RESUMEN
According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.
Asunto(s)
Antibacterianos/farmacología , Girasa de ADN/metabolismo , Diseño de Fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Inhibidores de Topoisomerasa II/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Bacterias Grampositivas/metabolismo , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.
Asunto(s)
Antibacterianos/química , ADN-Topoisomerasas de Tipo II/metabolismo , Tiazoles/química , Tiazolidinas/química , Inhibidores de Topoisomerasa II/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Supervivencia Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/química , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Mutación , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacología , Tiazolidinas/síntesis química , Tiazolidinas/farmacología , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/farmacologíaRESUMEN
An iron(III)-catalyzed method for the rapid and highly regioselective iodination of arenes has been developed. Use of the powerful Lewis acid, iron(III) triflimide, generated in situ from iron(III) chloride and a readily available triflimide-based ionic liquid allowed activation of N-iodosuccinimide (NIS) and efficient iodination under mild conditions of a wide range of substrates including biologically active compounds and molecular imaging agents.