2-N-Methyl modifications and SAR studies of manzamine A.
Quaternary carbolinium salts have been reported to show improved antimalarial activity and reduced cytotoxicity as compared to electronically neutral beta-carbolines. In this study, mono- and di-methylated quaternary carbolinium cations of manzamine A were synthesized and evaluated for their in vitro antimalarial and antimicrobial activity, cytotoxicity, and also their potential for glycogen synthase kinase (GSK-3beta) inhibition using molecular docking studies. Among the analogs, 2-N-methylmanzamine A (2) exhibited antimalarial activity (IC(50) 0.7-1.0microM) but was less potent than manzamine A. However the compound was significantly less cytotoxic to mammalian kidney fibroblasts and the selectivity index was in the same range as manzamine A.
Ibrahim
Mohamed A
MA
Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, 400C Faser Hall, University, MS 38677, USA.
Shilabin
Abbas G
AG
Prasanna
Sivaprakasam
S
Jacob
Melissa
M
Khan
Shabana I
SI
Doerksen
Robert J
RJ
Hamann
Mark T
MT
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D002227:Carbazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002243:Carbolines; D002522:Chlorocebus aethiops; D004912:Erythrocytes / Q000469:parasitology; D005347:Fibroblasts / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D008745:Methylation; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014709:Vero Cells
D000962:Antimalarials; D002227:Carbazoles; D002243:Carbolines; C078290:manzamine A; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3