Heterocyclic Compounds, 1-Ring

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

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: 
Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America

BACKGROUND: Artemisinin-based combination therapy is the first-line treatment for uncomplicated falciparum malaria. This study assessed the antimalarial efficacy and safety of a combination of 150 mg of arterolane maleate and 750 mg of piperaquine phosphate (AM-PQP) in comparison to Coartem (artemether and lumefantrine) in patients with acute uncomplicated P. falciparum malaria. METHODS: In this open-label, randomized, multicentric, parallel group clinical trial, 240 patients were randomized to receive AM-PQP (160 patients) or Coartem (80 patients). Patients with P.

Author(s): 
Valecha, Neena
Krudsood, Srivicha
Tangpukdee, Noppadon
Mohanty, Sanjib
Sharma, S. K.
Tyagi, P. K.
Anvikar, Anupkumar
Mohanty, Rajesh
Rao, B. S.
Jha, A. C.
Shahi, B.
Singh, Jai Prakash Narayan
Roy, Arjun
Kaur, Pawandeep
Kothari, Monica
Mehta, Shantanu
Gautam, Anirudh
Paliwal, Jyoti K.
Arora, Sudershan
Saha, Nilanjan
Publication Title: 
Antimicrobial Agents and Chemotherapy

The declining efficacy of artemisinin derivatives against Plasmodium falciparum highlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against both P. falciparum and P.

Author(s): 
Marfurt, Jutta
Chalfein, Ferryanto
Prayoga, Pak
Wabiser, Frans
Wirjanata, Grennady
Sebayang, Boni
Piera, Kim A.
Wittlin, Sergio
Haynes, Richard K.
Möhrle, Jörg J.
Anstey, Nicholas M.
Kenangalem, Enny
Price, Ric N.
Publication Title: 
Malaria Journal

BACKGROUND: Semi-synthetic artemisinin derivatives are powerful peroxidic drugs in artemisinin-based combination therapy (ACT) recommended as first-line treatment of Plasmodium falciparum malaria in disease-endemic countries. Studies by Eckstein-Ludwig and co-workers showed both thapsigargin and artemisinin specifically inhibit the sarcoplasmic reticulum Ca²?-ATPase of Plasmodium falciparum (PfATP6). In the present study the type of interaction between thapsigargin and artemisinin derivatives as well as the ozonide OZ277 (RBx11160 or arterolane) was evaluated in parasite cultures.

Author(s): 
Abiodun, Oyindamola O.
Brun, Reto
Wittlin, Sergio
Publication Title: 
Antimicrobial Agents and Chemotherapy

Novel synthetic endoperoxides are being evaluated as new components of artemisinin combination therapies (ACTs) to treat artemisinin-resistant Plasmodium falciparum malaria. We conducted blinded ex vivo activity testing of fully synthetic (OZ78 and OZ277) and semisynthetic (artemisone, artemiside, artesunate, and dihydroartemisinin) endoperoxides in the histidine-rich protein 2 enzyme-linked immunosorbent assay against 200 P. falciparum isolates from areas of artemisinin-resistant malaria in western and northern Cambodia in 2009 and 2010.

Author(s): 
Lanteri, Charlotte A.
Chaorattanakawee, Suwanna
Lon, Chanthap
Saunders, David L.
Rutvisuttinunt, Wiriya
Yingyuen, Kritsanai
Bathurst, Ian
Ding, Xavier C.
Tyner, Stuart D.
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