RESUMO
In this work the synthesis, structure-activity relationship (SAR) and biological evaluation of a novel series of triazole-containing 5-lipoxygenase (5-LO) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent 5-LO inhibition with IC50 of 0.2 and 3.2 µm in cell-based and cell-free assays, respectively. Optimization of binding and functional potencies resulted in the identification of compound 13d, which showed an enhanced activity compared to the parent bioactive compound caffeic acid 5 and the clinically approved zileuton 3. Compounds 15 and 16 were identified as lead compounds in inhibiting 5-LO products formation in neutrophils. Their interference with other targets on the arachidonic acid pathway was also assessed. Cytotoxicity tests were performed to exclude a relationship between cytotoxicity and the increased activity observed after structure optimization.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Ácidos Cafeicos/farmacologia , Desenho de Fármacos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Triazóis/farmacologia , Adulto , Ácidos Cafeicos/síntese química , Ácidos Cafeicos/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Inibidores de Lipoxigenase/química , Masculino , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/química , Células U937Assuntos
Anestésicos Locais/toxicidade , Sistema Enzimático do Citocromo P-450/metabolismo , Éteres Fenílicos/toxicidade , Anestesia por Condução , Anestesia Local , Anestésicos Locais/síntese química , Anestésicos Locais/química , Animais , Química Farmacêutica , Excipientes , Dose Letal Mediana , Luminescência , Oxigenases de Função Mista/metabolismo , Paralisia/induzido quimicamente , Éteres Fenílicos/síntese química , Éteres Fenílicos/química , Ratos , Solventes , Relação Estrutura-AtividadeRESUMO
Fomocaine (CAS 56583-43-6) is a basic ether-type local anaesthetic used in dermatological practice for surface anaesthesia. For many years, modifications of the fomocaine molecule have been pursued, e.g. to improve its physicochemical properties and also in view of possible new (systemic) applications, e.g. in the treatment of migraine or as antiarrhythmic. The present paper provides a survey of the investigations undertaken with all the different series of fomocaine derivatives synthesized so far with respect to their in vitro interaction capacity at the cytochrome P450 system, in vivo toxicity (LD50; paresis of the N. ischiadicus) and local anaesthetic effects (conduction anaesthesia at the N. ischiadicus; surface anaesthesia of the cornea) in rats. The main objective of this systematic comparison of the effects of all these substances was to assess possible basic structure-activity relationships.
Assuntos
Anestésicos Locais/química , Anestésicos Locais/farmacologia , Sistema Enzimático do Citocromo P-450/química , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Anestésicos Locais/toxicidade , Animais , Fenômenos Químicos , Físico-Química , Córnea/efeitos dos fármacos , Citocromo P-450 CYP1A1/metabolismo , Feminino , Dose Letal Mediana , Luminescência , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Condução Nervosa/efeitos dos fármacos , Neutrófilos/fisiologia , Paralisia/induzido quimicamente , Éteres Fenílicos/toxicidade , Procaína/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tetracaína/farmacologiaAssuntos
Anestésicos Locais/farmacologia , Inibidores das Enzimas do Citocromo P-450 , Éteres Fenílicos/farmacologia , Anestésicos Locais/síntese química , Anestésicos Locais/química , Anestésicos Locais/toxicidade , Animais , Inibidores Enzimáticos/farmacologia , Éteres Fenílicos/síntese química , Éteres Fenílicos/química , Éteres Fenílicos/toxicidade , Ratos , Relação Estrutura-AtividadeRESUMO
Fomocaine (CAS 56583-43-8) is a local anaesthetic (LA) with long lasting surface effect and low toxicity. Nevertheless, it is not optimal yet. Therefore, 7 newly synthesised derivatives, 4 diethanolamines (OE 6000, OE 7000, OE 8000, OE 9000) and 3 morpholines (OE 500, OE 1000, OE 5000) were compared with procaine-HCl (CAS 51-05-8) and tetracaine-HCl (CAS 136-47-0) in rats. Based on standard methods for the testing of LA effects and using two methods for characterising side effects and toxicity of LA (paresis of the N. ischiadicus, LD50) it can be concluded that: a) The very good surface anaesthesia caused by especially fomocaine and tetracaine could be stated but concerning conduction anaesthesia procaine is better qualified. b) Concerning conduction anaesthesia, diethanolamine derivatives are more potent compared to morpholine derivatives. c) Surface anaesthesia shows a different picture: the effect of fomocaine is in between. d) The paresis of the N. ischiadicus as a first sign of toxic side effects indicated that low effect is combined with short paresis. e) Compared to the LD50 of fomocaine, the toxicity of OE 500 and OE 5000 is only one half. On the basis of the experiments with fomocaine derivatives, distinct structure-activity relationships could be demonstrated for fomocaine derivatives concerning a) LA effects and b) toxicity. Altogether OE 9000 could be a promising candidate for systemic use.