RESUMO
Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases and the discovery of antioxidants is an attractive approach that can simultaneously tackle two or more therapeutic targets of the arachidonic acid cascade. We report that the simple structural variations on the 4-aryl-benzene-1,2-diol side-arm of the scaffold significantly influence the selectivity against 5-LOX vs 12- and 15-LOX. Derivatives 4 a-l were evaluated for their antioxidant activity, using the DPPH, and ferric ion reducing antioxidant power (FRAP) methods. Docking simulations proposed concrete binding of the catechol series to 5-LO. Selected active compound 4-(3,4-dihydroxyphenyl)dibenzofuran (4l) was also tested in different in vivo mouse models of inflammation. 4l (0.1 mg/kg; i.p.) impaired (I) bronchoconstriction in ovalbumin-sensitized mice challenged with acetylcholine, (II) exudate formation in carrageenan-induced paw edema, and (III) zymosan-induced leukocyte infiltration in air pouches. These results pave the way for investigating the therapeutic potential of 4-aryl-benzene-1,2-diol, as novel multitarget therapeutic drugs, able to regulate the complex inflammatory cascade mechanisms.
Assuntos
Benzeno , Inibidores de Lipoxigenase , Camundongos , Animais , Inibidores de Lipoxigenase/farmacologia , Benzeno/uso terapêutico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Carragenina , Inflamação/tratamento farmacológico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Catecóis/farmacologiaRESUMO
The anti-inflammatory effects of 3bromo5(ethoxymethyl)1,2benzenediol (BEMB) from Polysiphonia morrowii were evaluated in lipopolysaccharide (LPS)-induced RAW264.7 cells and zebrafish embryo. BEMB showed anti-inflammatory effects by inhibiting the production of nitric oxide (NO) and reactive oxygen species (ROS), and the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in the LPS-activated RAW264.7 cells and zebrafish embryo without cytotoxicity. Moreover, BEMB suppressed the protein and mRNA expression levels of nuclear factor (NF)-κB (p65 and inhibitor of NF-κB [IκB]-A) in RAW264.7 cells and zebrafish embryo, respectively. Collectively, the results of this study indicate that BEMB suppressed the production of pro-inflammatory mediators such as NO, iNOS, and COX-2 as well as their regulation in LPS-induced RAW264.7 cells and zebrafish embryos by inhibiting ROS production and NF-κB expression. Therefore, this study suggests that BEMB could be a potential anti-inflammatory agent for the treatment of inflammatory diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Benzeno/uso terapêutico , Proteínas de Peixes/metabolismo , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Benzeno/química , Modelos Animais de Doenças , Regulação para Baixo , Embrião não Mamífero , Proteínas de Peixes/genética , Humanos , Lipopolissacarídeos/imunologia , Camundongos , NF-kappa B/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Rodófitas/imunologia , Peixe-ZebraRESUMO
Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.
Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Desenho de Fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Neovascularização Retiniana/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Animais , Benzeno/química , Benzeno/farmacologia , Benzeno/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Camundongos , Solubilidade , Relação Estrutura-Atividade , Água/químicaRESUMO
A series of benzoates (or phenylacetates or cinnamates) - tacrine hybrids (7a-o) were designed, synthesized and evaluated as multi-potent anti-Alzheimer drug candidates. The screening results showed that most of them exhibited a significant ability to inhibit ChEs, certain selectivity for AChE over BuChE and strong potency inhibitory of self-induced ß-amyloid (Aß) aggregation. All IC50 values of biological activity were at the nanomolar range. Especially, compound 7c displayed the greatest ability to inhibit AChE with an IC50 value of 5.63 nM and the highest selectivity with ratio of BuChE/AChE value of 64.6. Moreover, it also exhibited a potent inhibitory of Aß aggregation with an IC50 value of 51.81 nM. A Lineweaver-Burk plot and molecular modeling study showed that compound 7c targeted both the CAS and PAS of ChEs. A structure-activity relationship analysis suggested that the electron density of aromatic ring which was linked with tacrine through acetyl group played a significant role in determining the inhibitory activity.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzeno/química , Benzeno/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Tacrina/química , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/química , Animais , Benzeno/síntese química , Benzeno/uso terapêutico , Butirilcolinesterase/metabolismo , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/uso terapêutico , Cinética , Modelos Moleculares , Fragmentos de Peptídeos/química , Multimerização Proteica , Estrutura Secundária de Proteína/efeitos dos fármacosRESUMO
A newer series of 1-(4-substitutedphenyl)-3-(4-((2,4-dioxothiazolidin-5-lidene)methyl)phenyl sulfonyl)urea/thiourea (4a-l) were synthesized for their anticonvulsant activity. The activity is attributed to its potential to restrain astrocytic Na+, 2HCl, and K+ co-transport similar to torasemide which has sulfonylurea in its structure. Torasemide having the similar action as the furosemide that obstructs kainic acid-induced electrical discharges observed from cortex and it has neuroprotective agents, for instance antagonizing the N-methyl-D-aspartate (NMDA) and non-NMDA receptors for evaluating antiepileptic activity. The structures of new derivatives were established by elemental analysis and spectroscopic techniques viz. FTIR, 1H NMR and LC-MS. The all twelve derivatives were assessed for anticonvulsant activity at three different doses at 30, 100 and 300 mg/kg body weight into maximal electroshock (MES) and subcutaneous pentylenetetrazole (sports) models. Compounds 4c and 4e were formed to be most active among all the derivatives for both the models of anticonvulsant activity. Beside these compounds 4g, 4i and 4k also possessed the prominent anticonvulsant activity devoid of any neurotoxicity. The sulfonylurea and sulfonylthiourea both were proved to be effective anticonvulsant pharmacophore. Other structure activity relationships were established by considering the aspect of substitution in the lead.
