RESUMO
The present study describes the synthesis and pharmacological evaluation of 2-substituted-6-(4-acylaminophenyl)-4,5-dihydropyridazin-3(2H)-ones as potent inodilating agents. The synthesis of target compounds 2-4 and 7-11 was achieved by Friedel-Crafts acylation of appropriate anilide derivative with succinic anhydride or methylsuccinic anhydride and subsequent cyclization of intermediary keto acids with various hydrazine derivatives. The newly synthesized pyridazinone derivatives were evaluated for cardiotonic activity using isolated rat atria and for vasorelaxant activity using descending thoracic aortic rings of Wistar rats precontracted with phenylephrine (10-6 mol L-1). 6-(4-Methanesulfonamidophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one (7) exhibited significant inodilatory properties and showed vasorelaxant activity in a nanomolar range (IC50 = 0.08 +/- 0.01 mumol L-1).
Assuntos
Piridazinas/síntese química , Vasodilatadores/síntese química , Animais , Feminino , Masculino , Piridazinas/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Vasodilatadores/farmacologiaRESUMO
The learning and memory deficits have been recognized as severe and consistent neurological disorders associated with numerous neurodegenerative states. Research in this area has gained momentum only in the recent past after the biochemical and physiological basis of these processes have been understood. A considerable alteration in the neurotransmission is a consistent finding in cognitive disorders. Therefore, many therapeutic strategies to augment the concentration of neurotransmitters in brain such as cholinergic agents, biogenic amines and neuropeptides etc. have been evaluated in cognitive deficits. CNS modulators are the type of antiamnesics that act via modulation of the neurological processes underlying memory storage. These include psychostimulants, excitatory amino acids and most important of all "nootropics". Nootropics are a heterogeneous group of compounds of diverse chemical composition and biological function that allegedly facilitate learning and memory or overcome natural or induced cognitive impairments. The literature survey incorporated in this article hallmarks the success achieved in the design and development of potential nootropic agents. Additionally, this review is an attempt towards discussing various approaches available to enhance memory, along with the classification of the known memory enhancers, authors research work towards various structural modifications carried out and the biological screening.
Assuntos
Nootrópicos/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacosRESUMO
A new series of N-substituted imide derivatives have been synthesized by treating phthalic anhydride, naphthalic anhydride and their substituted derivatives with 2-hydrazino-1-imidazoline hydrobromide, various para-substituted aryl amines, aminoglutethimide and 2,4-dinitrophenyl hydrazine. Compounds 9, 10, 12, 18, 19, 23, 24 and 34-36 have been selected and screened for antineoplastic activity by National Cancer Institute, Bethesda, USA. Some newer aminoglutethimide derivatives 37-39 have also been prepared in order to study the effect of N-substitution on its pharmacological profile for the treatment of carcinoma. These compounds (37-39) have exhibited weak inhibition of human placental aromatase as compared to aminoglutethimide.
Assuntos
Antineoplásicos/síntese química , Inibidores da Aromatase/síntese química , Imidas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imidas/química , Imidas/farmacologia , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Various steroidal oxime ether derivatives in androstene and estrane series have been synthesized and evaluated for the antineoplastic activity at National Cancer Institute, Bethesda, Maryland, USA. O-alkylation of the oximes by various alkylaminoethyl halides gave the oxime ether derivatives. The 17alpha-ethynylandrostene derivatives 29 (DPJ-684), 30 (DPJ-685), 31 (DPJ-686) and estrane derivatives 35 (DPJ-531) and 36 (DPJ-532) were among the small percentage of compounds, which have been screened by NCI for in vivo hollow fiber assay by virtue of their activity against one or more human tumour cell lines in 60 cell line in vitro prescreen. The preliminary in vivo reports of hollow fiber assays have been referred to the Biological Evaluation Committee for Cancer Drugs for considering these compounds for further detailed in vivo testing.
