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Sent on Sunday, 2011 Jan 30Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | ChemMedChem. 2011 Feb 7;6(2):321-328. doi: 10.1002/cmdc.201000442. Epub 2010 Dec 15.Synthesis and Evaluation of Indatraline-Based Inhibitors for Trypanothione Reductase.Walton JG, Jones DC, Kiuru P, Durie AJ, Westwood NJ, Fairlamb AH.School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST (UK), Fax: (+44) 1334-462595. AbstractThe search for novel compounds of relevance to the treatment of diseases caused by trypanosomatid protozoan parasites continues. Screening of a large library of known bioactive compounds has led to several drug-like starting points for further optimisation. In this study, novel analogues of the monoamine uptake inhibitor indatraline were prepared and assessed both as inhibitors of trypanothione reductase (TryR) and against the parasite Trypanosoma brucei. Although it proved difficult to significantly increase the potency of the original compound as an inhibitor of TryR, some insight into the preferred substituent on the amine group and in the two aromatic rings of the parent indatraline was deduced. In addition, detailed mode of action studies indicated that two of the inhibitors exhibit a mixed mode of inhibition. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
| PMID: 21275055 [PubMed - as supplied by publisher] | |
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| 2. | ChemMedChem. 2011 Feb 7;6(2):302-308. doi: 10.1002/cmdc.201000450. Epub 2010 Dec 29.Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1.Spinks D, Ong HB, Mpamhanga CP, Shanks EJ, Robinson DA, Collie IT, Read KD, Frearson JA, Wyatt PG, Brenk R, Fairlamb AH, Gilbert IH.Drug Discovery Unit, Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, Scotland, DD1 5EH (UK), Fax: (+44) 1382-386-373. AbstractGenetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for the survival of the protozoan parasite Trypanosoma brucei. Herein, we describe the development and optimisation of a novel series of PTR1 inhibitors, based on benzo[d]imidazol-2-amine derivatives. Data are reported on 33 compounds. This series was initially discovered by a virtual screening campaign (J. Med. Chem., 2009, 52, 4454). The inhibitors adopted an alternative binding mode to those of the natural ligands, biopterin and dihydrobiopterin, and classical inhibitors, such as methotrexate. Using both rational medicinal chemistry and structure-based approaches, we were able to derive compounds with potent activity against T. brucei PTR1 (${K{{{\rm app}\hfill \atop {\rm i}\hfill}}}$=7 nM), which had high selectivity over both human and T. brucei dihydrofolate reductase. Unfortunately, these compounds displayed weak activity against the parasites. Kinetic studies and analysis indicate that the main reason for the lack of cell potency is due to the compounds having insufficient potency against the enzyme, which can be seen from the low K(m) to K(i) ratio (K(m) =25 nM and K(i) =2.3 nM, respectively). Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
| PMID: 21275054 [PubMed - as supplied by publisher] | |
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| 3. | ChemMedChem. 2011 Feb 7;6(2):292-301. doi: 10.1002/cmdc.201000420. Epub 2010 Dec 16.Improved Inh ibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities.Eberle C, Lauber BS, Fankhauser D, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F.Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zürich (Switzerland), Fax: (+41) 44-632-1109. AbstractTrypanothione reductase (TR) is an essential enzyme in the trypanothione-based redox metabolism of trypanosomatid parasites. This system is absent in humans and, therefore, offers a promising target for the development of selective new drugs against African sleeping sickness and Chagas' disease. Over the past two decades, a variety of nonpeptidic small-molecule ligands of the parasitic enzyme were discovered. A current goal is to decipher the binding mode of these known inhibitors in order to optimize their structures. We analyzed the binding mode of recently reported 1-(1-(benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues using computer modeling methods. This led us to conclude that the analogues occupy a different region of the active site than the diaryl sulfide-based class of inhibitors. A combination of the two motifs significantly increased affinity for the enzyme compared to the respective parent compounds. The newly synthesized conjugates exhibit K(ic) values for TR as low as 0.51±0.1 μM and high selectivity for the parasitic enzyme over the related human glutathione reductase (hGR), as was predicted by our molecular modeling studies. In vitro studies showed IC(50) values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense, often in combination with low cytotoxicity against mammalian cells. Interestingly, even stronger activities were found against Plasmodium falciparum. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
| PMID: 21275053 [PubMed - as supplied by publisher] | |
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| 4. | ChemMedChem. 2011 Feb 7;6(2):273-278. doi: 10.1002/cmdc.201000449. Epub 2010 Nov 25.Potent and S elective Inhibition of Cysteine Proteases from Plasmodium falciparum and Trypanosoma brucei.Ehmke V, Heindl C, Rottmann M, Freymond C, Schweizer WB, Brun R, Stich A, Schirmeister T, Diederich F.Laboratory of Organic Chemistry, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland), Fax: (+41) 44-632-1109. |
