1.
Eur J Med Chem
; 179: 208-217, 2019 Oct 01.
Artigo
em Inglês
| MEDLINE
| ID: mdl-31254922
RESUMO
IMB1603, a new benzothiazinone lead discovered by our lab, exhibited potent anti-MTB activity in vitro and in vivo, but significant hERG binding potency (IRâ¯>â¯90% at 10⯵M). Thus, we embarked on a lead optimization program with the goal of identifying alternative leads that could reduce the hERG liability without sacrificing antimycobacterial potency. Compounds 2c and 4c were identified to maintain the anti-MTB activity (MICs <0.035-0.078⯵M), and had lower hERG binding affinity (IRâ¯<â¯50% at 10⯵M). Both of them were also found to have acceptable safety and pharmacokinetic properties. Studies to determine the in vivo efficacy of 2c and 4c are currently underway.