Assuntos
Anticonvulsivantes/síntese química , Benzeno/síntese química , Convulsões/tratamento farmacológico , Compostos de Sulfonilureia/síntese química , Tiazolidinedionas/síntese química , Animais , Anticonvulsivantes/uso terapêutico , Benzeno/uso terapêutico , Feminino , Masculino , Ratos , Ratos Wistar , Convulsões/patologia , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/uso terapêuticoRESUMO
The synthesis of a series of benzocoumarin keto-enamine schiff bases is reported. The novel compounds were evaluated for their antihyperlipidemic activity in the hyperlipidemic hamster model. The compound 11 at a dose of 10 mg/kg body weight significantly lowered the plasma triglyceride levels (TG) by 70%, total cholesterol (TC) by 47%, accompanied by an increase in HDL-C/TC ratio by 80% in hyperlipidemic hamsters to a greater degree than the reference drugs atorvastatin and lovastatin.
Assuntos
Cumarínicos/química , Cumarínicos/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/química , Hipolipemiantes/uso terapêutico , Animais , Benzeno/síntese química , Benzeno/química , Benzeno/uso terapêutico , Colesterol/sangue , HDL-Colesterol/sangue , Cumarínicos/síntese química , Cricetinae , Hiperlipidemias/sangue , Hipolipemiantes/síntese química , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/uso terapêutico , Triglicerídeos/sangueRESUMO
Chronic pain is inadequately managed with currently available classes of analgesic drugs. Recently, peptide antagonists of the α9α10 nicotinic acetylcholine receptor were shown to be analgesic. The present study was conducted to characterize a novel small molecule, non-peptide antagonist at nicotinic receptors. The tetrakis-quaternary ammonium compound ZZ-204G was evaluated for functional activity on cloned nicotinic receptors expressed in Xenopus oocytes. In-vivo efficacy was assessed in rat models of tonic inflammatory pain (formalin test), neuropathic pain (chronic constriction nerve injury), and thermal nociception (tail flick test). ZZ-204G was an antagonist at nicotinic receptors inhibiting the α9α10 subtype with an IC50 of 0.51 (0.35-0.72) nM. Antagonist activity at other nicotinic subtypes (α1ß1δε, α2ß2, α2ß4, α3ß2, α3ß4, α4ß2, α4ß4, α6/α3ß2ß3, α6/α3ß4 and α7) was 10-1000-fold lower than at the α9α10 subtype. In competition binding assays, the k(i) of ZZ-204G at γ-aminobutyric acid(A), serotonin(3), γ-aminobutyric acid(B), κ- and µ-opioid receptors was 1000- to >10,000-fold lower than at α9α10 nicotinic receptors. Parenteral administration of ZZ-204G dose-dependently decreased nociceptive behaviors (paw flinches) in the formalin test and mechanical hyperalgesia in the chronic constriction nerve injury model of neuropathic pain. ZZ-204G was not antinociceptive in the tail flick assay. Results from the rotarod assay indicated that lower doses of ZZ-204G that were analgesic did not alter motor function. In summary, ZZ-204G represents a prototype small molecule antagonist for α9α10 nicotinic receptors and provides a novel molecular scaffold for analgesic agents with the potential to treat chronic inflammatory or neuropathic pain.
