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Abstract:

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.


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