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Scientific Articles

Cell-based optimization of novel benzamides as potential antimalarial leads.

November 18, 2009 - 12:57 -- Patrick Sampao
Author(s): 
Tao Wu, Advait Nagle, Tomoyo Sakata, Kerstin Henson, Rachel Borboa, Zhong Chen, Kelli Kuhen, David Plouffe, Elizabeth Winzeler, Francisco Adrian, Tove Tuntland, Jonathan Chang, Susan Simerson, Steven Howard, Jared Ek, John Isbell, Xianming Deng, Nathanael S. Gray, David C. Tully, Arnab K. Chatterjee
Reference: 
Bioorganic & Medicinal Chemistry Letters, Volume 19, Issue 24, 15 December 2009, Pages 6970-6974, doi:10.1016/j.bmcl.2009.10.050

Screening our in-house compound collection using a cell based Plasmodium falciparum proliferation assay we discovered a known pan-kinase inhibitor scaffold as a hit. Further optimization of this series led us to a novel benzamide scaffold which was devoid of human kinase activity while retaining its antiplasmodial activity. The evolution of this compound series leading to optimized candidates with good cellular potency against multiple strains as well as decent in vivo profile is described in this Letter.

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Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines.

November 18, 2009 - 12:56 -- Kabogo Ndegwa
Author(s): 
Martin Michaelis, Malte C. Kleinschmidt, Susanne Barth, Florian Rothweiler, Janina Geiler, Rainer Breitling, Bernd Mayer, Hedwig Deubzer, Olaf Witt, Jörg Kreuter, Hans Wilhelm Doerr, Jaroslav Cinatl, Jindrich Cinatl Jr.
Reference: 
Biochemical Pharmacology, Volume 79, Issue 2, 15 January 2010, Pages 130-136, doi:10.1016/j.bcp.2009.08.013

Artemisinin derivatives are well-tolerated anti-malaria drugs that also exert anti-cancer activity. Here, we investigated artemisinin and its derivatives dihydroartemisinin and artesunate in a panel of chemosensitive and chemoresistant human neuroblastoma cells as well as in primary neuroblastoma cultures.

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Synthesis and structure–activity relationships of cassiarin A as potential antimalarials with vasorelaxant activity.

November 18, 2009 - 12:54 -- Kabogo Ndegwa
Author(s): 
Hiroshi Morita, Yuichiro Tomizawa, Jun Deguchi, Tokio Ishikawa, Hiroko Arai, Kazumasa Zaima, Takahiro Hosoya, Yusuke Hirasawa, Takayuki Matsumoto, Katsuo Kamata, Wiwied Ekasari, Aty Widyawaruyanti, Tutik Sri Wahyuni, Noor Cholies Zaini, Toshio Honda.
Reference: 
Bioorganic & Medicinal Chemistry, Volume 17, Issue 24, 15 December 2009, Pages 8234-8240, doi:10.1016/j.bmc.2009.10.013

Cassiarin A 1, a tricyclic alkaloid, isolated from the leaves of Cassia siamea (Leguminosae), shows powerful antimalarial activity against Plasmodium falciparum in vitro as well as P. berghei in vivo, which may be valuable leads for novel antimalarials.

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Anti-tumoral activity of imidazoquines, a new class of antimalarials derived from primaquine.

November 18, 2009 - 12:53 -- Patrick Sampao
Author(s): 
Iva Fernandes, Nuno Vale, Victor de Freitas, Rui Moreira, Nuno Mateus, Paula Gomes.
Reference: 
Bioorganic & Medicinal Chemistry Letters, Volume 19, Issue 24, 15 December 2009, Pages 6914-6917, doi:10.1016/j.bmcl.2009.10.081

The growth inhibitory activity of imidazoquines, antimalarial imidazolidin-4-ones derived from primaquine, on human cancer cell lines HT-29, Caco-2, and MCF-7 has been evaluated.

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Transport of purines and purine salvage pathway inhibitors by the Plasmodium falciparum equilibrative nucleoside transporter PfENT1.

