Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: novel antibacterial agents against Mycobacterium tuberculosis.
Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high-throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6μg/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents.
Li
Xiaokai
X
Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
Liu
Nina
N
Zhang
Huaning
H
Knudson
Susan E
SE
Slayden
Richard A
RA
Tonge
Peter J
PJ
D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D007652:Oxo-Acid-Lyases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D048588:Benzoxazines; D007652:Oxo-Acid-Lyases