Antiprotozoal Agents

Publication Title: 
The Journal of Infectious Diseases

Toxoplasma gondii infection, like malaria, is sensitive to inhibition by artemisinin (ART). Mechanisms of action for ART in malaria treatment have been proposed, but little is known about its effects in T. gondii infection. To better understand its inhibitory effects on T. gondii, mutants resistant to ART were selected by progressive culture in permissive levels of the drug. Five clonal isolates were established and characterized.

Berens, R. L.
Krug, E. C.
Nash, P. B.
Curiel, T. J.
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

In this study we have evaluated the application and reliability of using fluorescence (FLUO)-based high throughput screening assays with recombinant CYPs (rCYP). This was accomplished by screening 29 clinically important antiparasitic drugs for inhibition of the five major drug-metabolizing CYPs (-1A2, -2C9, -2C19, -2D6, and -3A4). Data from FLUO/rCYP assays were compared with that obtained by conventional HPLC assays using human liver microsomes (HLM) and rCYPs.

Bapiro, T. E.
Egnell, A. C.
Hasler, J. A.
Masimirembwa, C. M.
Publication Title: 
PLoS medicine

BACKGROUND: Malaria remains a serious health problem because resistance develops to all currently used drugs when their parasite targets mutate. Novel antimalarial drug targets are urgently needed to reduce global morbidity and mortality. Our prior results suggested that inhibiting erythrocyte Gs signaling blocked invasion by the human malaria parasite Plasmodium falciparum. METHODS AND FINDINGS: We investigated the erythrocyte guanine nucleotide regulatory protein Gs as a novel antimalarial target.

Murphy, Sean C.
Harrison, Travis
Hamm, Heidi E.
Lomasney, Jon W.
Mohandas, Narla
Haldar, Kasturi
Publication Title: 
Antimicrobial Agents and Chemotherapy

Artemisinin is a plant sesquiterpene lactone that has become an important drug for combating malaria, especially in regions where resistance to other drugs is widespread. While the mechanism of action is debated, artemisinin has been reported to inhibit the sarcoplasmic endoplasmic reticulum Ca(2+) ATPase (SERCA) in the malaria parasite. Artemisinin is also effective against Toxoplasma in vitro and in vivo, although it is less potent and, hence, is generally not used therapeutically to treat toxoplasmosis.

Nagamune, Kisaburo
Moreno, Silvia N. J.
Sibley, L. David
Publication Title: 
The Journal of Antimicrobial Chemotherapy

OBJECTIVES: We sought to improve upon the usefulness of artemisinins as anti-Toxoplasma agents by synthesizing new unsaturated, carba derivatives and then testing them for in vitro efficacy against three steps of the lytic cycle of Toxoplasma gondii tachyzoites. METHODS: Novel derivatives of ART were synthesized and then tested for in vitro antiparasitic activity using T. gondii tachyzoites constitutively expressing beta-galactosidase and human fibroblast host cells.

D'Angelo, John G.
Bordón, Claudia
Posner, Gary H.
Yolken, Robert
Jones-Brando, Lorraine
Publication Title: 
Bioorganic & Medicinal Chemistry Letters

A series of artemisinin-vinyl sulfone hybrid molecules with the potential to act in the parasite food vacuole via endoperoxide activation and falcipain inhibition was synthesized and screened for antiplasmodial activity and falcipain-2 inhibition. All conjugates were active against the Plasmodium falciparum W2 strain in the low nanomolar range and those containing the Leu-hPhe core inhibited falcipain-2 in low micromolar range.

Capela, Rita
Oliveira, Rudi
Gonçalves, Lídia M.
Domingos, Ana
Gut, Jiri
Rosenthal, Philip J.
Lopes, Francisca
Moreira, Rui
Publication Title: 
Bioorganic & Medicinal Chemistry

Nine dihydroartemisinin acetal dimers (6-14) with diversely functionalized linker units were synthesized and tested for in vitro antiprotozoal, anticancer and antimicrobial activity. Compounds 6, 7 and 11 [IC(50): 3.0-6.7 nM (D6) and 4.2-5.9 nM (W2)] were appreciably more active than artemisinin (1) [IC(50): 32.9 nM (D6) and 42.5 nM (W2)] against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of the malaria parasite, Plasmodium falciparum.

Slade, Desmond
Galal, Ahmed M.
Gul, Waseem
Radwan, Mohamed M.
Ahmed, Safwat A.
Khan, Shabana I.
Tekwani, Babu L.
Jacob, Melissa R.
Ross, Samir A.
Elsohly, Mahmoud A.
Publication Title: 
Journal of Medicinal Chemistry

Novel dicationic triazoles 1-60 were synthesized by the Pinner method from the corresponding dinitriles, prepared via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The type and the placement of cationic moieties as well as the nature of aromatic substituents influenced in vitro antiprotozoal activities of compounds 1-60 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and their cytotoxicity for mammalian cells. Eight congeners displayed antitrypanosomal IC(50) values below 10 nM. Thirty-nine dications were more potent against P.

Bakunov, Stanislav A.
Bakunova, Svetlana M.
Wenzler, Tanja
Ghebru, Maedot
Werbovetz, Karl A.
Brun, Reto
Tidwell, Richard R.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

Immune effector mechanisms can enhance the activity of antischistosomal drugs. We examined the in vivo effect of single oral doses of the antimalarials artemether (400 mg/kg) and mefloquine (200 mg/kg), recently described to have promising antischistosomal properties, against juvenile and adult Schistosoma mansoni in T cell-deficient and in comparably infected age- and sex-matched immunologically intact control mice. Artemether and mefloquine are equally effective in athymic and immunocompetent mice.

Keiser, Jennifer
Vargas, Mireille
Doenhoff, Michael J.
Publication Title: 
Journal of Medicinal Chemistry

We have prepared 23 new dehydroartemisinin (DART) trioxane derivatives (11 thiazoles, 2 oxadiazoles, and 10 carboxamides) and have screened them for in vitro activity in the Toxoplasma lytic cycle. Fifteen (65%) of the derivatives were noncytotoxic to host cells (TD(50) > or = 320 microM).

Hencken, Christopher P.
Jones-Brando, Lorraine
Bordón, Claudia
Stohler, Remo
Mott, Bryan T.
Yolken, Robert
Posner, Gary H.
Woodard, Lauren E.


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