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Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling.

Abstract：

:A series of salicylanilides was synthesized based on a high-throughput screening hit against Mycobacterium tuberculosis. A free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure-activity relationship of the aniline ring is largely driven by the presence of electron withdrawing groups. We synthesized 94 analogs exploring substitutions of both rings and the linker region in this series and we have identified multiple compounds with low micromolar potency. Unfortunately, cytotoxicity in a murine macrophage cell line trends with antimicrobial activity, suggesting a similar mechanism of action. We propose that salicylanilides function as proton shuttles that kill cells by destroying the cellular proton gradient, limiting their utility as potential therapeutics.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Lee IY,Gruber TD,Samuels A,Yun M,Nam B,Kang M,Crowley K,Winterroth B,Boshoff HI,Barry CE 3rd

doi

10.1016/j.bmc.2012.10.056

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

114-26

issue

1

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(12)00886-3

journal_volume

21

pub_type

杂志文章

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