634185-66-3Relevant academic research and scientific papers
Structure–Function Studies on IMD-0354 Identifies Highly Active Colistin Adjuvants
Barker, William T.,Basak, Akash K.,Hendricks, Tyler A.,Jania, Leigh A.,Koller, Beverly H.,Marrujo, Santiana A.,Melander, Christian,Melander, Roberta J.,Nemeth, Ansley M.,O'Connor, Patrick M.,Sullivan, Ashley E.,Weig, Alexander W.
supporting information, (2019/12/24)
Infections caused by multidrug-resistant (MDR) bacteria, particularly Gram-negative bacteria, are an escalating global health threat. Often clinicians are forced to administer the last-resort antibiotic colistin; however, colistin resistance is becoming increasingly prevalent, giving rise to the potential for a situation in which there are no treatment options for MDR Gram-negative infections. The development of adjuvants that circumvent bacterial resistance mechanisms is a promising orthogonal approach to the development of new antibiotics. We recently disclosed that the known IKK-β inhibitor IMD-0354 potently suppresses colistin resistance in several Gram-negative strains. In this study, we explore the structure–activity relationship (SAR) between the IMD-0354 scaffold and colistin resistance suppression, and identify several compounds with more potent activity than the parent against highly colistin-resistant strains of Acinetobacter baumannii and Klebsiella pneumoniae.
Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling
Lee, Ill-Young,Gruber, Todd D.,Samuels, Amanda,Yun, Minhan,Nam, Bora,Kang, Minseo,Crowley, Kathryn,Winterroth, Benjamin,Boshoff, Helena I.,Barry III, Clifton E.
, p. 114 - 126 (2013/02/22)
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.
