title: Oxa, Thia, Heterocycle, and Carborane Analogues of SQ109: Bacterial and Protozoal Cell Growth Inhibitors.
abstract: We synthesized a library of 48 analogs of theMycobacterium tuberculosiscell growth inhibitor SQ109 in which the ethylene diamine 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 againstMycobacterium tuberculosis(H37Rv and/or Erdman),Mycobacterium smegmatis,Bacillus subtilis,Escherichia coli,Saccharomyces cerevisiae,Trypanosoma bruceiand two human cell lines (human embryonic kidney, HEK293T, and the hepatocellular carcinoma, HepG2). Most potent activity was found againstT. brucei, the causative agent of human African trypanosomiasis, and involved targeting of the mitochondrial membrane potential with 15 SQ109 analogs being more active than was SQ109 in cell growth inhibition, having IC50values as low as 12 nM (5.5 ng/mL) and a selectivity index of ~300.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Leishmania Research Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea, 463-400.
authors.forename: Gyongseon
authors.initials: G
authors.lastname: Yang
authors.affiliation: Leishmania Research Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea, 463-400.
authors.forename: Sooyoung
authors.initials: S
authors.lastname: Byun
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801.
authors.forename: Guodong
authors.initials: G
authors.lastname: Rao
authors.affiliation: Veterans Affairs Medical Center, 800 Irving Avenue, Syracuse, NY 13210.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Shoen
authors.affiliation: CVMBS Microbiology, Immunology and Pathology Department, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523-1601.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801.
authors.forename: Anmol
authors.initials: A
authors.lastname: Gulati
authors.affiliation: CVMBS Microbiology, Immunology and Pathology Department, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523-1601.
authors.forename: Dean C
authors.initials: DC
authors.lastname: Crick
authors.affiliation: Veterans Affairs Medical Center, 800 Irving Avenue, Syracuse, NY 13210.
authors.forename: Michael
authors.initials: M
authors.lastname: Cynamon
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602.
authors.forename: Guozhong
authors.initials: G
authors.lastname: Huang
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602.
authors.forename: Roberto
authors.initials: R
authors.lastname: Docampo
authors.affiliation: Leishmania Research Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea, 463-400.
authors.forename: Joo Hwan
authors.initials: JH
authors.lastname: No
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801.
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
keywords: Tuberculosis; menaquinone; sleeping-sickness; trypanosomes; uncouplers