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

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 <= 15.6 mu M 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 mu M (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.