Assuntos
Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/farmacologia , Oximas/síntese química , Oximas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , HumanosRESUMO
A series of tricyclic nitrogen bridgehead compounds 7-22 have been synthesised and evaluated for their in vitro bronchodilatory activity using isolated guinea pig tracheal chain, precontracted with acetylcholine. The relaxant effect of 2,3,4,5-tetrahydroazepino[2,1-b]-8,9-dimethoxyquinazolin-11(1H)-one (7) (DPJ-386) was greater than that of theophylline, aminophylline and quinazoline derivative 3, which lacks methoxy groups at positions 8 and 9. Various nitrogen containing functionalities such as benzylamino, acetamido, benzamido and phthalimido were also introduced at 9 position of 3. This resulted in loss of relaxation activity in precontracted guinea pig tracheal chain. These results show that the better relaxation property possessed by compound 7 hydrochloride is due to methoxy groups at 8 and 9 positions.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Broncodilatadores/síntese química , Relaxamento Muscular/efeitos dos fármacos , Nitrogênio/química , Quinazolinas/síntese química , Traqueia/efeitos dos fármacos , Acetilcolina , Animais , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Broncodilatadores/farmacologia , Cobaias , Técnicas In Vitro , Músculo Liso/efeitos dos fármacos , Quinazolinas/farmacologiaRESUMO
Steroidal quaternary ammonium compounds 12 and 13 with quaternised nitrogen at positions 3 and 16 of the steroidal nucleus in androstane series were synthesised and their neuromuscular blocking activities and ganglion blocking activities were studied using chick biventer and anaesthetised cat as the models. The bisquaternary compounds 12 and 13 have been found to be greater in potency than D-tubocurarine. Acetoxy derivative 13 has been found to be more potent than pipecuronium bromide taking D-tubocurarine as the standard compound indicating the need of acetoxy function at position 16.
Assuntos
Bloqueadores Neuromusculares/síntese química , Esteroides/síntese química , Animais , Gatos , Galinhas , Gânglios/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Bloqueadores Neuromusculares/farmacologia , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/farmacologia , Esteroides/farmacologia , Relação Estrutura-AtividadeRESUMO
In a systematic effort aimed at identifying new steroidal cytotoxic agents with potent antiproliferative activity against cancer cells, we synthesized certain 16-[4-(NO2, CN, and i-Pr)substituted]benzylidene derivatives of androst-5-ene, 7-25, with pyrrolidino functionality in the 3beta-position of the steroid nucleus, i.e., 13-18 and 25. The selected compounds were examined for their cytotoxicity against a panel of three human cancer cell lines at the National Cancer Institute (NCI), Bethesda, USA. The results presented herein provide experimental evidence that compounds 7, 9, 10, 12, 16, and 19-21 induced apoptosis in human cancer cells.
Assuntos
Androstenóis/síntese química , Antineoplásicos/síntese química , Compostos de Benzilideno/síntese química , Androstenóis/farmacologia , Antineoplásicos/farmacologia , Compostos de Benzilideno/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , HumanosRESUMO
The compounds 1-isopropylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate (5) and 1-tert-butylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate (6) were synthesized from thymol (1), a naturally occurring agent in Thymus vulgaris L. Pharmacological evaluation of 5 and 6 were carried out using mouse ECG and isolated rat uterus models. Pretreatment of 5 (100 microg/kg, i.v.) and 6 (50 microg/kg, i.v.) antagonized isoprenaline (2 microg/kg, i.v.) induced tachycardia, similar to that of atenolol (CAS 29122-68-7, 20 microg/kg, i.v.) pretreatment in mouse ECG experiments as measured by R-R interval. Pretreatment of 5 and 6 blocked isoprenaline and adrenaline induced relaxation of isolated rat uterus (unprimed). Also the compounds 5 and 6 were subjected to in vitro beta1- and beta2-adrenergic receptor binding assay using turkey erythrocyte membrane (beta1) and lung homogenate of rats (beta2). Both 5 and 6 showed beta-adrenergic receptor affinity comparable with that of propranolol (propranolol hydrochloride, CAS 318-98-9) with out selectivity to any one beta-adrenergic receptor. These results suggest that both the compounds possess non-selective beta-adrenergic blocking activity, with the tert-butyl derivative 6 being more active than the isopropyl derivative 5.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1 , Antagonistas de Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Oxalatos/síntese química , Oxalatos/farmacologia , Antagonistas Adrenérgicos beta/metabolismo , Animais , Atenolol/farmacologia , Ligação Competitiva , Eletrocardiografia/efeitos dos fármacos , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Feminino , Frequência Cardíaca/efeitos dos fármacos , Isoproterenol/farmacologia , Masculino , Camundongos , Oxalatos/metabolismo , Propanóis/síntese química , Propanóis/metabolismo , Propanóis/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Timol/química , Thymus (Planta)/química , Útero/efeitos dos fármacosRESUMO
