Kinetic studies and bioactivity of potential manzamine prodrugs.
The manzamines represent a class of marine natural products that show considerable promise in the control of malaria but generate GI distress in rodents when administered orally in high doses. In an effort to generate manzamine prodrugs with improved antimalarial activity and reduced GI toxicity, we prepared acetylated 8-hydroxymanzamine A analogues including 8-acetoxymanzamine A (3) and 8,12-diacetoxymanzamine A (4), and 8-methoxymanzamine A (5) beginning with 8-hydroxymanzamine A (2). The semisynthetic analogues were assayed for antimalarial and antimicrobial activities, cytotoxicity, and biological and chemical stability. Due to gradual hydrolysis of the ester group, application of monoacetate 3 as an antimalarial prodrug was investigated. The in vitro and in vivo bioassays show that acetylated analogues exhibit significant antimalarial activity (IC50( 3) 9.6-30 ng/mL), which are comparable to the parent molecule; however the monoaceate 3 was shown to actually produce higher toxicity at 30 mg/kg when administered orally.
Shilabin
Abbas Gholipour
AG
Department of Pharmacognosy and National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, USA.
Kasanah
Noer
N
Tekwani
Babu L
BL
Hamann
Mark T
MT
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003455:Cryptococcus neoformans / Q000187:drug effects; D004195:Disease Models, Animal; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects; D016106:Methicillin Resistance / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014709:Vero Cells
C531431:8,12-diacetoxymanzamine A; C531430:8-methoxymanzamine A; D000962:Antimalarials; D002243:Carbolines; D011355:Prodrugs; C086783:8-hydroxymanzamine A