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1.
Chem Rec ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33570242

RESUMO

The triazole heterocycle is a privileged scaffold in medicinal chemistry, since its structure is present in a large number of biologically active molecules, including several drugs currently in the market. Due to their vast applications, a wide variety of methods are described for their preparation, such as the 1,3-dipolar cycloaddition and processes involving diazo compounds and diazo transfer reactions. Considering the significant number of contributions from our research group to this chemistry in recent decades, in this account we discuss both the development of new methods for the synthesis of 1,2,3-triazoles and the preparation of new triazole-functionalized biologically active molecules using classical approaches.

2.
Bioorg Chem ; : 104488, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33261844

RESUMO

In December 2019, a new variant of SARS-CoV emerged, the so-called acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes the new coronavirus disease (COVID-19) and has been plaguing the world owing to its unprecedented spread efficiency, which has resulted in a huge death toll. In this sense, the repositioning of approved drugs is the fastest way to an effective response to a pandemic outbreak of this scale. Considering these facts, in this review we provide a comprehensive and critical discussion on the chemical aspects surrounding the drugs currently being studied as candidates for COVID-19 therapy. We intend to provide the general chemical community with an overview on the synthetic/biosynthetic pathways related to such molecules, as well as their mechanisms of action against the evaluated viruses and some insights on the pharmacological interactions involved in each case. Overall, the review aims to present the chemical aspects of the main bioactive molecules being considered to be repositioned for effective treatment of COVID-19 in all phases, from the mildest to the most severe.

3.
Eur J Med Chem ; 194: 112255, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32244098

RESUMO

Human immunodeficiency virus type 1 (HIV-1) is a public health problem that affects over 38 million people worldwide. Although there are highly active antiretroviral therapies, emergence of antiviral resistant strains is a problem which leads to almost a million death annually. Thus, the development of new drugs is necessary. The viral enzyme reverse transcriptase (RT) represents a validated therapeutic target. Because the oxoquinolinic scaffold has substantial biological activities, including antiretroviral, a new series of 4-oxoquinoline ribonucleoside derivatives obtained by molecular hybridization were studied here. All synthesized compounds were tested against human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), and 9a and 9d displayed the highest antiviral activities, with IC50 values of 1.4 and 1.6 µM, respectively. These compounds were less cytotoxic than AZT and showed CC50 values of 1486 and 1394 µM, respectively. Molecular docking studies showed that the most active compounds bound to the allosteric site of the enzyme, suggesting a low susceptibility to the development of antiviral resistance. In silico pharmacokinetic and toxicological evaluations reinforced the potential of the active compounds as anti-HIV candidates for further exploration. Overall, this work showed that compounds 9a and 9d are promising scaffold for future anti-HIV-1 RT drug design.


Assuntos
4-Quinolonas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Ribonucleosídeos/farmacologia , 4-Quinolonas/síntese química , 4-Quinolonas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Transcriptase Reversa do HIV/metabolismo , HIV-1/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonucleosídeos/síntese química , Ribonucleosídeos/química , Relação Estrutura-Atividade
4.
Curr Top Med Chem ; 20(3): 244-255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995008

RESUMO

4-Oxoquinoline derivatives constitute an important family of biologically important substances, associated with different bioactivities, which can be synthesized by different synthetic methods, allowing the design and preparation of libraries of substances with specific structural variations capable of modulating their pharmacological action. Over the last years, these substances have been extensively explored by the scientific community in efforts to develop new biologically active agents, with greater efficiency for the treatment of a variety of diseases. Viral infections have been one of the targets of these studies, although to a lesser extent than other diseases such as cancer and bacterial infections. Nevertheless, the literature provides examples that corroborate with the fact that these substances may act on different pharmacological targets in different viral pathogens. This review provides a compilation of some of the major studies published in recent years showing the discovery and/or development of new antiviral oxoquinoline agents, highlighting, whenever possible, their mechanisms of action.


Assuntos
4-Quinolonas/farmacologia , Antivirais/farmacologia , Viroses/tratamento farmacológico , Vírus/efeitos dos fármacos , 4-Quinolonas/síntese química , 4-Quinolonas/química , Antivirais/síntese química , Antivirais/química , Desenvolvimento de Medicamentos , Humanos , Estrutura Molecular
5.
Beilstein J Org Chem ; 15: 388-400, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873225

RESUMO

4-Oxoquinolines are a class of organic substances of great importance in medicinal chemistry, due to their biological and synthetic versatility. N-1-Alkylated-4-oxoquinoline derivatives have been associated with different pharmacological activities such as antibacterial and antiviral. The presence of a carboxamide unit connected to carbon C-3 of the 4-oxoquinoline core has been associated with various biological activities. Experimentally, the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide occurs at the nitrogen of the oxoquinoline group, in a regiosselective way. In this work, we employed DFT methods to investigate the regiosselective ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, evaluating its acid/base behavior and possible reaction paths.

