RESUMEN
A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2, 3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6. 3 µM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).
Asunto(s)
Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Bacterias Grampositivas/efectos de los fármacos , Inhibidores de Proteínas Quinasas , Salicilanilidas/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Bacillus subtilis/enzimología , Bacillus subtilis/metabolismo , Bacillus subtilis/fisiología , Evaluación Preclínica de Medicamentos , Farmacorresistencia Microbiana , Enterococcus faecium/efectos de los fármacos , Enterococcus faecium/enzimología , Enterococcus faecium/genética , Enterococcus faecium/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Bacterias Grampositivas/enzimología , Bacterias Grampositivas/fisiología , Luciferasas/genética , Luciferasas/metabolismo , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana , Fosforilación , Proteínas Quinasas/genética , Salicilanilidas/química , Salicilanilidas/farmacología , Esporas Bacterianas/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Vancomicina/farmacologíaRESUMEN
Ellagic acid was found to inhibit E. coli DNA gyrase supercoiling with approximately the same potency as nalidixic acid. Tricyclic analogs of ellagic acid, which vary in the number and position of the hydroxy groups as well as their replacement with halogens, have been synthesized. The biological activity of these analogs is discussed.
Asunto(s)
Ácido Elágico/análogos & derivados , Inhibidores Enzimáticos/farmacología , Inhibidores de Topoisomerasa II , Ácido Elágico/farmacología , Inhibidores Enzimáticos/química , Escherichia coli/enzimología , Relación Estructura-ActividadRESUMEN
This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, hydrophobicity is not the sole determinant for inhibition; structural and electronic requirements also exist. Closantel (1) was found to inhibit a two-component system and to have antibacterial activity against drug resistant S. aureus and E. faecium.