Assuntos
Alcinos/química , Alcinos/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Benzeno/química , Benzeno/farmacologia , Antagonistas Nicotínicos/química , Antagonistas Nicotínicos/farmacologia , Compostos de Piridínio/química , Compostos de Piridínio/farmacologia , Receptores Nicotínicos/metabolismo , Alcinos/uso terapêutico , Analgésicos/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Benzeno/uso terapêutico , Constrição Patológica/complicações , Estudos de Viabilidade , Formaldeído/efeitos adversos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Atividade Motora/efeitos dos fármacos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Antagonistas Nicotínicos/uso terapêutico , Subunidades Proteicas/antagonistas & inibidores , Compostos de Piridínio/uso terapêutico , RatosRESUMO
A series of 37 dicationically substituted bis(phenoxymethyl)benzene bis(phenoxymethyl)naphthalene, and bis(benzyloxy)naphthalene analogues of pentamidine was prepared and evaluated for antiprotozoal activities and cytotoxicity in in vitro. 1,3-Bis(4-amidinophenoxymethyl)benzene (1) was the most active against Trypanosoma brucei rhodesiense (IC(50)=2.1 nM). 1,3-Bis[4-(N-isopropylamidino)phenoxymethyl]benzene (2) was most active against Plasmodium falciparum (IC(50)=3.6 nM) and displayed a selectivity index more than 50 times greater than that of pentamidine. Several other compounds displayed lower antiplasmodial IC(50) values and higher selectivity indices relative to pentamidine. 1,4-Bis(4-amidinophenoxymethyl)benzene (14) was the most active against Leishmania donovani (IC(50)=1.3 microM). Compound 2 displayed the greatest activity against T. b. rhodesiense in vivo, curing three of four infected mice dosed intraperitoneally at 5 mg/kg x 4 days.
Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Benzeno/química , Benzeno/farmacologia , Naftalenos/química , Naftalenos/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/uso terapêutico , Benzeno/síntese química , Benzeno/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Leishmania donovani/efeitos dos fármacos , Camundongos , Mioblastos/efeitos dos fármacos , Naftalenos/síntese química , Naftalenos/uso terapêutico , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológicoRESUMO
Benzene-induced acute myeloid leukemia (AML) is considered a secondary form of AML, based both in theory and on limited cohort observations. Its latency, cytogenetic aberrations, and clinical features are thought similar to, or identical with, AML resulting from the use of modern day cytotoxic agents for chemotherapy and immunotherapy. Although distinction between secondary AML and the far more common de novo AML is difficult to establish with certainty in any given case, latency from toxic therapeutic and environmental exposure and certain clinical and pathological features generally separate these two entities. AML is the only human neoplasm proven to be potentially caused by benzene, which actually is an obsolete form of chemotherapy. Despite many years of environmental regulation, alleged toxic exposure to this ubiquitous chemical has become an expanding area of litigation. A review of benzene-induced AML suggests that, in developed countries, this entity should no longer merit serious consideration among workers in the modern petrochemical industry and related fields.
Assuntos
Atitude do Pessoal de Saúde , Benzeno/efeitos adversos , Países Desenvolvidos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Leucemia Mieloide/etiologia , Doença Aguda , Benzeno/uso terapêutico , Aberrações Cromossômicas/induzido quimicamente , Inversão Cromossômica , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Humanos , Leucemia Mieloide/induzido quimicamente , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/epidemiologia , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Petróleo/efeitos adversos , Translocação GenéticaRESUMO
A series of 1-substituted 2-[(4-aryl)-methyl]-4,5-methylenedioxybenzene derivatives (13-25), structurally related to model compound 5 (2-[(4-aminophenyl)-(4-methylsemicarbazono)-methyl]-4,5-methylenedioxyphenylacetic acid methyl ester), were synthesized and tested as anticonvulsant agents in DBA/2 mice against sound-induced seizures. The new compounds possess anticonvulsant properties lower than those of prototype 5 but, in some instances, comparable to that of GYKI 52466, a well-known noncompetitive AMPA receptor antagonist.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Benzeno/síntese química , Benzeno/uso terapêutico , Dioxóis/síntese química , Dioxóis/uso terapêutico , Desenho de Fármacos , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Benzeno/química , Benzeno/farmacologia , Células Cultivadas , Dioxóis/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos DBA , Estrutura Molecular , Neurônios/efeitos dos fármacos , Convulsões/fisiopatologiaRESUMO
In our hands, benzene proved to be a valuable drug for the treatment of chronic leukaemia. When correctly administered it did not provoke the harmful side effects reported by several authors in accord with the first description of von Koranyi in 1912. In many cases benzene induced complete remission persisting for over 18 months. This compound was found to be active even in patients who had not responded to busulphan, although the contrary was also observed for certain subjects. In accordance with previous investigations carried out in the rabbit, concomitant administration of cysteine-HCl blocked the leucopenic effect of benzene in 5 of 6 cases whereas ethionine, an antimetabolite of methionine and/or cysteine, appeared to enhance its therapeutic action. It is worthy of note that in at least one case ethionine administered alone led to complete clinical and haematological remission of the leukaemic state.