Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility.
Eur J Med Chem
; 279: 116829, 2024 Sep 03.
Article
in En
| MEDLINE
| ID: mdl-39243457
ABSTRACT
Nitrobenzothiazinones (BTZs) represent a novel type of antitubercular agents targeting DprE1. Two clinical candidates BTZ043 and PBTZ169, as well as many other BTZs showed potent anti-TB activity, but they are all highly lipophilic and their poor aqueous solubility is still a serious issue need to be addressed. Here, we designed and synthesized a series of new BTZ derivatives, wherein a hydrophilic COOH or NH2 group is directly attached to the oxime moiety of TZY-5-84 discovered in our lab, through various linkers. Two compounds 1a and 3 were first reported to possess excellent activity against MTB H37Rv and MDR-MTB strains (MIC <0.029-0.095 µM), low toxicity and acceptable oral PK profiles, as well as significantly improved water solubility (1200 and > 2000 µg/mL, respectively), suggesting they may serve as promising hydrophilic BTZs for further antitubercular drug discovery.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Eur J Med Chem
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
France