Recent Advances in the Discovery of Haem-Targeting Drugs for Malaria and Schistosomiasis
"> Figure 1
<p>The mainstays of malaria and schistosomiasis chemotherapy: (a) chloroquine and (b) praziquantel, respectively.</p> "> Figure 2
<p>Haemozoin inhibitors identified through HTS [<a href="#B50-molecules-14-02868" class="html-bibr">50</a>]. The compound classes (a) miscellaneous, (b) benzophenone, (c) triarylcarbinol and (d) piperazine were identified experimentally, while compounds (c) – (g) were identified using <span class="html-italic">in silico</span> methods. The structures in bold [(c) and (d)] represent the intersection of these two methods.</p> "> Figure 3
<p>Classes of novel haem-targeting chemotypes identified through a modified HTS assay [<a href="#B51-molecules-14-02868" class="html-bibr">51</a>]: (a) pyrimidines and (b) 1,3-benzoxathiol-2-ones.</p> "> Figure 4
<p>A potentially new haem-targeting antimalarial compound discovered by virtual screening: nicotinic acid [trans-3-(4-ethoxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)-allylidene]-hydrazide [<a href="#B57-molecules-14-02868" class="html-bibr">57</a>].</p> "> Figure 5
<p>The crystal structure of the Fe(III)PPIX-halofantrine complex. Thermal ellipses are drawn at 50% probability, illustrating significant disorder in the Fe(III)PPIX vinyl groups, butyl chain termini of halofantrine and the included acetone molecule. Atom colouring: C: grey, Cl: yellow; F: Prussian blue, Fe: cyan, H: white, N: blue, O: red. Reprinted with permission from reference [<a href="#B63-molecules-14-02868" class="html-bibr">63</a>]. Copyright 2008 Elsevier.</p> "> Figure 6
<p>(a) A model of β-haematin viewed along the <span class="html-italic">a</span> axis. The corrugation of the (001) face is indicated by the green line. Reprinted with permission from reference [<a href="#B65-molecules-14-02868" class="html-bibr">65</a>]. Copyright 2002 American Chemical Society. Quinolines (for example chloroquine) are able to dock into the grooves and are stabilised by various close contacts discussed in the text (b). The original coordinates for β-haematin were used to build the crystal [<a href="#B67-molecules-14-02868" class="html-bibr">67</a>].</p> "> Figure 7
<p>Piperazinyl derivatives of acetylursolic acid with nanomolar <span class="html-italic">in vitro</span> activities against FcB1 <span class="html-italic">P. falciparum</span> [<a href="#B68-molecules-14-02868" class="html-bibr">68</a>]. (a) R<sub>1</sub> = R<sub>2</sub> = H, (b) the deacetylated version of (a), (c) R<sub>1</sub> = R<sub>2</sub> = 4-hydroxybenzyl, (d) R<sub>1</sub> = R<sub>2</sub> = methylcyclopropyl, (e) R<sub>1</sub> = R<sub>2</sub> = propyl, (f) R<sub>1</sub> = H, R<sub>2</sub> = 4-hydroxybenzyl, (g) R<sub>1</sub> = H, R<sub>2</sub> = methylferrocenyl.</p> "> Figure 8
<p>Novel clotrimazole-based antimalarial compounds. (a) A typical clotrimazole derivative showing imidazole (solid ring) and protonatable amine (dashed ring) [<a href="#B73-molecules-14-02868" class="html-bibr">73</a>]. Generalised hybrid compounds combining a 4-aminoquinoline nucleus with (b) a simplified benzhydryl moiety or (c) the triarylmethyl moiety of clotrimazole. (d) The 4-aminoquinoline-benzhydryl analogue chosen for preclinical studies.</p> "> Figure 9
<p>Acridone derivative T3.5, highlighting the haem-targeting nucleus overlapping the chemosensitising diamine moiety. Redrawn based on the original reference [<a href="#B77-molecules-14-02868" class="html-bibr">77</a>].</p> ">
Abstract
:Introduction
Chemotherapy of Human Malaria and Schistosomiasis
Advances in High-Throughput Screening Methods
Interactions of Existing Antimalarials with Haem
Drug Discovery: Pharmacophore-Based Drug Design
Conclusions
References
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De Villiers, K.A.; Egan, T.J. Recent Advances in the Discovery of Haem-Targeting Drugs for Malaria and Schistosomiasis. Molecules 2009, 14, 2868-2887. https://doi.org/10.3390/molecules14082868
De Villiers KA, Egan TJ. Recent Advances in the Discovery of Haem-Targeting Drugs for Malaria and Schistosomiasis. Molecules. 2009; 14(8):2868-2887. https://doi.org/10.3390/molecules14082868
Chicago/Turabian StyleDe Villiers, Katherine A., and Timothy J. Egan. 2009. "Recent Advances in the Discovery of Haem-Targeting Drugs for Malaria and Schistosomiasis" Molecules 14, no. 8: 2868-2887. https://doi.org/10.3390/molecules14082868