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

Title: Oxa, Thia, Heterocycle, and Carborane Analogues of SQ109: Bacterial and Protozoal Cell Growth Inhibitors
Authors: 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, and Eric Oldfield
Date: 04/17/2015
Reference: The following file is available free of charge on the ACS publicatins website, Infectious Diseases, April 10, 2015, Volume 1, Issue 4, Pages 149-184.
DOI: http://dx.doi.org/10.1021/acsinfecdis.5b00026
Download link:  http://pubs.acs.org/doi/abs/10.1021/acsinfecdis.5b00026


Eric Oldfield has published an article detailing the search for bacterial and protozoan cell growth inhibitors. All final compounds were ≥90% pure as determined by quantitative spin count NMR (qNMR, processed with Mnova NMR software).

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. Full details of all assays; representative dose −response curves; selectivity index results; mitochondrial membrane bioenergetics; full synthesis and characterization of SQ-109 and its analogues as well as qNMR spectra.

For further information please read the supporting article.

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