RESUMEN
Isothiocyanates (ITCs) are natural plant products generated by the enzymic hydrolysis of glucosinolates found in Brassicaceae vegetables. These natural sulfur compounds and their dithiocarbamate conjugates have been previously evaluated for their anti-cancerous properties. Their antimicrobial properties have been previously studied as well, mainly for food preservation and plant pathogen control. Recently, several revelations concerning the mode of action of ITCs in prokaryotes have emerged. This review addresses these new studies and proposes a model to summarize the current knowledge and hypotheses for the antibacterial effect of ITCs and whether they may provide the basis for the design of novel antibiotics.
Asunto(s)
Antibacterianos/farmacología , Brassicaceae/química , Isotiocianatos/farmacología , Extractos Vegetales/farmacología , Antibacterianos/química , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/genética , Membrana Celular/metabolismo , Isotiocianatos/química , Extractos Vegetales/químicaRESUMEN
Starting from a hit identified by focused screening, 3-aminopyrrolidine factor Xa inhibitors were designed. The binding mode as determined by X-ray structural analysis as well as the pharmacokinetic behaviour of selected compounds is discussed.
Asunto(s)
Aminoquinolinas/farmacología , Antitrombina III/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Factor Xa/metabolismo , Aminoquinolinas/química , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacocinética , Antitrombina III/química , Antitrombina III/metabolismo , Antitrombina III/farmacocinética , Cristalografía por Rayos X , Factor Xa/química , Humanos , Modelos Moleculares , Conformación MolecularRESUMEN
The discovery of a highly potent and selective tissue factor/factor VIIa inhibitor is described. Upon oral administration of its double prodrug in the guinea pig, a dose-dependent antithrombotic effect is observed in an established model of arterial thrombosis without prolonging bleeding time. The pharmacodynamic properties of this selective inhibitor are compared to the behaviour of a mixed factor VIIa/factor Xa inhibitor.
Asunto(s)
Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Inhibidores de Factor de Coagulación Sanguínea/síntesis química , Inhibidores de Factor de Coagulación Sanguínea/farmacología , Factor VIIa/antagonistas & inhibidores , Tromboplastina/antagonistas & inhibidores , Administración Oral , Animales , Tiempo de Sangría , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Cobayas , Humanos , Modelos Moleculares , Estructura Molecular , Profármacos/síntesis química , Profármacos/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Trombosis/tratamiento farmacológico , Trombosis/prevención & controlRESUMEN
Various computational disciplines, such as cheminformatics, ADME modeling, virtual screening, chemogenomics search strategies and classic structure-based design, should be seen as one multifaceted discipline contributing to the early drug discovery process. Although significant resources enabling these activities have been established, their true integration into daily research should not be taken for granted. This article reviews value-adding activities from target assessment to lead optimization, and highlights the technical and process-related aspects that can be considered essential for performance and alignment within the research organization.