Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines.
OBJECTIVE
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.


CONCLUSIONS
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.
Protopopova
Marina
M
Sequella, Inc., 9610 Medical Center Drive, Suite 200, Rockville, MD 20850, USA. marinaprotopopova@sequella.com
Hanrahan
Colleen
C
Nikonenko
Boris
B
Samala
Rowena
R
Chen
Ping
P
Gearhart
Jackie
J
Einck
Leo
L
Nacy
Carol A
CA
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D015169:Colony Count, Microbial; D020650:Combinatorial Chemistry Techniques; D004195:Disease Models, Animal; D004977:Ethambutol / Q000737:chemistry; D005029:Ethylenediamines / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014376:Tuberculosis / Q000188:drug therapy*; D014709:Vero Cells
D000995:Antitubercular Agents; D005029:Ethylenediamines; C031234:ethylenediamine; D004977:Ethambutol