used to assess MCF-7 cells viability and SERCA activity. Fura-2 and rhodamine 123 were used to measure the intracellular Ca2+ concentration and the mitochondrial electrochemical potential, respec tively. TUNEL assay was used to analyze DNA fragmentation, while caspase activity and NF-κB-dependent gene expression were assessed by luminescence. In silico models were used for molecular docking analysis. These compounds increase intracellular Ca2+ concentration; the main contribution is the Ca2+ entry from the extracellular milieu. Both JS-56 and JS-92 inhibit the activity of SERCA and dissipate the mitochondrial electrochemical potential through processes dependent and independent of the Ca2+ uptake by this organelle. Furthermore, JS-56 and JS-92 generate cytotoxicity in MCF-7 cells. The effect of JS-92 is higher than JS-56. Both compounds activate caspases 7 and 9, cause DNA fragmentation, and potentiate the effect of phorbol 12-myristate-13-acetate on NF-κB-dependent gene expression. Molecular docking analysis suggests that both compounds have a high interaction for SERCA, similar to thapsigargin. Both tetrahydroquinoline derivatives induced cell death through a combination of apoptotic events, increase [Ca2+]i, and inhibit SERCA activity by direct interaction.
Resumen Los derivados de tetrahidroquinolina son estructuras interesantes que exhiben una amplia gama de actividades biológicas, incluyendo efectos antitumorales. Se determinó el efecto de las tetrahidroquinolinas sintetizadas JS-56 y JS-92 sobre la apoptosis, concentración intracelular de Ca2+ ([Ca2+]i) y la actividad Ca2+-ATPasa del retículo sarco(endo)plásmico (SERCA) en células de cáncer de mama MCF-7. Se usaron ensayos colorimétricos para evaluar la viabilidad de las células MCF-7 y la actividad SERCA. Se emplearon Fura-2 y rodamina 123 para medir la concentración de Ca2+ intracelular y el potencial electroquímico mitocondrial, respectivamente. El ensayo TUNEL se utilizó para analizar la fragmentación del ADN, mientras que la actividad de caspasas y la expresión génica dependiente de NF-κB se evaluaron mediante luminiscencia. Modelos in silico permitieron el análisis del acoplamiento molecular. Estos compuestos aumentan la concentración de Ca2+ intracelular; la principal contribución es la entrada de Ca2+ desde el medio extracelular. Tanto JS-56 como JS-92 inhiben la actividad de SERCA y disipan el potencial electroquímico mitocondrial a través de procesos dependientes e independientes de la captación de Ca2+ por este orgánulo. Además, JS-56 y JS-92 generan citotoxicidad en células MCF-7. El efecto de JS-92 es mayor que JS-56. Ambos compuestos activan las caspasas 7 y 9, provocan la fragmentación del ADN y potencian el efecto del 12-miristato-13-acetato de forbol en la expresión génica dependiente de NF-κB. El análisis de acoplamiento molecular sugiere que ambos compuestos tienen una alta interacción con SERCA, similar a la tapsigargina. Ambos derivados de tetrahidroquinolina indujeron la muerte celular a través de una combinación de eventos apoptóticos, aumento de [Ca2+]i e inhibición de la actividad SERCA por interacción directa.
RESUMO
BACKGROUND: Hexahydro-2H-pyrano[3,2-c]quinolines are known to have antibacterial, antifungal, and antitumor properties. Great efforts have been made to develop new synthetic methods that lead to the synthesis of valuable libraries. Extensive methodologies, low yields, excessive amounts of catalyst and expensive reactants are some of the limitations of current methodologies. AIMS AND OBJECTIVE: Developing a useful and efficient method to construct diversely substituted hexahydro-2Hpyrano[ 3,2-c]quinolines into good to excellent yields through a cationic imino-Diels-Alder/N-debenzylation methodology. METHOD: The cationic imino-Diels-Alder/N-debenzylation methodology was used for the preparation of substituted hexahydro-2H-pyrano[3,2-c]quinolines. It involves the use of Sc(OTf)3 for activation of cationic imino- Diels-Alder cycloaddition reaction of N-benzylanilines, 3,4-dihydro-2H-pyran and paraformaldehyde in MeCN; and microwave irradiation to shorten reaction time to afford new 6-benzyl-hexahydro-2H-pyrano[3,2- c]quinolines whose catalytic transfer debenzylation reactions with HCO2NH4 in the presence of Pd/C (10%) and methanol give the new 5-unsubstituted pyrano[3,2-c]quinolines in excellent yields. RESULTS: We found that optimal conditions for the preparation of hexahydro-2H-pyrano[3,2-c]quinolines were Sc(OTf)3 0.5 % and acetonitrile at 160°C for 15 min; and using paraformaldehyde obtained the 6-benzylhexahydro- 2H-pyrano [3,2-c]quinolines with excellent yields, while the N-debenzylation process using ammonium formate in the presence of Pd/C and methanol resulted in the synthesis of hexahydro-2H-pyrano [3,2-c] quinolines with quantitative yields (95-98%). CONCLUSION: We describe an efficient method to synthesize hexahydro-2H-pyrano[3,2-c]quinolines via the cationic imino-Diels-Alder/N-debenzylation methodology using Sc(OTf)3 0.5 % as Lewis Acid catalyst. Excellent yields of the products, use of MW irradiation, short times of reactions, and an efficient and highly diversified method are some of the main advantages of this new protocol.
