Structure-activity relationship and mechanism of action studies of manzamine analogues for the control of neuroinflammation and cerebral infections.
Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3beta (GSK-3beta), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases.
Peng
Jiangnan
J
Department of Pharmacognosy, The University of Mississippi, Oxford, Mississippi 38677, USA.
Kudrimoti
Sucheta
S
Prasanna
Sivaprakasam
S
Odde
Srinivas
S
Doerksen
Robert J
RJ
Pennaka
Hari K
HK
Choo
Yeun-Mun
YM
Rao
Karumanchi V
KV
Tekwani
Babu L
BL
Madgula
Vamsi
V
Khan
Shabana I
SI
Wang
Bin
B
Mayer
Alejandro M S
AM
Jacob
Melissa R
MR
Tu
Lan Chun
LC
Gertsch
Jürg
J
Hamann
Mark T
MT
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002526:Cerebellar Diseases / Q000188:drug therapy*; D026121:Indole Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D020078:Neurogenic Inflammation / Q000188:drug therapy*; D011161:Porifera / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D002227:Carbazoles; D026121:Indole Alkaloids; C513454:ircinal A; C436389:manzamine F; C078290:manzamine A