Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity: pharmacophore identification based on the screening hit closantel

D J Hlasta; J P Demers; B D Foleno; S A Fraga-Spano; J Guan; J J Hilliard; M J Macielag; K A Ohemeng; C M Sheppard; Z Sui; G C Webb; M A Weidner-Wells; H Werblood; J F Barrett

doi:10.1016/s0960-894x(98)00326-6

Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity: pharmacophore identification based on the screening hit closantel

Bioorg Med Chem Lett. 1998 Jul 21;8(14):1923-8. doi: 10.1016/s0960-894x(98)00326-6.

Authors

D J Hlasta¹, J P Demers, B D Foleno, S A Fraga-Spano, J Guan, J J Hilliard, M J Macielag, K A Ohemeng, C M Sheppard, Z Sui, G C Webb, M A Weidner-Wells, H Werblood, J F Barrett

Affiliation

¹ R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869, USA.

PMID: 9873460
DOI: 10.1016/s0960-894x(98)00326-6

Abstract

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.

MeSH terms

Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Drug Resistance, Microbial
Enterococcus faecium / drug effects
Gram-Positive Bacteria / drug effects*
Microbial Sensitivity Tests
Phosphorylation
Salicylanilides / chemistry
Salicylanilides / pharmacology*
Staphylococcus aureus / drug effects
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Salicylanilides
closantel