Substituted salicylanilides as inhibitors of two-component regulatory systems in bacteria

被引：124

作者：

Macielag, MJ ^{[1
]}

Demers, JP ^{[1
]}

Fraga-Spano, SA ^{[1
]}

Hlasta, DJ ^{[1
]}

Johnson, SG ^{[1
]}

Kanojia, RM ^{[1
]}

Russel, RK ^{[1
]}

Sui, ZH ^{[1
]}

Weidner-Wells, MA ^{[1
]}

Werblood, H ^{[1
]}

Foleno, BD ^{[1
]}

Goldschmidt, RM ^{[1
]}

Loeloff, MJ ^{[1
]}

Webb, GC ^{[1
]}

Barrett, JF ^{[1
]}

机构：

[1] RW Johnson Pharmaceut Res Inst, Raritan, NJ 08869 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 16期

关键词：

D O I：

10.1021/jm9803572

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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/SpoOF, 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-dihydroxy-benzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC(50)s of 2.8 and 6.3 mu M, 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).

引用

页码：2939 / 2945

页数：7

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