6.
Curr Top Med Chem ; 18(17): 1454-1464, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30277154

RESUMO

BACKGROUND: Leishmaniasis is a neglected public health problem caused by several protozoanspecies of the genus Leishmania. The therapeutic arsenal for treating leishmaniasis is quite limited, raising concerns about the occurrence of resistant strains. Furthermore, most of these drugs were developed more than 70 years ago and suffer from poor efficacy and safety and are not well adapted to the needs of patients. Therefore, research on novel natural or synthetic compounds with antiparasitic activity is urgently needed. In this paper, we evaluated the effect and the mechanism of action of naphthotriazolyl-4-oxoquinolines on promastigotes and intracellular amastigotes of Leishmania amazonensis. MATERIALS AND METHODS: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields via the [3+2] cycloaddition reaction between 1,4-naphtoquinone and azido-4- oxoquinoline derivatives. HMPA at 100°C was established as the best solvent and temperature condition for this reaction. The structures of the compounds were confirmed by spectral analyses (infrared spectroscopy, one- and two-dimensional ¹H and ¹³C NMR spectroscopy, and high-resolution mass spectrometry). The compounds exhibited promising activities with IC50 values ranging from 0.7 to 2.0 µM against intracellular amastigotes of Leishmania amazonensis. The most selective compound was the Npentyl- substituted derivative, which showed a Selectivity Index (SI) of 8.6, making it less toxic than pentamidine (SI 4.5). RESULTS: Our results demonstrated that all compounds, except the N-propyl-substituted derivative, induce ROS production by parasites early in the culture. As a proof of concept, we demonstrated that the most selective compound was able to interfere with sterol biosynthesis in L. amazonensis. CONCLUSION: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields. These conjugates have potent in vitro antileishmanial activity involving at least two different mechanisms of action, making them promising lead compounds for the development of new therapeutic alternatives for leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Desenho de Fármacos , Leishmania/efeitos dos fármacos , Quinolinas/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
7.
Bioorg Med Chem ; 23(24): 7777-84, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26643220

RESUMO

We described the synthesis of a new congener series of 1,2,3-triazolyl-4-oxoquinolines and evaluated their ability to inhibit oseltamivir (OST)-resistant influenza strains. Oxoquinoline derivative 1i was the most potent compound within this series, inhibiting 94% of wild-type (WT) influenza neuraminidase (NA) activity. Compound 1i inhibited influenza virus replication with an EC50 of 0.2µM with less cytotoxicity than OST, and also inhibited different OST-resistant NAs. These results suggest that 1,2,3-triazolyl-4-oxoquinolines represent promising lead molecules for further anti-influenza drug design.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Oseltamivir/farmacologia , Quinolonas/farmacologia , Triazóis/farmacologia , Antivirais/química , Desenho de Fármacos , Farmacorresistência Viral , Humanos , Vírus da Influenza A/enzimologia , Vírus da Influenza B/enzimologia , Influenza Humana/virologia , Simulação de Acoplamento Molecular , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Quinolonas/química , Triazóis/química
8.
Eur J Med Chem ; 84: 708-17, 2014 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-25064348

RESUMO

Leukemia is the most common blood cancer, and its development starts at diverse points, leading to distinct subtypes that respond differently to therapy. This heterogeneity is rarely taken into account in therapies, so it is still essential to look for new specific drugs for leukemia subtypes or even for therapy-resistant cases. Naphthoquinones (NQ) are considered privileged structures in medicinal chemistry due to their plethora of biological activities, including antimicrobial and anticancer effects. Nitrogen-containing heterocycles such as 1,2,3-1H-triazoles have been identified as general scaffolds for generating glycosidase inhibitors. In the present study, the NQ and 1,2,3-1H-triazole cores have been combined to chemically synthesize 18 new 1,2-furanonaphthoquinones tethered to 1,2,3-1H-triazoles (1,2-FNQT). Their cytotoxicities were evaluated against four different leukemia cell lines, including MOLT-4 and CEM (lymphoid cell lines) and K562 and KG1 (myeloid cell lines), as well as normal human peripheral blood mononucleated cells (PBMCs). The new 1,2-FNQT series showed high cytotoxic potential against all leukemia cell lines tested, and some compounds (12o and 12p) showed even better results than the classical therapeutic compounds such as doxorubicin or cisplatin. Others compounds, such as 12b, are promising because of their high selectivity against lymphoblastic leukemia and their low activity against normal hematopoietic cells. The cells of lymphoid origin (MOLT and CEM) were generally more sensitive than the myeloid cell lines to this series of compounds, and most of the compounds that showed the highest cytotoxicity were similarly active against both cell lines.


