RESUMO
Amidino benzimidazoles have been identified as inhibitors of the bacterial KinA/Spo0F two-component system (TCS). Many of these inhibitors exhibit good in vitro antibacterial activity against a variety of susceptible and resistant Gram-positive organisms. The moiety at the 2-position of the benzimidazole was extensively modified. In addition, the regioisomeric benzoxazoles, heterocyclic replacements for the benzimidazole, have been synthesized and their activity against the TCS evaluated.
Assuntos
Antibacterianos/síntese química , Benzimidazóis/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Proteínas Quinases , Amidinas/síntese química , Amidinas/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Benzimidazóis/síntese química , Técnicas de Química Combinatória , Bactérias Gram-Positivas/fisiologia , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Inibidores de Proteínas Quinases , Transdução de Sinais/efeitos dos fármacosRESUMO
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).
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Inibidores de Proteínas Quinases , Salicilanilidas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Bacillus subtilis/enzimologia , Bacillus subtilis/metabolismo , Bacillus subtilis/fisiologia , Avaliação Pré-Clínica de Medicamentos , Resistência Microbiana a Medicamentos , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/enzimologia , Enterococcus faecium/genética , Enterococcus faecium/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Positivas/enzimologia , Bactérias Gram-Positivas/fisiologia , Luciferases/genética , Luciferases/metabolismo , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Fosforilação , Proteínas Quinases/genética , Salicilanilidas/química , Salicilanilidas/farmacologia , Esporos Bacterianos/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Vancomicina/farmacologiaRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Salicilanilidas/farmacologia , Antibacterianos/química , Resistência Microbiana a Medicamentos , Enterococcus faecium/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Fosforilação , Salicilanilidas/química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
