TY - JOUR
T1 - Oxa, Thia, Heterocycle, and Carborane Analogues of SQ109
T2 - Bacterial and Protozoal Cell Growth Inhibitors
AU - Li, Kai
AU - Wang, Yang
AU - Yang, Gyongseon
AU - Byun, Sooyoung
AU - Rao, Guodong
AU - Shoen, Carolyn
AU - Yang, Hongliang
AU - Gulati, Anmol
AU - Crick, Dean C.
AU - Cynamon, Michael
AU - Huang, Guozhong
AU - Docampo, Roberto
AU - No, Joo Hwan
AU - Oldfield, Eric
N1 - This work was supported by NIH Grants GM065307, AI104120, and AI049151; a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. 2007-00559), Gyeonggi-do, and KISTI.
PY - 2015/5/8
Y1 - 2015/5/8
N2 - 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 μ300.
AB - 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 μ300.
KW - menaquinone
KW - sleeping sickness
KW - trypanosomes
KW - tuberculosis
KW - uncouplers
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U2 - 10.1021/acsinfecdis.5b00026
DO - 10.1021/acsinfecdis.5b00026
M3 - Article
AN - SCOPUS:84969246716
SN - 2373-8227
VL - 1
SP - 215
EP - 221
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 5
ER -