OBJECTIVES: The aim of this study was to identify a candidate drug for clinical development from a previously synthesized combinatorial library based on the 1,2-ethylenediamine structure of ethambutol. METHODS: Sixty-nine of the most potent hits against Mycobacterium tuberculosis from the original studies were subjected to a sequential set of tests in vitro and in vivo--determination of MIC for M. tuberculosis H37Rv, cytotoxicity, intracellular antimycobacterial activity, permeability evaluation and in vivo efficacy testing. RESULTS: Twenty-seven compounds with MICs of < or = 15.6 microM were tested on Vero cells to determine in vitro cytotoxicity (IC50) and to establish a selectivity index (SI) (SI = IC50/MIC). Ten compounds with acceptable SI were tested for activity against intracellular bacteria--all were equivalent (within 1%) or superior to ethambutol and several demonstrated cidal activity. Five of the most potent compounds were tested for in vivo efficacy in a murine model of chronic tuberculosis infection. CONCLUSION: Compound SQ109 with an MIC of 0.7-1.56 microM (H37Rv, Erdman and drug-resistant strains of M. tuberculosis), an SI of 16.7 and 99% inhibition activity against intracellular bacteria, demonstrated potency in vivo and limited toxicity in vitro and in vivo, and was selected for further development.
OBJECTIVES: The aim of this study was to identify a candidate drug for clinical development from a previously synthesized combinatorial library based on the 1,2-ethylenediamine structure of ethambutol. METHODS: Sixty-nine of the most potent hits against Mycobacterium tuberculosis from the original studies were subjected to a sequential set of tests in vitro and in vivo--determination of MIC for M. tuberculosis H37Rv, cytotoxicity, intracellular antimycobacterial activity, permeability evaluation and in vivo efficacy testing. RESULTS: Twenty-seven compounds with MICs of < or = 15.6 microM were tested on Vero cells to determine in vitro cytotoxicity (IC50) and to establish a selectivity index (SI) (SI = IC50/MIC). Ten compounds with acceptable SI were tested for activity against intracellular bacteria--all were equivalent (within 1%) or superior to ethambutol and several demonstrated cidal activity. Five of the most potent compounds were tested for in vivo efficacy in a murine model of chronic tuberculosis infection. CONCLUSION: Compound SQ109 with an MIC of 0.7-1.56 microM (H37Rv, Erdman and drug-resistant strains of M. tuberculosis), an SI of 16.7 and 99% inhibition activity against intracellular bacteria, demonstrated potency in vivo and limited toxicity in vitro and in vivo, and was selected for further development.
Authors: Boris V Nikonenko; Marina Protopopova; Rowena Samala; Leo Einck; Carol A Nacy Journal: Antimicrob Agents Chemother Date: 2007-01-22 Impact factor: 5.191
Authors: Elena Bogatcheva; Colleen Hanrahan; Boris Nikonenko; Rowena Samala; Ping Chen; Jacqueline Gearhart; Francis Barbosa; Leo Einck; Carol A Nacy; Marina Protopopova Journal: J Med Chem Date: 2006-06-01 Impact factor: 7.446
Authors: Krupa Naran; Atica Moosa; Clifton E Barry; Helena I M Boshoff; Valerie Mizrahi; Digby F Warner Journal: Antimicrob Agents Chemother Date: 2016-10-21 Impact factor: 5.191
Authors: Marie H Foss; Sovitj Pou; Patrick M Davidson; Jennifer L Dunaj; Rolf W Winter; Sovijja Pou; Meredith H Licon; Julia K Doh; Yuexin Li; Jane X Kelly; Rozalia A Dodean; Dennis R Koop; Michael K Riscoe; Georgiana E Purdy Journal: ACS Infect Dis Date: 2016-05-13 Impact factor: 5.084