Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 1, Pages 114-126Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.10.056
Keywords
Tuberculosis; Salicylanilide; Proton gradient; Antibacterial
Funding
- National Institute of Allergy and Infectious Disease
- National Institutes of Health
- Bill and Melinda Gates Foundation
- Korea Research Institute of Chemical and Technology
- Ministry of Education, Science and Technology of Korea
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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. Published by Elsevier Ltd.
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