November 18, 2009 - 12:51 -- Kabogo Ndegwa
Author(s): 
Paul M. Riegelhaupt, María B. Cassera, Richard F.G. Fröhlich, Keith Z. Hazleton, Jonathan J. Hefter, Vern L. Schramm, Myles H. Akabas
Reference: 
Molecular and Biochemical Parasitology, Volume 169, Issue 1, January 2010, Pages 40-49, doi:10.1016/j.molbiopara.2009.10.001

Plasmodium falciparum is a purine auxotroph. The transport of purine nucleosides and nucleobases from the host erythrocyte to the parasite cytoplasm is essential to support parasite growth. P. falciparum equilibrative nucleoside transporter 1 (PfENT1) is a major route for purine transport across the parasite plasma membrane. Malarial parasites are sensitive to inhibitors of purine salvage pathway enzymes. The immucillin class of purine nucleoside phosphorylase inhibitors and the adenosine analog, tubercidin, block growth of P. falciparum under in vitro culture conditions. We sought to determine whether these inhibitors utilize PfENT1 to gain access to the parasite cytosol.

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In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in pfcrt and pfmdr1.

November 18, 2009 - 12:47 -- Patrick Sampao
Author(s): 
Leah Mwai, Steven M. Kiara, Abdi Abdirahman, Lewa Pole, Anja Rippert, Abdi Diriye, Pete Bull, Kevin Marsh, Steffen Borrmann, and Alexis Nzila
Reference: 
Antimicrobial Agents and Chemotherapy, December 2009, p. 5069-5073, Vol. 53, No. 12, doi:10.1128/AAC.00638-09

We have analyzed the in vitro chemosensitivity profiles of 115 Kenyan isolates for chloroquine (CQ), piperaquine, lumefantrine (LM), and dihydroartemisinin in association with polymorphisms in pfcrt at codon 76 and pfmdr1 at codon 86, as well as with variations of the copy number of pfmdr1.

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Transcriptomic Profiling of the Saccharomyces cerevisiae Response to Quinine Reveals a Glucose Limitation Response Attributable to Drug-Induced Inhibition of Glucose Uptake

November 18, 2009 - 12:43 -- Patrick Sampao
Author(s): 
Sandra C. dos Santos, Sandra Tenreiro, Margarida Palma,Jorg Becker, and Isabel Sá-Correia.
Reference: 
Antimicrobial Agents and Chemotherapy, December 2009, p. 5213-5223, Vol. 53, No. 12, doi:10.1128/AAC.00794-09

Quinine has been employed in the treatment of malaria for centuries and is still used against severe Plasmodium falciparum malaria. However, its interactions with the parasite remain poorly understood and subject to debate. In this study, we used the Saccharomyces cerevisiae eukaryotic model to better understand quinine's mode of action and the mechanisms underlying the cell response to the drug.

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Review; Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria

November 18, 2009 - 12:42 -- Kabogo Ndegwa
Author(s): 
Richard T. Eastman1 & David A. Fidock1
Reference: 
Nature Reviews Microbiology 7, 864-874 (December 2009) doi:10.1038/nrmicro2239

Plasmodium falciparum resistance to chloroquine and sulphadoxine–pyrimethamine has led to the recent adoption of artemisinin-based combination therapies (ACTs) as the first line of treatment against malaria. ACTs comprise semisynthetic artemisinin derivatives paired with distinct chemical classes of longer acting drugs. These artemisinins are exceptionally potent against the pathogenic asexual blood stages of Plasmodium parasites and also act on the transmissible sexual stages.

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The dynamics of mutations associated with anti-malarial drug resistance in Plasmodium falciparum.

November 18, 2009 - 12:38 -- Kabogo Ndegwa
Author(s): 
Ananias A. Escalante, David L. Smith, Yuseob Kim.
Reference: 
Trends in Parasitology, Volume 25, Issue 12, December 2009, Pages 557-563, doi:10.1016/j.pt.2009.09.008

The evolution of resistance in Plasmodium falciparum against safe and affordable drugs such as chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) is a major global health threat. Investigating the dynamics of resistance against these antimalarial drugs will lead to approaches for addressing the problem of resistance in malarial parasites that are solidly based in evolutionary genetics and population biology. In this article, we discuss current developments in population biology modeling and evolutionary genetics.

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Redefining the role of de novo fatty acid synthesis in Plasmodium parasites.

November 18, 2009 - 12:36 -- Kabogo Ndegwa
Author(s): 
Alice S. Tarun, Ashley M. Vaughan, Stefan H.I. Kappe.
Reference: 
Trends in Parasitology, Volume 25, Issue 12, December 2009, Pages 545-550, doi:10.1016/j.pt.2009.09.002

Fatty acids are essential components of membranes, and are also involved in cell signalling. Plasmodium, the parasite that causes malaria, scavenges fatty acids from its hosts. However, Plasmodium also possesses enzymes for a prokaryotic-like de novo fatty acid synthesis pathway, which resides in the apicoplast. Recent research has demonstrated that Plasmodium parasites depend on de novo fatty acid synthesis only for liver-stage development.

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