Kinetic Studies and Bioactivity of Potential Manzamine Prodrugs

Abstract

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.

Current Approaches to Discover Marine Antileishmanial Natural Products

“…This class of alkaloids is known to display a number of potent biological activities, including cytotoxic, insecticidal, antibacterial, anti-inflammatory, anti-infective, and antiparasitic activities [95][96][97]. Several of such alkaloids displayed potent antiparasitic activity against L. (L.) donovani [95][96][97][98], including manzamine A (48), (+)-8-hydroxymanzamine A (49), manzamine Y (50), manzamine E (51), 6-hydroxymanzamine E (52), and manzamine F (53). In tests using L. (L.) donovani promastigotes, manzamine A (48) displayed the most potent activity against viability (l " Table 1) [95,97].…”

PhI(OAc)2-mediated one-pot oxidative decarboxylation and aromatization of tetrahydro-β-carbolines: synthesis of norharmane, harmane, eudistomin U and eudistomin I

“…Yellow solid: 89 mg (90% yield); R f = 0.51 (ethyl acetate/nhexane, 3:7), mp: 192-194 °C;IR (KBr): 3640, 3325, 3028, 2946, 1716, 1621, 1457, 1433, 1350, 1258, 1218, 1109, 1047 142.1, 141.4, 138.4, 136.5, 134.6, 134.4, 129.3,129.0, 128.5, 128.4, 121.9, 121.1, 120.3, 116.4, 112.7, 52.0, 20.9 165.7, 147.4, 143.5, 141.5, 139.3, 139.8, 1345.7, 129.8, 129.0, 123.8, 122.1, 120.9, 120.6, 117.5, 112.6, 52. …”

Antimalarial natural products of marine and freshwater origin

“…Three acetylated 8‐hydroxymanzamine A ( 22 ) analogues 23 , 24 , and 25 were prepared by modification at the 8‐position in an effort to generate manzamine prodrugs with improved antimalarial activity and reduced GI toxicity 56. These synthetic analogues exhibited antimalarial activity against the chloroquine‐sensitive (D6) and the chloroquine‐resistant (W2) strains of Plasmodium falciparum with values ranging from 9 to 1300 ng/mL.…”

“…Analogues 23 and 25 exhibited toxicity to the normal Vero cell line, while the diacetate 24 did not show cytotoxicity at the highest tested concentration of 4700 ng/mL. Analogue 23 was also evaluated for in vivo antimalarial activity against Plasmodium berghei sensitive strain, but appeared being rather toxic 56. Interesting results of quaternary manzamine derivatives similar to nostocarboline ( 13 ) were reported 57.…”