Kai Li1, Yang Wang1, Gyongseon Yang2, Sooyoung Byun2, Guodong Rao1, Carolyn Shoen3, Hongliang Yang4, Anmol Gulati1, Dean C Crick4, Michael Cynamon3, Guozhong Huang5, Roberto Docampo5, Joo Hwan No2, Eric Oldfield1. 1. Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801. 2. Leishmania Research Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea, 463-400. 3. Veterans Affairs Medical Center, 800 Irving Avenue, Syracuse, NY 13210. 4. CVMBS Microbiology, Immunology and Pathology Department, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523-1601. 5. Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602.
Abstract
We synthesized a library of 48 analogs of the Mycobacterium tuberculosis cell 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 against Mycobacterium 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). 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 analogs 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.
We synthesized a library of 48 analogs of the Mycobacterium tuberculosis cell growth inhibitor n class="Chemical">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 against Mycobacterium tuberculosis (H37Rv and/or Erdman), Mycobacterium smegmatis, Bacillus subtilis, Escherichia coli, Saccharomyces cerevisiae, Trypanosoma brucei and two human cell lines (humanembryonic kidney, HEK293T, and the hepatocellular carcinoma, HepG2). 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 analogs 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.
Authors: Helena I M Boshoff; Timothy G Myers; Brent R Copp; Michael R McNeil; Michael A Wilson; Clifton E Barry Journal: J Biol Chem Date: 2004-07-09 Impact factor: 5.157
Authors: Wei Li; Ashutosh Upadhyay; Fabio L Fontes; E Jeffrey North; Yuehong Wang; Debbie C Crans; Anna E Grzegorzewicz; Victoria Jones; Scott G Franzblau; Richard E Lee; Dean C Crick; Mary Jackson Journal: Antimicrob Agents Chemother Date: 2014-08-18 Impact factor: 5.191
Authors: Kapil Tahlan; Regina Wilson; David B Kastrinsky; Kriti Arora; Vinod Nair; Elizabeth Fischer; S Whitney Barnes; John R Walker; David Alland; Clifton E Barry; Helena I Boshoff Journal: Antimicrob Agents Chemother Date: 2012-01-17 Impact factor: 5.191
Authors: Anna A Druzina; Natalia E Grammatikova; Olga B Zhidkova; Natalia A Nekrasova; Nadezhda V Dudarova; Irina D Kosenko; Mikhail A Grin; Vladimir I Bregadze Journal: Molecules Date: 2022-05-03 Impact factor: 4.927
Authors: Xinxin Feng; Wei Zhu; Lici A Schurig-Briccio; Steffen Lindert; Carolyn Shoen; Reese Hitchings; Jikun Li; Yang Wang; Noman Baig; Tianhui Zhou; Boo Kyung Kim; Dean C Crick; Michael Cynamon; J Andrew McCammon; Robert B Gennis; Eric Oldfield Journal: Proc Natl Acad Sci U S A Date: 2015-12-07 Impact factor: 11.205
Authors: Albert Byungyun Jeon; David F Ackart; Wei Li; Mary Jackson; Roberta J Melander; Christian Melander; Robert B Abramovitch; Adam J Chicco; Randall J Basaraba; Andrés Obregón-Henao Journal: Sci Rep Date: 2019-02-06 Impact factor: 4.379
Authors: Satish R Malwal; Matthew D Zimmerman; Nadine Alvarez; Jansy P Sarathy; Véronique Dartois; Carol A Nacy; Eric Oldfield Journal: ACS Infect Dis Date: 2021-07-19 Impact factor: 5.084