Oxime and dioxime derivatives of various 16E-arylidenosteroids in the androstene series have been prepared and evaluated at the National Cancer Institute (NCI), Bethesda (USA) for their antineoplastic activity against various tumor cell lines in order to determine the structural requirements for cytotoxic activity. Aldol condensation of dehydroepiandrosterone (DHA) and DHA acetate with various aldehydes followed by treatment with hydroxylamine hydrochloride resulted in the formation of 16E-arylidenosteroid-oxime system. Oximes 15, 16 and compound 20 with a higher degree of oxidation in ring A have been found active in a 60 cell line antitumor prescreen by virtue of their cytotoxic effect against one or more tumor cell line and were further referred for in vivo hollow fiber bioassay. These compounds showed interesting intraperitoneal and subcutaneous scores in the in vivo hollow fiber bioassay and have been referred to the Biological Evaluation Committee for Cancer Drugs for further detailed in vivo testing.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Esteroides/síntese química , Esteroides/farmacologia , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Desidroepiandrosterona/análogos & derivados , Desidroepiandrosterona/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidroxilaminas/química , Indicadores e Reagentes , Dose Letal Mediana , Espectroscopia de Ressonância Magnética , Esteroides/toxicidadeRESUMO
Inflammation is now marked as a central feature of asthma pathophysiology and aims of current asthma management are not only to treat acute symptoms of wheezing, breathlessness, chest tightness, cough but also to suppress the underlying inflammatory component. Despite the availability of a number of drugs, corticosteroids remain the mainstay in the management of all types of asthma as these are the most potent and effective antiinflammatory agents available so far. Corticosteroids suppress virtually every step in inflammation. However therapeutic doses of oral glucocorticoids are associated with a range of adverse reactions. To overcome these side effects, inhalations have been developed to deliver glucocorticoids directly to the lungs and in the process a number of aerosol preparations have become available, which have advantage of significantly lower toxicity due to low systemic absorption from the respiratory tract and rapid inactivation. Despite considerable efforts by pharmaceutical industry, it has been difficult to develop novel therapeutic agents for asthma management, which could surpass inhaled corticosteroids. Currently the data favours using inhaled corticosteroids as monotherapy in the majority of patients in all kinds of asthma. If combination therapy is recommended to achieve additional control in severe asthma cases, other drugs such as beta-agonists, antileukotrienes, theophylline, etc. are considered as adjunct therapies to corticosteroids. This review discusses the importance of corticosteroids as first line therapy for asthma treatment with the availability of inhaled corticosteroids for chronic treatment and oral formulations for treating acute exacerbations of moderate to severe asthma.
Assuntos
Corticosteroides/química , Asma/tratamento farmacológico , Corticosteroides/efeitos adversos , Corticosteroides/farmacocinética , Corticosteroides/uso terapêutico , Asma/patologia , Humanos , Inflamação/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
The object of this study was to investigate the beta-adrenergic receptor binding affinity of 4-acylaminophenoxypropanolamine (10-15) and 5-acylaminonaphthyloxypropanolamine (21-24) derivatives, which were prepared from 4-aminophenol (5) and 5-amino-1-naphthol (16), respectively. The in vitro beta 1- and beta 2-adrenergic receptor binding affinities of the newly synthesized compounds were assessed in turkey erythrocyte membrane (beta 1) and lung homogenates of rats (beta 2). The binding affinities were compared with that of propranolol (3) (propranolol hydrochloride, CAS 318-98-9). The compound N-[5-(3-tert-butylamino-2-hydroxy-propoxy)-naphthalen-1-yl]-acetamide (22) has beta-adrenergic receptor affinity comparable with that of propranolol and shows selectivity to beta 1-adrenergic receptors.
