Oxa, Thia, Heterocycle, and Carborane Analogues of SQ109: Bacterial and Protozoal Cell Growth Inhibitors

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• 作者：Kai Li ; Yang Wang ; Gyongseon Yang ; Sooyoung Byun ; Guodong Rao ; Carolyn Shoen ; Hongliang Yang ; Anmol Gulati ; Dean C. Crick ; Michael Cynamon ; Guozhong Huang ; Roberto Docampo ; Joo Hwan No ; Eric Oldfield
• 刊名：ACS Infectious Diseases
• 出版年：2015
• 出版时间：May 8, 2015
• 年：2015
• 卷：1
• 期：5
• 页码：215-221
• 全文大小：429K
• ISSN：2373-8227

文摘

We synthesized a library of 48 analogues of the Mycobacterium tuberculosis cell growth inhibitor SQ109 in which the ethylenediamine linker was replaced by oxa, thia, or heterocyclic species, and in some cases, the adamantyl group was replaced by a 1,2-carborane or the N-geranyl group by another hydrophobic species. Compounds were tested against M. tuberculosis (H37Rv and/or Erdman), Mycobacterium smegmatis, Bacillus subtilis, Escherichia coli, Saccharomyces cerevisiae, Trypanosoma brucei, and two human cell lines (human embryonic kidney, HEK293T, and the hepatocellular carcinoma, HepG2). The most potent activity was found against T. brucei, the causative agent of human African trypanosomiasis, and involved targeting of the mitochondrial membrane potential with 15 SQ109 analogues being more active than was SQ109 in cell growth inhibition, having IC₅₀ values as low as 12 nM (5.5 ng/mL) and a selectivity index of ∼300.