| PMID: 21275051 [PubMed - as supplied by publisher] | |
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| 5. | Exp Parasitol. 2011 Jan 24. [Epub ahead of print]Trypanocidal properties, structure-activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives.Estevez Y, Quiliano M, Burguete A, Cabanillas B, Zimic M, Málaga E, Verástegui M, Pérez-Silanes S, Aldana I, Monge A, Castillo D, Deharo E.Université de Toulouse ;UPS ;UMR 152 (Laboratoire de pharmacochimie des substances naturelles et pharmacophores redox), 118, rte de Narbonne, F-31062 Toulouse cedex 9, France. AbstractPyrazole and propenone quinoxaline derivatives were tested against intracellular forms of Leishmania peruviana and Trypanosoma cruzi. Both series were tested for toxicity against proliferative and non-proliferative cells. The pyrazole quinoxaline series was quite inactive against T. cruzi; however, the compound 2,6-dimethyl-3-f-quinoxaline 1,4-dioxide was found to inhibit 50% of Leishmania growth at 8.9 μM, with no impact against proliferative kidney cells and with low toxicity against THP-1 cells and murine macrophages. The compounds belonging to the propenone quinoxaline series were moderately active against T. cruzi. Among these compounds, two were particularly interesting, (2E)-1-(7-Fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone and (2E)-3-(3,4,5-Trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone. The former possessed selective activity against proliferative cells (cancer and parasites) and was inactive against murine peritoneal macrophages; the latter was active against Leishmania and inactive against the other tested cells. Furthermore, insilico studies showed that both series respected Lipinski's rules and that they confirmed a linear correlation between trypanocidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi. Copyright © 2011. Published by Elsevier Inc. |
| PMID: 21272583 [PubMed - as supplied by publisher] | |
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| 6. | Exp Parasitol. 2011 Jan 24. [Epub ahead of print]Leishmania mexicana: LACK (Leishmania homologue of receptors for activated C-kinase) i s a plasminogen binding protein.Gómez-Arreaza A, Acosta H, Barros-Álvarez X, Concepción JL, Albericio F, Avilan L.Laboratorio de Fisiología, Facultad de Ciencias, Universidad de Los Andes, La Hechicera, Mérida 5101, Venezuela. AbstractLeishmania mexicana is able to interact with the fibrinolytic system through its component plasminogen, the zymogenic form of the protease plasmin. In this study a new plasminogen binding protein of this parasite was identified: LACK, the Leishmania homologue of receptors for activated C-kinase. Plasminogen binds recombinant LACK with a K(d) value of 1.6 ± 0.4 μM, and binding is lysine-dependent since it is inhibited by the lysine analogue ε-aminocaproic acid. Inhibition studies with specific peptides and plasminogen binding activity of a mutated recombinant LACK have highlighted the internal motif (260)VYDLESKAV(268), similar to those found in several enolases, as involved in plasminogen binding. Recombinant LACK and secreted proteins, in medium conditioned by parasites, enhance plasminogen activation to plasmin by the tissue plasminogen activator (t-PA). In addition to its localization in the cytosol, in the microsomal fraction and as secreted protein in conditioned medium, LACK was also localized on the external surface of the membrane. The results presented here suggest that LACK might bind and enhance plasminogen activation in vivo promoting the formation of plasmin. Plasminogen binding of LACK represents a new function for this protein and might contribute to the invasiveness of the parasite. Copyright © 2011. Published by Elsevier Inc. |
| PMID: 21272581 [PubMed - as supplied by publisher] | |
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| 7. | Neotrop Entomol. 2010 Dec;39(6):1032-1038.Sand flies (Diptera: Psychodidae) in a cerrado area of the Maranhão state, Brazil.Silva FS, Carvalho LP, Cardozo FP, Moraes JL, Rebêlo JM.Depto de Biologia, Centro de Ciências Agrárias e Ambientais, Univ Federal do Maranhão, Chapadinha, MA, Brasil. AbstractThe present paper aims to increase the knowledge on the sand fly fauna in the cerrado areas of Maranhão state in urban, rural and forest environments. The research was carried out from October 2007 to September 2008, between 18:00h and 06:00h, in the municipality of Chapadinha, northeast Maranhão. For insect sampling, CDC light traps were set up in peridomicile and domicile areas of urban and rural zones as well as in Cerrado and Gallery forests. The total of 1,401 specimens belonging to 17 species were sampled, all within the genus Lutzomyia. Lutzomyia longipalpis (Lutz & Neiva) (52.5%), Lu. evandroi (Costa Lima & Antunes) (18.3%), Lu. whitmani (Antunes & Coutinho) (12.1%), Lu. lenti (Mangabeira) (4.7%) and Lu. termitophila (Martins, Falcão & Silva) (4.0%) were the most frequently collected. From an epidemiological viewpoint, five from all of the collected species are vectors of leishmaniasis: Lu. longipalpis, Lu. whitmani, Lu. flaviscutellata (Mangabeira), Lu. gomezi (Nitzulescu) and Lu. chagasi (Costa Lima). Lutzomyia chagasi was registered for the first time in Maranhão state and Lu. saulensis (Floch & Abonnenc), Lu. monstruosa (Floch & Abonnenc) and Lu. gomezi were found for the first time in the eastern part of the state, since they had been reported only in the Amazonian region of Maranhão. Regarding to the studied environments, the urban chicken house had the highest number of specimens collected (801), while the Gallery Forest was the most diverse (15 species). This study demonstrates that the northeast cerrado exhibits a mixed sand fly fauna characterized by an extremely important species vectors assortment involved in the epidemiological cycle of leishmaniasis in Maranhão state. |
