hERG optimizations of IMB1603, discovery of alternative benzothiazinones as new antitubercular agents

IMB1603, a new benzothiazinone lead discovered by our lab, exhibited potent anti-MTh activity in vitro and in vivo, but significant hERG binding potency (IR > 90% at 10 mu 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-MTh activity (MICs <0.035-0.078 mu M), and had lower hERG binding affinity (IR < 50% at 10 mu 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. (C) 2019 Elsevier Masson SAS. All rights reserved.