Assuntos
Receptores Adrenérgicos beta 1/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Antagonistas Adrenérgicos beta , Animais , Ligação Competitiva/efeitos dos fármacos , Di-Hidroalprenolol , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Técnicas In Vitro , Indicadores e Reagentes , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Espectroscopia de Ressonância Magnética , Ratos , Ratos Sprague-Dawley , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , PerusRESUMO
The synthesis of some steroidal bisquaternary ammonium substances (compounds 10 and 11), and their in vitro and in vivo neuromuscular blocking action are described in this report. The pyrrolidino functionality was incorporated at both the 3-beta and 16-beta positions of the steroid nucleus to study the importance of the interonium distance between the two quaternary ammonium heads. The 16-beta-pyrrolidino monoquaternary derivatives (compounds 14, 15, 16) were also prepared. The 17-beta-acetoxy bisquaternary derivative compound 11 was found to be more potent than d-tubocurarine (CAS 57-94-3) in in vivo studies. The 17-beta-hydroxy bisquaternary derivative, compound 10, and its 16-beta-pyrrolidino monoquaternary partner, compound 15, were found to be less active as compared to d-tubocurarine in in vitro studies. The monoquaternary compounds 14 and 16 were not tested due to their solubility problems. The intermediate substance, compound 12 was selected by the National Cancer Institute (NCI), Bethesda (USA) for investigation for antineoplastic activity but was found to be inactive.
Assuntos
Bloqueadores Neuromusculares/síntese química , Esteroides Heterocíclicos/química , Esteroides Heterocíclicos/farmacologia , Acetilcolina/metabolismo , Animais , Ligação Competitiva/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Gatos , Embrião de Galinha , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Indicadores e Reagentes , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Bloqueadores Neuromusculares/farmacologia , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/metabolismo , Fármacos Neuromusculares não Despolarizantes/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , Tubocurarina/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
A novel dimer of 2-(4-pyridylmethyl)-1-indanone (2) was obtained while carrying out aldol condensation of 1-indanone with pyridine-4-carboxaldehyde in potassium hydroxide. The structure of dimer 3 has been established using various spectral techniques and was screened for its ability to inhibit the cytochrome P(450) enzyme aromatase. The dimer showed strong inhibition of human placental aromatase and was found 3 times more potent (RP = 3, IC(50) = 10.2 microM) as compared to aminoglutethimide (RP = 1, IC(50) = 18.5 microM.
Assuntos
Inibidores da Aromatase , Indanos/síntese química , Humanos , Técnicas In Vitro , Indanos/farmacologia , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Placenta/efeitos dos fármacos , Placenta/enzimologiaRESUMO
The synthesis of 2-substituted-N-(2-diethylaminoethyl)acetamide oxalates (6a, 6b) and the evaluation of their in vivo local anaesthetic activities are described. The compounds 6a and 6b were obtained starting from 4-acetamidophenol and 1-naphthol, respectively. The in vivo local anesthetic activity was evaluated by infiltration anaesthesia, sciatic nerve block and corneal anaesthesia models. N-(2-Diethylaminoethyl)-2-(naphthalen-1-yloxy)acetamide oxalate (6b) was found to have potency, onset and duration of action comparable to that of lidocaine (2) (lidocaine hydrochloride, CAS 6108-05-0). Procaine (1) (procaine hydrochloride, CAS 51-05-8) was also used for comparison. Dissociation constants (pKa) of compounds 5a and 5b (2-substituted-N-(2-diethylaminoethyl)acetamide) have been determined to be 8.9 and 8.6, respectively.