Assuntos
Piranos , Compostos de Anilina , Catálise , Reação de Cicloadição , Formaldeído , PolímerosRESUMO
Tuberculosis (TB) disease remains to be an alarming infection worldwide with nearly 1.6 million deaths per year ranking above HIV/AIDS. Although Mycobacterium tuberculosis (Mtb), which causes TB, was identified more than 130 years ago, nowadays only old vaccine (Bacillus Calmette-Guérin vaccine) and classical toxic drugs that are losing its effectiveness are available in clinic practice. Despite enormous efforts in drug research on TB treatment including vaccines and diagnostics investigations, this old contagious, infectious disease is still a major public health problem. The goal of elimination of epidemic TB disease by 2035 will not be achieved without combined strategies based on faster diagnostic tools, effective vaccines and drugs. In the field of TB chemotherapy, novel molecular design of new compounds able to efficiently kill Mtb via a disruption of new diverse biological targets is evidently required. In this sense, pyridine and quinoline compounds stand out as promising molecules against drug-resistant tuberculosis. Indeed, many candidate drugs based on heterocyclic skeletons are currently being tested. Among them, quinoline derivatives like gatifloxacin, moxifloxacin and bedaquiline (sirturo), and pyridine molecules such as sudoterb and agent BRD-8000.3 have been shown to have high potential for more effective treatment of the drug-resistant forms of TB disease. In this work we review the most significant advances in the design of such molecules discussing briefly their physicochemical parameters (descriptors) calculated by available Molinspiration software.
Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Antituberculosos/uso terapêutico , Humanos , Piridinas , Tuberculose/tratamento farmacológicoRESUMO
The anti-acetylcholinesterase, larvicidal, antifeedant activities and general toxicity of 15 semisynthetic eugenol derivatives based on clove oil (including the own oil), were evaluated against the maize armyworm, Spodoptera frugiperda (J.E. Smith). Therefore, promising eugenol molecules were classified with larvicidal, anti-acetylcholinesterase and antifeedant activities for controlling this pest. During structure-activity relationship studies and physicochemical profile analysis, it was found that among tested molecules 1-15, eugenol 1, prenyl eugenol 4, isoeugenol 8 and isoeugenol acetate 11 exhibited lethal effects LD50 at concentrations <1â¯mg/g of insect. On the other hand, eugenol 1, metallyl eugenol 3, isoeugenol 8 and isoeugenol acetate 11 showed a good antifeedant activity (CE50â¯=â¯158-209⯵g/mL) with a high antifeedant index (70-78%) at concentration 1000⯵g/mL, possessing a weak anti-acetylcholinesterase activity (IC50â¯=â¯21-31⯵g/mL). According to their ecotoxicological profiles (LC50â¯=â¯2033.1-6303.8⯵g/mL on Artemia salina larvae), isoeugenol 8 and its acetate derivative 11 could be potential used in control of the growth, feeding, or reproduction of S. frugiperda larvae, acting as moderate insecticidal acetylcholinesterase inhibitors and/or antifeedant molecules. Such structure-activity relationship studies could stimulate the identification of lead structures from natural sources for the development of larvicidal and deterrent products against S. frugiperda and related insect pests.
RESUMO
A five-step total synthesis of Dysoxylum alkaloids has been achieved using a biomimetic approach from zanthoxylamide protoalkaloids. The synthesis featured a direct amidation and a Bischler-Napieralski reaction to form the dihydroisoquinoline ring, which was then subjected to a Noyori asymmetric transfer hydrogenation to establish the stereogenic center at C-1. Our synthetic sequence provides an important perspective on the biosynthetic origin of Dysoxylum alkaloids, since 6 natural alkaloids and 12 synthetic analogues were obtained with high enantioselectivity and in overall yields up to 68%. In addition, we describe the acute toxicity toward zebrafish embryos of Dysoxylum alkaloids, comparing their toxicity with that of their corresponding zanthoxylamide protoalkaloids and establishing an enantioselectivity-toxicity relationship.
