RESUMO
A novel pharmacophore with theophylline and acetylene moieties was constructed by using a fragment-based drug design and a series of twenty theophylline containing acetylene conjugates were designed and synthesized, and all the compounds were evaluated by enzyme-based in vitro α-amylase inhibition activity. The in vitro evaluation revealed that most of the compounds displayed good inhibitory activities, and among them nine analogs 13-15, 20, 21 and 24-27 were exhibited more or nearly as equipotent inhibitory activity with IC50 values 1.11⯱â¯0.07, 1.14⯱â¯0.17, 1.07⯱â¯0.01 and 1.21⯱â¯0.03, 1.33⯱â¯0.09, 1.17⯱â¯0.01, 1.05⯱â¯0.02, 1.61⯱â¯0.04, 1.02⯱â¯0.03⯵M respectively, as compared with standard, acarbose 1.37⯱â¯0.26⯵M. Further, molecular docking simulation studies were done to identify the interactions and binding mode of synthesized analogs at binding site of α-amylase enzyme (PBD ID: 4GQR). Among the synthesized analogs, two compounds 25 and 27 were selected on the basis of α-amylase inhibition activity and evaluated for in vivo anti-diabetic activity by High Fat Diet-Streptozotocin (HFD-STZ) model in normal rats. At the dose of 10â¯mg/kg, bw, po these compounds have significantly reduced Plasma Glucose level in rats as compared to pioglitazone. The anti-diabetic activity results showed that the animal treated with the compounds 25 and 27 could better reverse and control the progression of the disease compared to the standard.
Assuntos
Acetileno/química , Inibidores de Glicosídeo Hidrolases/síntese química , Hipoglicemiantes/síntese química , Teofilina/síntese química , alfa-Amilases/antagonistas & inibidores , Acarbose/normas , Animais , Sítios de Ligação , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental , Dieta Hiperlipídica , Avaliação Pré-Clínica de Medicamentos , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Pioglitazona/farmacologia , Ligação Proteica , Ratos , Estreptozocina/metabolismo , Relação Estrutura-Atividade , Teofilina/farmacologiaRESUMO
We synthesized several theophylline analogs and tested the hypothesis that these compounds may be nootropic or cognitive enhancers by examining their effects on evoked population spikes recorded extracellularly in the CA1 region of the rat hippocampus. Whereas the length of the carbon chain on N7 had no effect, different size of the terminal lactam ring strongly influenced neuroactivity. Our results suggest that hexahydroazepin-2-one analogs have potential for further development as cognitive enhancers.
Assuntos
Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Nootrópicos/síntese química , Nootrópicos/farmacologia , Teofilina/síntese química , Teofilina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eletrodos , Hipocampo/citologia , Hipocampo/fisiologia , Masculino , Estrutura Molecular , Neurônios/classificação , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Teofilina/análogos & derivados , Fatores de TempoRESUMO
The three different kinds of imidazo[2,1-f]theophylline derivatives were synthesized and tested for their CNS activity. A series of alkoxy-alkylamides and amino-alkylamides with basic function, derived from 8-benzyl-6,7-dihydroimidazo[2,1-f]theophylline-7-carboxylic acid showed stimulating influence on CNS as they increased the locomotor activity (compound 8 and 10) or enhanced amphetamine and apomorphine effects in mice (compounds 3, 4 and 9). Compounds 1, 5, 8-10 and 12 had anticonvulsant activity in the pentetrazole test; 12 with anellated imidazol-7-on ring (lactam structure) showed sedative properties and antiserotonin effects.
Assuntos
Estimulantes do Sistema Nervoso Central/síntese química , Teofilina/síntese química , Anfetamina/farmacologia , Animais , Apomorfina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Agonistas de Dopamina , Antagonismo de Drogas , Avaliação Pré-Clínica de Medicamentos , Camundongos , Atividade Motora/efeitos dos fármacos , Convulsões/tratamento farmacológico , Convulsões/prevenção & controle , Relação Estrutura-Atividade , Teofilina/farmacologiaRESUMO
Some esters of 7-theophyllinylacetic acid were synthetized, characterized physicochemically and tested for their anti-inflammatory properties. As compared to indomethacin, reference anti-inflammatory drug, all synthetized compounds were less toxic. The anti-inflammatory properties are influenced by the nature of the ester group radicals, the more active having ramified alchils.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Teofilina/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Inflamatórios não Esteroides/toxicidade , Carragenina , Avaliação Pré-Clínica de Medicamentos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Ésteres/síntese química , Ésteres/uso terapêutico , Ésteres/toxicidade , Indometacina/toxicidade , Camundongos , Ratos , Relação Estrutura-Atividade , Teofilina/síntese química , Teofilina/uso terapêutico , Teofilina/toxicidadeRESUMO
A series of theophyllinyl-7'-ethyl derivatives of (RS), (R)(-) and (S)(+) 2-aminobutanol were synthesized and tested in various models of experimental arrhythmia for their preventive and curative properties; (R)(-) 2-N-theophyllinyl-7'-ethyl amino-1-butanol (1a) and (R)(-) theophyllinyl-7'-ethyl-2-N-methylamino-1-butanol (3a) hydrochlorides showed interesting antiarrhythmic properties. The levorotatory compounds of R configuration showed stronger protective and also therapeutic effect in different experimental arrhythmias.