Spiro Compounds

Publication Title: 
Journal of Natural Products

The endophytic fungus Pestalotiopsis virgatula, derived from the plant Terminalia chebula and previously found to produce a large excess of a single metabolite when grown in the minimal M1D medium, was induced to produce a variety of unusual metabolites by growing in potato dextrose broth medium. Analysis of the fermentation medium extract was performed using an HPLC-PDA-MS-SPE-NMR hyphenated system, which led to the identification of a total of eight metabolites (1-8), six of which are new.

Author(s): 
Kesting, Julie R.
Olsen, Lars
Staerk, Dan
Tejesvi, Mysore V.
Kini, Kukkundoor R.
Prakash, Harishchandra S.
Jaroszewski, Jerzy W.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

The antimalarial peroxide, dispiro-1,2,4,5-tetraoxane WR 148999, was synergistic with chloroquine, quinine, mefloquine, and artemisinin against both D6 and W2 clones of Plasmodium falciparum. In consideration of the contrasting antagonism between artemisinin and chloroquine, these drug combination data imply that WR 148999 and artemisinin may not share a common mechanism of action.

Author(s): 
Vennerstrom, J. L.
Ager, A. L.
Andersen, S. L.
Grace, J. M.
Wongpanich, V.
Angerhofer, C. K.
Hu, J. K.
Wesche, D. L.
Publication Title: 
Nature

The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite.

Author(s): 
Vennerstrom, Jonathan L.
Arbe-Barnes, Sarah
Brun, Reto
Charman, Susan A.
Chiu, Francis C. K.
Chollet, Jacques
Dong, Yuxiang
Dorn, Arnulf
Hunziker, Daniel
Matile, Hugues
McIntosh, Kylie
Padmanilayam, Maniyan
Santo Tomas, Josefina
Scheurer, Christian
Scorneaux, Bernard
Tang, Yuanqing
Urwyler, Heinrich
Wittlin, Sergio
Charman, William N.
Publication Title: 
The Journal of Antimicrobial Chemotherapy

OBJECTIVES: Using synchronous cultures of Plasmodium falciparum malaria, the stage sensitivity of the parasite to OZ277 (RBx-11160), the first fully synthetic antimalarial peroxide that has entered Phase II clinical trials, was investigated in vitro over a concentration range of 1 x to 100 x the IC50. Secondly, partitioning of OZ277 into P. falciparum-infected red blood cells (RBCs) and uninfected RBCs was studied in vitro by measuring its distribution between RBCs and plasma (R/P).

Author(s): 
Maerki, Sonja
Brun, Reto
Charman, Susan A.
Dorn, Arnulf
Matile, Hugues
Wittlin, Sergio
Publication Title: 
Antimicrobial Agents and Chemotherapy

RBX11160 (OZ277) is a fully synthetic peroxidic antimalarial in clinical development. To study the possible mechanisms of action of RBX11160, we have examined its ability to inhibit PfATP6, a sarcoplasmic reticulum calcium ATPase and proposed target for semisynthetic peroxidic artemisinin derivatives. RBX11160 inhibits PfATP6 (apparent half-maximal inhibitory constant=7,700 nM) less potently than artemisinin (79 nM). Inhibition of PfATP6 is abrogated by desferrioxamine, an iron-chelating agent.

Author(s): 
Uhlemann, Anne-Catrin
Wittlin, Sergio
Matile, Hugues
Bustamante, Leyla Y.
Krishna, Sanjeev
Publication Title: 
Antimicrobial Agents and Chemotherapy

Using nonperoxidic analogs of artemisinin and OZ277 (RBx11160), the strong in vitro antiplasmodial activities of the latter two compounds were shown to be peroxide bond dependent. In contrast, the weak activities of artemisinin and OZ277 against six other protozoan parasites were peroxide bond independent. These data support the iron-dependent artemisinin alkylation hypothesis.

Author(s): 
Kaiser, Marcel
Wittlin, Sergio
Nehrbass-Stuedli, Angela
Dong, Yuxiang
Wang, Xiaofang
Hemphill, Andrew
Matile, Hugues
Brun, Reto
Vennerstrom, Jonathan L.
Publication Title: 
Antimicrobial Agents and Chemotherapy

The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate.

Author(s): 
Creek, Darren J.
Charman, William N.
Chiu, Francis C. K.
Prankerd, Richard J.
Dong, Yuxiang
Vennerstrom, Jonathan L.
Charman, Susan A.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in the treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode of action is still not well understood. Using combination experiments with cultured Plasmodium falciparum cells, we investigated the interactions of the nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and four of its analogs with artemisinin and the ozonide drug development candidate OZ277.

Author(s): 
Fügi, Matthias A.
Wittlin, Sergio
Dong, Yuxiang
Vennerstrom, Jonathan L.
Publication Title: 
Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America

BACKGROUND: Drug-resistant Plasmodium falciparum malaria necessitates development of novel drugs for treatment.The present study assessed the efficacy and safety of 3 dose levels of arterolane (RBx 11160), a synthetic trioxolane, for treatment of acute uncomplicated falciparum malaria. METHODS: In this randomized, double-blind, multicenter, parallel-group, dose-finding, phase II trial, 230 patients from 4 centers in Thailand, India, and Tanzania (mainland and Zanzibar) received either 50 mg (n=78), 100mg (n=76), or 200 mg (n=76) of arterolane once daily for 7 days.

Author(s): 
Valecha, Neena
Looareesuwan, Sornchai
Mårtensson, Andreas
Abdulla, Salim Mohammed
Krudsood, Srivicha
Tangpukdee, Noppadon
Mohanty, Sanjib
Mishra, Saroj K.
Tyagi, P. K.
Sharma, S. K.
Moehrle, Joerg
Gautam, Anirudh
Roy, Arjun
Paliwal, Jyoti K.
Kothari, Monica
Saha, Nilanjan
Dash, Aditya P.
Björkman, Anders
Publication Title: 
Science (New York, N.Y.)

Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4).

Author(s): 
Rottmann, Matthias
McNamara, Case
Yeung, Bryan K. S.
Lee, Marcus C. S.
Zou, Bin
Russell, Bruce
Seitz, Patrick
Plouffe, David M.
Dharia, Neekesh V.
Tan, Jocelyn
Cohen, Steven B.
Spencer, Kathryn R.
González-Páez, Gonzalo E.
Lakshminarayana, Suresh B.
Goh, Anne
Suwanarusk, Rossarin
Jegla, Timothy
Schmitt, Esther K.
Beck, Hans-Peter
Brun, Reto
Nosten, François
Renia, Laurent
Dartois, Veronique
Keller, Thomas H.
Fidock, David A.
Winzeler, Elizabeth A.
Diagana, Thierry T.

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