Assuntos
Alcaloides/síntese química , Materiais Biomiméticos/síntese química , Meliaceae/química , Alcaloides/química , Alcaloides/farmacologia , Animais , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Embrião não Mamífero/efeitos dos fármacos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Peixe-Zebra/embriologiaRESUMO
The insecticidal and antifeedant activities of five 7-chloro-4-(1H-1,2,3-triazol-1-yl)quinoline derivatives were evaluated against the maize armyworm, Spodoptera frugiperda (J.E. Smith). These hybrids were prepared through a copper-catalyzed azide alkyne cycloaddition (CuAAC, known as a click reaction) and displayed larvicidal properties with LD50 values below 3 mg/g insect, and triazolyl-quinoline hybrid 6 showed an LD50 of 0.65 mg/g insect, making it 2-fold less potent than methomyl, which was used as a reference insecticide (LD50 = 0.34 mg/g insect). Compound 4 was the most active antifeedant derivative (CE50 = 162.1 µg/mL) with a good antifeedant index (56-79%) at concentrations of 250-1000 µg/mL. Additionally, triazolyl-quinoline hybrids 4-8 exhibited weak inhibitory activity against commercial acetylcholinesterase from Electrophorus electricus (electric-eel AChE) (IC50 = 27.7 µg/mL) as well as low anti-ChE activity on S. frugiperda larvae homogenate (IC50 = 68.4 µg/mL). Finally, molecular docking simulations suggested that hybrid 7 binds to the catalytic active site (CAS) of this enzyme and around the rim of the enzyme cavity, acting as a mixed (competitive and noncompetitive) inhibitor like methomyl. Triazolyl-quinolines 4-6 and 8 inhibit AChE by binding over the perimeter of the enzyme cavity, functioning as noncompetitive inhibitors. The results described in this work can help to identify lead triazole structures from click chemistry for the development of insecticide and deterrent products against S. frugiperda and related insect pests.
Assuntos
Inseticidas/síntese química , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Spodoptera/efeitos dos fármacos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Química Click , Simulação por Computador , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Inseticidas/química , Larva/enzimologia , Larva/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Doenças das Plantas/parasitologia , Spodoptera/enzimologia , Spodoptera/crescimento & desenvolvimento , Zea mays/parasitologiaRESUMO
Diverse spiro dihydroquinoline-oxindoles (JS series) were prepared using the BF3â¢OEt2-catalyzed imino Diels-Alder reaction between ketimine-isatin derivatives and trans-isoeugenol. Ten spiro-oxiindole derivatives were selected and evaluated at different stages of the life cycle of Leishmania braziliensis parasites, responsible for cutaneous leishmaniasis in South America. Among them, the 8'-ethyl-4'-(4-hydroxy-3-methoxyphenyl)-3'-methyl-3',4'-dihydro-1'H-spiro[indoline-3,2'-quinolin]-2-one called JS87 was able to inhibit the growth of promastigotes without affecting the mammalian cells viability, and to decrease the number of intracellular amastigotes of L. braziliensis. This spiro compound was found to act through the alteration of parasite internal regulation by disrupting the regulatory volume decrease (RVD), and to affect the sterol biosynthetic pathway at level of squalene epoxidase (SE) enzyme. These results revealed that the spiro annulation between quinoline and oxindole scaffolds enhances the anti-leishmanial activity, and could assist in the development of potent quinoline-oxindole hybrids against Leishmania braziliensis, the main etiological agent of cutaneous leishmaniasis in South America.
Assuntos
Antiprotozoários/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Oxindóis/farmacologia , Quinolinas/farmacologia , Compostos de Espiro/farmacologia , Animais , Antiprotozoários/química , Concentração Inibidora 50 , Leishmania braziliensis/crescimento & desenvolvimento , Leishmania braziliensis/metabolismo , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Oxindóis/química , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Fosforilcolina/farmacologia , Quinolinas/química , Compostos de Espiro/químicaRESUMO
Inspired by the simple and attractive structure of zanthoxylamide protoalkaloids: armatamide, rubecenamide, lemairamin, rubemamine and zanthosine; isolated from plants of the genus Zanthoxylum. We report the synthesis of a series of 29 substituted N-phenylethyl cinnamamides through the direct amidation of a variety of cinnamic acids with a broad range of phenylethylamines promoted by tris-(2,2,2-trifluoroethyl) borate (B(OCH2CF3)3) in excellent yields and under mild reaction conditions. Then, the toxicological profile of the prepared compounds was studied through in silico computational methods, analyzing eight toxicity risks (hepatotoxicity, mutagenic, carcinogenicity, tumorigenic, immunotoxicity, cytotoxicity, irritant and reproductive effects) and two toxicity targets (AOFA and PGH1), while the acute toxicity toward zebrafish embryos (96 hpf-LC50, 50% lethal concentration) was also determined in the present study. From the results of the toxicity tests, we concluded that zanthoxylamide protoalkaloids can be classified as slightly toxic compounds, with a LC50 values around 217⯵M that gave an understanding of their toxicity on living organisms and their possible environmental impact.