期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 179, 期 -, 页码 208-217出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.06.053
关键词
Antitubercular agents; Benzothiazinones; Structure-activity relationships; hERG
资金
- National Mega -project for Innovative Drugs [2018ZX09721001-004-007, 2018ZX09711001-007-002]
- CAMS Innovation Fund for Medical Science [CAMS-2018-I2M-3-004]
- National Natural Science Foundation of China [81872753, 21502041]
- University Science and Technology Research Project of Hebei [YQ2014031]
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.
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