| PMID: 21271075 [PubMed - as supplied by publisher] | |
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| 8. | Int J Nanomedicine. 2010 Dec 9;5:1113-1121.Andrographolide nanoparticles in leishmaniasis: characterization and in vitro evaluations.Roy P, Das S, Bera T, Mondol S, Mukherjee A.Department of Chemical Technology, University of Calcutta, Kolkata, West Bengal, India. AbstractAndrographolide (AG) is a diterpenoid lactone isolated from the leaves of Andrographis paniculata. AG is a potent and low-toxicity antileishmanial agent. Chemotherapy applications of AG are, however, seriously constrained because of poor bioavailability, short plasma half-life, and inappropriate tissue localization. Nanoparticulation of AG was therefore envisaged as a possible solution. AG nanoparticles (AGnp) loaded in 50:50 poly(DL-lactide-co-glycolic acid) were prepared for delivery into the monocyte-macrophage cells infested with the amastigote form of leishmanial parasite for evaluation in the chemotherapy of leishmaniasis. Particle characteristics of AGnp were optimized by proportionate application of a stabilizer, polyvinyl alcohol (PVA). Physicochemical characterization of AGnp by photon correlation spectroscopy exhibited an average particle size of 173 nm and zeta potential of -34.8 mV. Atomic force microscopy visualization revealed spherical nanoparticles with a smooth surface. Antileishmanial activity was found to be significant for the nanoparticle preparation with 4% PVA (IC(50) 34 μM) in about one-fourth of the dosage of the pure compound AG (IC(50) 160 μM). AGnp therefore have significant potential to target the infested macrophage cells and prove valuable in chemotherapy of neglected tropical diseases such as leishmaniasis. |
| PMID: 21270962 [PubMed - as supplied by publisher] | |
| 9. | J Egypt Soc Parasitol. 2010 Dec;40(3):797-808.Opportunistic parasitic infections among immunocompromised Egyptian patients.Baiomy AM, Mohamed KA, Ghannam MA, Shahat SA, Al-Saadawy AS.Department of Parasitology, Faculties of Medicine, Al-Azhar University, Nasr City, Cairo, Egypt. AbstractThe commonest opportunistic parasites causing morbidity and/or mortality in the immuno-compromised subjects are mainly the gastro-intestinal ones. This study clarified the prevalence of the opportunistic parasites among a group of immunocompromised patients selected from Al Azhar University Hospitals. One hundred immunocompromised patients (GI) were divided into GIa: 40 malignancy patients. GIb: 30 with diabetes mellitus. GIc: 30 with chronic renal failure. GII: included 20 cross-matched healthy subjects as controls. Sheets were filled out on each subject including all personal and medical history. Both groups were subjected to stool and blood examinations for parasites. The results showed opportunistic parasites in 30% of patients and in 10% of healthy controls. The highest group had parasitosis was patients suffering from malignancy (18%). The patients suffering from chronic renal failure or from diabetes mellitus were equally affected (6% each group). There was significant relation between malignant patients and diabetic or chronic renal failure ones, but without significant relation between diabetic and chronic renal failure patients. Giardia lamblia was the most common parasite found in the patients (10%) of which 5% were among patients suffering from malignancy. Others were Cryptospotidium parvum (7%) Cyclospora cayetanensis (3%) and Microsporidia species (2%). Mixed infection was detected in 2 cases that had C. parvum and Cyclospora. But, neither Isospora belli nor Strongyloides stercoralis were detected. Also, ELISA showed antibodies against Toxoplasma gondii in sex patients but none against Leishmania d. infantum. |
| PMID: 21268546 [PubMed - in process] | |
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| 10. | J Egypt Soc Parasitol. 2010 Dec;40(3):609-16.Efficacy of two rodenticides against Leishmania reservoir host rat (Psammomys obesus) in the rural area of Al-Ahsa Oasis, Saudi Arabia.Al-Mohammed HI.Department of Medical Microbiology and Parasitology, College of Medicine, King Faisal University, P.O. Box:400, Al-Ahsa:31982, Saudi Arabia. hamdan@kfu.edu.sa AbstractZoonotic cutaneous leishmaniasis (ZCL) is a serious and increasing public health problem in many parts of Saudi Arabia. Rodent control operations are effective in destroying rodents and reducing the incidence of disease. This study tested the efficacy of zinc phosphide and fenacoum against the reservoir host Psammomys obesus rat. The results showed that both the rodenticides were significantly (P < 0.01) effective in reducing the number of active holes during one year of application. |
| PMID: 21268531 [PubMed - in process] | |
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