RESUMO
Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64⯵M) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16⯵M). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200⯵M. The phenolic acetate derivative of natural dehydrodieugenol B was effective against both parasite forms and eliminated 100% of amastigotes inside macrophages. This compound caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular reactive oxygen species being observed. Fluorescence assays demonstrated that this derivative affected neither the permeability nor the electric potential of the parasitic plasma membrane, an effect also corroborated by scanning electron microscopy studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivatives represents a promising starting point for future Chagas disease drug discovery studies.
Assuntos
Anisóis/farmacologia , Lignanas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Anisóis/síntese química , Anisóis/química , Anisóis/toxicidade , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Humanos , Lignanas/síntese química , Lignanas/química , Lignanas/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/toxicidade , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/metabolismoRESUMO
This study investigated the in vitro and in silico biological properties of the methyl chavicol (MC) and its analogue 2-[(4-methoxyphenyl)methyl]oxirane (MPMO), emphasizing the antioxidant and antilipase effects. MPMO was synthesized from MC that reacted with meta-chloroperbenzoic acid and, after separation and purification, was identified by 1H and 13C NMR and GC-MS. The antioxidant activity was investigated by DPPH, cooxidation ß-carotene/linoleic acid, and thiobarbituric acid assays. With the use of colorimetric determination, the antilipase effect on the pancreatic lipase was tested, while the molecular interaction profiles were evaluated by docking molecular study. MC (IC50 = 312.50 ± 2.28 µg/mL) and MPMO (IC50 = 8.29 ± 0.80 µg/mL) inhibited the DPPH free radical. The inhibition of lipid peroxidation (%) was 73.08 ± 4.79 and 36.16 ± 4.11 to MC and MPMO, respectively. The malonaldehyde content was significantly reduced in the presence of MC and MPMO. MC and MPMO inhibited the pancreatic lipase in 58.12 and 26.93%, respectively. MC and MPMO (-6.1 kcal·mol-1) produced a binding affinity value lower than did diundecylphosphatidylcholine (-5.6 kcal·mol-1). These findings show that MC and MPMO present antioxidant and antilipase activities, which may be promising molecular targets for the treatment of diseases associated with oxidative damage and lipid metabolism.
Assuntos
Anisóis/química , Compostos de Epóxi/química , Lipase/antagonistas & inibidores , Derivados de Alilbenzenos , Anisóis/síntese química , Anisóis/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos de Epóxi/síntese química , Compostos de Epóxi/farmacologia , Cinética , Lipase/química , Simulação de Acoplamento MolecularRESUMO
The synthesis of a series of 5-carba-pterocarpens derivatives involving the cyclization of α-aryl-α-tetralones is described. Several compounds demonstrated potent activity and selectivity in vitro against HCV replicon reporter cells. The best profile in Huh7/Rep-Feo1b replicon reporter cells was observed with 2h (EC50 = 5.5 µM/SI = 20), while 2e was the most active in Huh7.5-FGR-JC1-Rluc2A replicon reporter cells (EC50 = 1.5 µM/SI = 70). Hydroxy groups at A- and D-rings are essential for anti-HCV activity, and substitutions in the A-ring at positions 3 and 4 resulted in enhanced activity of the compounds.
Assuntos
Antivirais/química , Antivirais/farmacologia , Guanidinas/química , Guanidinas/farmacologia , Hepacivirus/efeitos dos fármacos , Anisóis/síntese química , Anisóis/química , Anisóis/farmacologia , Antivirais/síntese química , Catálise , Linhagem Celular , Guanidinas/síntese química , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Paládio/química , Replicon/efeitos dos fármacos , Tetralonas/síntese química , Tetralonas/química , Tetralonas/farmacologiaRESUMO
Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg.
Assuntos
Anisóis/farmacologia , Antineoplásicos/farmacologia , Hidrazonas/farmacologia , Microtúbulos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Animais , Anisóis/síntese química , Anisóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Microtúbulos/metabolismo , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Células Tumorais CultivadasRESUMO
The asymmetric synthesis of 8,4'-oxyneolignans (-)-virolin, (-)-surinamensin and a number of analogues has been achieved. A divergent synthesis was used, with all compounds being elaborated from a single chiral aldehyde derived from ethyl lactate. In the 15 compounds that were tested, the level of substitution on the A-ring was found to directly influence the activity against Leishmania donovani whilst the activity against Plasmodium falciparum was influenced by numerous substitution and stereochemical factors.