Assuntos
Furanos/síntese química , Furanos/farmacologia , Leucemia Linfoide/patologia , Leucemia Mieloide/patologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Triazóis/química , Triazóis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Humanos , Células K562 , Leucemia Linfoide/tratamento farmacológico , Leucemia Mieloide/tratamento farmacológico , Estrutura Molecular , Naftoquinonas/química , Relação Estrutura-Atividade
9.
Curr Microbiol ; 69(3): 357-64, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24807624

RESUMO

Bacterial multiresistance is a health problem worldwide that demands new antimicrobials for treating bacterial-related infections. In this study, we evaluated the antimicrobial activity and the theoretical toxicology profile of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazide derivatives against gram-positive and gram-negative bacteria clinical strains. On that purpose we determined the minimum inhibitory (MIC) and bactericidal (MBC) concentrations, the in vitro cytotoxicity, and in silico risk profiles, also comparing with antimicrobial agents of clinical use. Among the 16 derivatives analyzed, four nitrofurans (N-H-FUR-NO(2), N-Br-FUR-NO(2), N-F-FUR-NO(2), N-Cl-FUR-NO(2)) showed promising MIC and MBC values (MIC = MBC = 1-16 µg/mL). The experimental data revealed the potential of these derivatives, which were comparable to the current antimicrobials with similar bactericidal and bacteriostatic profiles. Therefore, these molecules may be feasible options to be explored for treating infections caused by multiresistant strains. Our in vitro and in silico toxicity reinforced these results as these derivatives presented low cytotoxicity against human macrophages and low theoretical risk profile for irritant and reproductive effects compared to the current antimicrobials (e.g., vancomycin and ciprofloxacin). The molecular modeling analysis also revealed positive values for their theoretical druglikeness and drugscore. The presence of a 5-nitro-2-furfur-2-yl group seems to be essential for the antimicrobial activity, which pointed these acylhydrazone derivatives as promising for designing more potent and safer compounds.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hidrazonas/farmacologia , Infecções Bacterianas/microbiologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/isolamento & purificação , Humanos , Macrófagos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos
10.
Molecules ; 19(5): 6651-70, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24858098

RESUMO

As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10-18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active against a normal cell line, in contrast to doxorubicin, a standard chemotherapeutic drug in clinical use. Interestingly, no hemolytical activity was observed when the toxicity of 16b and 17b was tested against blood cells. The in silico and in vitro mechanistic evaluation indicated the potential of 16b as a lead for the development of novel anticancer agents against gastric cancer cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Técnicas de Química Sintética , Simulação por Computador , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Eritrócitos/efeitos dos fármacos , Hemolíticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolonas/química , Neoplasias Gástricas/tratamento farmacológico
11.
Bioorg Med Chem Lett ; 23(16): 4597-601, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23850203

RESUMO

The 1,4-dihydro-4-oxoquinoline ribonucleoside, Neq135, is the first low micromolar trypanosomatidae inhibitor to show good ligand efficiency (0.28 kcal mol(-1)atom(-1)) and good ligand lipophilicity efficiency (0.37 kcal mol(-1)atom(-1)) when acting against Trypanosoma cruzi glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH). This and other six ribonucleosides were synthesized using our in-house technology, and assayed against the GAPDH NAD(+) site using isothermal titration calorimetry (ITC). Compound Neq135 had acceptable in vitro cytotoxicity, inhibited TcGAPDH with a Ki(app) value of 16 µM and killed the trypomastigote form of Trypanosoma cruzi Tulahuen strain with a concentration similar to that displayed by the control drug benznidazole. Neq135 is tenfold lower kinetic affinity against hGAPDH and does not kill Balb-c fibroblast nor spleen mouse cells. These results emphasize the possibility of integrating ligand- and target-based designs to uncover potent and selective TcGAPDH inhibitors that expands the opportunity for further medicinal chemistry endeavor towards NAD(+) TcGAPDH site.


