Preparation and antitubercular activities in vitro and in vivo of novel Schiff bases of isoniazid.
Structural modification of the frontline antitubercular isonicotinic acid hydrazide (INH) provides lipophilic adaptations (3-46) of the drug in which the hydrazine moiety of the parent compound has been chemically blocked from the deactivating process of N(2)-acetylation by N-arylaminoacetyl transferases. As a class, these compounds show high levels of activity against Mycobacterium tuberculosis in vitro and in tuberculosis-infected macrophages. They provide strong protection in tuberculosis-infected mice and have low toxicity. With some representatives of this class achieving early peak plasma concentrations approximately three orders of magnitude above minimum inhibitory concentration, they may serve as tools for improving our understanding of INH-based treatment modalities, particularly for those patients chronically underdosed in conventional INH therapy.
Hearn
Michael J
MJ
Department of Chemistry, Wellesley College, 106 Central Street, Wellesley, MA 02481, USA. mhearn@wellesley.edu
Cynamon
Michael H
MH
Chen
Michaeline F
MF
Coppins
Rebecca
R
Davis
Jessica
J
Joo-On Kang
Helen
H
Noble
Abigail
A
Tu-Sekine
Becky
B
Terrot
Marianne S
MS
Trombino
Daniella
D
Thai
Minh
M
Webster
Eleanor R
ER
Wilson
Rebecca
R
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007538:Isoniazid / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012545:Schiff Bases / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*
D000995:Antitubercular Agents; D012545:Schiff Bases; D007538:Isoniazid