Assuntos
Anisóis/farmacologia , Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Lignanas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Anisóis/síntese química , Anisóis/química , Antiprotozoários/síntese química , Antiprotozoários/química , Lignanas/síntese química , Lignanas/química , Conformação Molecular , Testes de Sensibilidade ParasitáriaRESUMO
This paper describes a new method for the preparation of 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one 1 and its derivatives 2-5. This set of synthetic compounds exhibited high antitumoral activities regarding in vitro screening against several human tumor cell lines as lung carcinoma NCI-460, melanoma UACC-62, breast MCF-7, colon HT-29, renal 786-O, ovarian OVCAR-03 and ovarian expressing the resistance phenotype for adriamycin NCI-ADR/RES, prostate PC-3, and leukemia K-562. Compounds were also tested against murine tumor cell line B16F10 melanoma and lymphocytic leukemia L1210 as well as to their effect toward normal macrophages. Specific activity against colon cancer cells HT-29 was observed for all tested compounds and suggests further studies with models of colon cancer. Compounds 1, 2, and 4 showed significant cytotoxic activity with IC(50) values 2.3 microM for all human cancer cell lines. Intraperitoneal acute administration of compound 1 and 2 showed very low toxicity rate.
Assuntos
Anisóis/farmacologia , Antineoplásicos/farmacologia , Cetonas/farmacologia , Animais , Anisóis/síntese química , Anisóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cetonas/síntese química , Cetonas/química , Camundongos , Relação Estrutura-AtividadeRESUMO
A series of alpha-asarone-based analogues was designed by conducting docking experiments with published crystal structures of human HMG-CoA reductase. Indeed, synthesis and evaluation of this series showed a highly hypocholesterolemic in vivo activity in a murine model, as predicted by previous docking studies. In agreement with this model, the polar groups attached to the benzene ring could play a key role in the enzyme binding and probably also in its biological activity, mimicking the HMG-moiety of the natural substrate. The hypolipidemic action mechanism of these compounds was investigated by developing a simple, efficient, and novel model for determining HMG-CoA reductase inhibition. The partial purification of the enzyme from Schizosaccharomyces pombe allowed for testing of alpha-asarone- and fibrate-based analogues, resulting in positive and significant inhibitory activity.
Assuntos
Anisóis/química , Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Schizosaccharomyces/efeitos dos fármacos , Derivados de Alilbenzenos , Animais , Anisóis/síntese química , Anisóis/uso terapêutico , Sítios de Ligação , Simulação por Computador , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICRRESUMO
This work describes the synthesis and anti-inflammatory properties of a pentadienone derivative, HB2. The treatment with HB2 produced anti-oedematogenic, anti-inflammatory and antinociception without change locomotors performance. Finally, HB2 reduced the nitric oxide and prostaglandin E(2) production on RAW 264.7 cells stimulated with LPS without changing the cell viability. Taken together, our results show, for the first time, that HB2 can modulate the inflammatory response when administered to mice.
Assuntos
Analgésicos/uso terapêutico , Anisóis/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Cetonas/uso terapêutico , Dor/tratamento farmacológico , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Anisóis/síntese química , Anisóis/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dinoprostona/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inflamação/induzido quimicamente , Cetonas/síntese química , Cetonas/farmacologia , Masculino , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Dor/induzido quimicamenteRESUMO
Some derivatives of trans-anethole [1-methoxy-4-(1-propenyl)-benzene] (1) were synthesized, by introducing hydroxyl groups in the double bond of the propenyl moiety. Two types of reactions were performed: (i) oxymercuration/demercuration that formed two products, the mono-hydroxyl derivative, 1-hydroxy-1-(4-methoxyphenyl)-propane (2) and in lesser extent the dihydroxyl derivative, 1,2-dihydroxy-1-(4-methoxyphenyl)-propane (3) and (ii) epoxidation with m-chloroperbenzoic acid that also led to the formation of two products, the dihydroxyl derivative (3) and the correspondent m-chloro-benzoic acid mono-ester, 1-hydroxy-1(4-methoxyphenyl)-2-m-chlorobenzoyl-propane (4). The structures of these compounds were confirmed mainly by mass, IR, 1H and 13C NMR spectral data. The activity of anethole and hydroxylated derivatives was evaluated using antioxidant, anti-inflammatory and gastroprotector tests. Compounds (2) and (3) were more active antioxidant agents than (1) and (4). In the anti-inflammatory assay, anethole showed lower activity than hydroxylated derivatives. Anethole and in lesser extent its derivatives 2 and 4 showed significant gastroprotector activity. All tested compounds do not alter significantly the total number of white blood cells.
Assuntos
Anisóis/síntese química , Anisóis/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Úlcera Gástrica/prevenção & controle , Derivados de Alilbenzenos , Animais , Anisóis/química , Anti-Inflamatórios/química , Antioxidantes/química , Contagem de Leucócitos , Masculino , Camundongos , Úlcera Gástrica/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
A series of homologues of alpha-asarone (1), containing variable size and functionality on the side chain attached to the aromatic ring, has been subjected to a study of structure-activity relationship. For most of the prepared derivatives, either with a carbonyl (8a-8e), a hydroxy group (9a-9e), or with a conjugated double bond (10a-10d), significant effects on serum lipoprotein cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were displayed. The results showed an enhancement of the hypocholesterolemic activity as the length of the chain is decreased. Theoretical conformational and electrostatic potential analyses of I and olefins 10 suggest unfavorable steric interactions in the bulky superior side-chain homologues as the deactivating biological effect.