Assuntos
Desenho de Fármacos , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/antagonistas & inibidores , Ribonucleosídeos/síntese química , Ribonucleosídeos/farmacologia , Tripanossomicidas , Trypanosoma cruzi/efeitos dos fármacos , 4-Quinolonas/síntese química , 4-Quinolonas/química , 4-Quinolonas/farmacologia , Animais , Células 3T3 BALB , Fibroblastos/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Nitroimidazóis/química , Nitroimidazóis/farmacologia , Ribonucleosídeos/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/farmacologia
12.
Biomed Res Int ; 2013: 294289, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23710441

RESUMO

Snake venoms are complex mixtures of proteins of both enzymes and nonenzymes, which are responsible for producing several biological effects. Human envenomation by snake bites particularly those of the viperid family induces a complex pathophysiological picture characterized by spectacular changes in hemostasis and frequently hemorrhage is also seen. The present work reports the ability of six of a series of 1,2,3-triazole derivatives to inhibit some pharmacological effects caused by the venoms of Bothrops jararaca and Lachesis muta. In vitro assays showed that these compounds were impaired in a concentration-dependent manner, the fibrinogen or plasma clotting, hemolysis, and proteolysis produced by both venoms. Moreover, these compounds inhibited biological effects in vivo as well. Mice treated with these compounds were fully protected from hemorrhagic lesions caused by such venoms. But, only the B. jararaca edema-inducing activity was neutralized by the triazoles. So the inhibitory effect of triazoles derivatives against some in vitro and in vivo biological assays of snake venoms points to promising aspects that may indicate them as molecular models to improve the production of effective antivenom or to complement antivenom neutralization, especially the local pathological effects, which are partially neutralized by antivenoms.


Assuntos
Bothrops , Venenos de Serpentes/antagonistas & inibidores , Triazóis/administração & dosagem , Viperidae , Animais , Antivenenos/administração & dosagem , Antivenenos/química , Coagulação Sanguínea/efeitos dos fármacos , Humanos , Camundongos , Mordeduras de Serpentes/tratamento farmacológico , Triazóis/química
13.
Bioorg Med Chem Lett ; 22(15): 5055-8, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22763201

RESUMO

The emergence of a multidrug-resistant HIV-1 strain and the toxicity of anti-HIV-1 compounds approved for clinical use are the most significant problems facing antiretroviral therapies. Therefore, it is crucial to find new agents to overcome these issues. In this study, we synthesized a series of new oxoquinoline acyclonucleoside phosphonate analogues (ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a-3k), which contained different substituents at the C6 or C7 positions of the oxoquinoline nucleus and an N1-bonded phosphonate group. We subsequently investigated these compounds' in vitro inhibitory effects against HIV-1-infected peripheral blood mononuclear cells (PBMCs). The most active compounds were the fluoro-substituted derivatives 3f and 3g, which presented excellent EC(50) values of 0.4±0.2 µM (3f) and 0.2±0.005 µM (3g) and selectivity index values (SI) of 6240 and 14675, respectively.


Assuntos
Fármacos Anti-HIV/química , HIV-1/efeitos dos fármacos , Nucleosídeos/química , Ácidos Fosforosos/química , Quinolonas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/toxicidade , Humanos , Ácidos Fosforosos/síntese química , Ácidos Fosforosos/toxicidade , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
14.
Eur J Med Chem ; 46(4): 1448-52, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21334795

RESUMO

A series of 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones (3a-g) have been synthesized and evaluated for their in vitro antiproliferative activities against four human cancer cell lines: MDA-MB-435 (breast), HL-60 (leukemia), HCT-8 (colon) and SF-295 (central nervous system). The results showed that the compounds 3b (2-(benzo[d]thiazol-2-yl)-8-methyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) and 3c (2-(benzo[d]thiazol-2-yl)-8-bromo-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) exhibited good cytotoxicity for three cell lines with IC(50) values lower than 5 µg/mL. Analysis of theoretical toxicity risks have shown medium tumorigenic and irritant risks related to 3b and 3c in contrast to doxorubicin, the positive control.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Quinolinas/química
15.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 10): o2476-7, 2009 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-21577928

RESUMO

In the title compound, C(18)H(16)N(4)O(2), the plane defined by the ethyl C atoms and the attached N atom is inclined to the adjacent pyridine ring at an angle of 67.87 (16)°. The dihedral angle between the two heterocyclic rings is 3.33 (16)°. The mol-ecular conformation is stabilized by an intra-molecular N-H⋯O hydrogen bond and the crystal structure by inter-molecular C-H⋯O hydrogen bonds, forming a one-dimensional structure.

