期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 1, 页码 61-76出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm900672t
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资金
- National Institutes of Health [1R01A136596, 5K02A-101502]
- NIAID
- Division of AIDS [AI 27094]
- USDA Agricultural Research Service Specific Cooperative [58-6408-2-0009]
- Midwestern University
- National Science Foundation [EPS-0556308]
- Centers for Disease Control and Prevention National Center for Zoonotic, Vector-Borne, and Enteric Diseases (NCZVED)
- American Association of Colleges of Pharmacy New Investigator
- NIH National Center for Research Resources (NCRR) [P20 RR021929, C06 RR-14503-01]
- University of Mississippi's Office of Research and Sponsored Programs, Partners and Provost's Associates
- CORE-NPN Natural Products Neuroscience
- EPSCoR
- Office Of The Director [903787] Funding Source: National Science Foundation
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 Acanthostrongy-lophora. 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. I 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, I 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-3 beta (GSK-3 beta), 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.
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