New manzamine alkaloids from an Indo-Pacific sponge. Pharmacokinetics, oral availability, and the significant activity of several manzamines against HIV-I, AIDS opportunistic infections, and inflammatory diseases.
12,28-Oxamanzamine A (1), 12,28-oxa-8-hydroxymanzamine A (2), and 31-keto-12,34-oxa-32,33-dihydroircinal A (3) were isolated from two collections of an Indo-Pacific sponge, and their structures were assigned on the basis of 1D and 2D NMR spectroscopic data. These compounds possess a novel manzamine-type ring system generated through a new ether bridge formed between carbons 12 and 28 or between carbons 12 and 34 of the typical manzamine structure and add to our growing understanding of manzamine SAR and metabolism. Based on molecular modeling studies, the formation of these oxidation products is highly sterically favored. The potent antiinflammatory, antifungal, and anti-HIV-1 activity for a number of previously reported manzamines is also presented in addition to the pharmacokinetic studies of manzamine A (5). Oral and intravenous pharmacokinetic studies of manzamine A in rats indicated the compound to have low metabolic clearance, a reasonably long pharmacokinetic half-life, and good absolute oral bioavailability of 20.6%, which supports the value of these compounds as potential leads for further preclinical assessment and possible development.
Yousaf
Muhammad
M
Department of Pharmacognosy and National Center for the Development of Natural Products, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
Hammond
Nicholas L
NL
Peng
Jiangnan
J
Wahyuono
Subagus
S
McIntosh
Kylie A
KA
Charman
William N
WN
Mayer
Alejandro M S
AM
Hamann
Mark T
MT
D017088:AIDS-Related Opportunistic Infections / Q000821:virology; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D000935:Antifungal Agents / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002227:Carbazoles; D002243:Carbolines / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D005583:Fourier Analysis; D015497:HIV-1 / Q000187:drug effects*; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D011161:Porifera; D011758:Pyrroles / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C488105:12,28-oxa-8-hydroxymanzamine A; C488104:12,28-oxamanzamine A; C488106:31-keto-12,34-oxa-32,33-dihydroircinal; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D000893:Anti-Inflammatory Agents; D000935:Antifungal Agents; D002227:Carbazoles; D002243:Carbolines; D007211:Indoles; D011758:Pyrroles; D011804:Quinolines; C078290:manzamine A