16.
Eur J Med Chem ; 44(1): 373-83, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18486994

RESUMO

This paper describes the synthesis of several 1-benzyl-1H-1,2,3-triazoles attached to different carbohydrate templates and their in vitro inhibitory profile against HIV-1 reverse transcriptase. In addition a theoretical comparison of the most active compounds with other classical antivirals was also performed. Our results showed 2a, 2d and 2g as the most active compounds that inhibited the HIV-1 reverse transcriptase catalytic activity with cytotoxicity lower than AZT and SI higher than DDC and DDI. The overall theoretical analysis of the molecular descriptors of 2a, 2d and 2g revealed that their HOMO energy is similar to other antivirals in use (AZT, DDC, DDI and 3TC) and together with the volume may contribute for the biological profile as they may allow new interactions with the target. In fact the 1,2,3-triazole compounds presented more lipophilicity and higher molecular volume and weight than the antivirals studied, which suggested that these features might not only contribute for new interactions with the HIV-RT but also influence the specificity and consequently the low cytoxicity profile of these compounds. Thus these data point them as promising leading compounds for generating new anti-HIV-RT compounds.


Assuntos
Fármacos Anti-HIV/síntese química , Carboidratos/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/síntese química , Triazóis/síntese química , Fármacos Anti-HIV/farmacologia , Carboidratos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologia
17.
Magn Reson Chem ; 46(12): 1158-62, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18524015

RESUMO

Six new nor-beta-lapachones have been synthesized from reaction of 3-bromo-nor-beta-lapachone with arylamines. These derivatives have potent anticancer properties against several cell lines. Here, we report complete unambiguous assignments of (1)H and (13)C chemical shifts of the new compounds. The assignments were made using a combination of one- and two-dimensional NMR techniques ((1)H, (13)C, (1)H-(1)H COSY, (1)H-(13)C HSQC, and (1)H-(13)C HMBC).


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Quinonas/química , Aminas/química , Antineoplásicos/química , Isótopos de Carbono , Furanos/química , Naftalenos/química
18.
Bioorg Med Chem ; 16(9): 5030-8, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18378461

RESUMO

New naphthoquinone derivatives were synthesized and assayed against bloodstream trypomastigote forms of Trypanosoma cruzi, the etiological agent of Chagas' disease. The compounds were rationalized based on hybrid drugs and appear as important compounds against this parasite. From nor-lapachol were prepared five substituted ortho-naphthofuranquinones, a non-substituted para-naphthofuranquinone, a new oxyrane and an azide and from alpha-lapachone a new non-substituted para-naphthofuranquinone. Other five substituted ortho-naphthofuranquinones recently designed as cytotoxic, were also evaluated. The most active compounds were the ortho naphthofuranquinones 3-(4-methoxyphenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione and 3-(3-nitrophenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione with trypanocidal activity higher than that of benznidazole, the standard drug. The compounds were rationalized based on hybrid drugs and appear as important compounds against T. cruzi. The trypanocidal activity of these substances endowed with redox properties representing a good starting point for a medicinal chemistry program aiming the chemotherapy of Chagas' disease.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/química , Testes de Sensibilidade Parasitária , Estereoisomerismo
19.
Eur J Med Chem ; 43(8): 1774-80, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18045742

RESUMO

[1,2,3]-Triazole derivatives of nor-beta-lapachone were synthesized and assayed against the infective bloodstream trypomastigote form of Trypanosoma cruzi, the etiological agent of Chagas disease. All the derivatives were more active than the original quinones, with IC(50)/1 day values in the range of 17 to 359 microM, the apolar phenyl substituted triazole 6 being the most active compound. These triazole derivatives of nor-beta-lapachone emerge as interesting new lead compounds in drug development for Chagas disease.


Assuntos
Naftoquinonas/química , Triazóis/síntese química , Triazóis/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Azidas/química , Cátions/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/química , Tripanossomicidas/química
20.
Bioorg Med Chem ; 15(22): 7035-41, 2007 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17827021

RESUMO

Several arylamino derivatives of nor-beta-lapachone were synthesized in moderate to high yields and found to show very potent cytotoxicity against six neoplastic cancer cells: SF-295 (central nervous system), HCT-8 (colon), MDAMB-435 (breast), HL-60 (leukaemia), PC-3 (prostate), and B-16 (murine melanoma), with IC(50) below 1 microg/mL. Their cytotoxicities were compared to doxorubicin and with their synthetic precursors, beta-lapachone and nor-beta-lapachone. The activity against a normal murine fibroblast L-929 showed that some of the compounds were selective against cancer cells. The absence of hemolytic activity (EC(50)>200 microg/mL), performed with erythrocyte suspensions, suggests that the cytotoxicity of the compounds was not related to membrane damage of mouse erythrocytes. For comparison purposes, one isomeric compound based on nor-alpha-lapachone was also synthesized and showed lower activity than the related ortho-derivative. The modified arylamino quinones appear as interesting new lead compounds in anti-cancer drug development.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Naftoquinonas/química , Estereoisomerismo , Relação Estrutura-Atividade
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