Agrochemicals against Malaria, Sleeping Sickness, Leishmaniasis and Chagas Disease

<div><p>In tropical regions, protozoan parasites can cause severe diseases with malaria, leishmaniasis, sleeping sickness, and Chagas disease standing in the forefront. Many of the drugs currently being used to treat these diseases have been developed more than 50 years ago and can cause severe adverse effects. Above all, resistance to existing drugs is widespread and has become a serious problem threatening the success of control measures. In order to identify new antiprotozoal agents, more than 600 commercial agrochemicals have been tested on the pathogens causing the above mentioned diseases. For all of the pathogens, compounds were identified with similar or even higher activities than the currently used drugs in applied <em>in vitro</em> assays. Furthermore, <em>in vivo</em> activity was observed for the fungicide/oomyceticide azoxystrobin, and the insecticide hydramethylnon in the <em>Plasmodium berghei</em> mouse model, and for the oomyceticide zoxamide in the <em>Trypanosoma brucei rhodesiense</em> STIB900 mouse model, respectively.</p> </div

<i>In vitro</i> activity of the top 10 most active commercial agrochemicals on <i>P. falciparum</i> NF54 strain.

<p>The IC₅₀ values are the means of two independent assays; the individual values vary by less than a factor of 2.</p

Top 10 most active commercial agrochemicals on <i>T. cruzi</i>.

<p>The IC₅₀ values are the means of two independent assays; the individual values vary by less than a factor of 2.</p

Top 10 most active commercial agrochemicals on <i>T. b. rhodesiense</i>.

<p>The IC₅₀ values are the means of two independent assays; the individual values vary by less than a factor of 2.</p

Most active commercial agrochemicals on <i>L. donovani</i>.

<p>The IC₅₀ values are the means of two independent assays; the individual values vary by less than a factor of 2.</p

Final Report of the Evaluation of the Teaching and Learning Technology Programme

<p>^<i>a</i><i>L</i>. <i>don</i>. axen.: axenic amastigotes of <i>L</i>. <i>donovani</i>, strain MHOM-ET-67/L82.</p><p>^<i>b</i><i>L</i>. <i>don</i>. intracell: intracellular amastigotes of <i>L</i>. <i>donovani</i> strain MHOM-ET-67/L82.</p><p>^cCytotoxicity on macrophages infected with <i>L</i>. <i>donovani</i>.</p><p>^dCytotoxicity on peritoneal mouse macrophages.</p><p>^eSelectivity index: IC₅₀ Cytotoxicity macrophages/ IC₅₀<i>L</i>. <i>donovani</i>. IC₅₀ values are means of two independent assays, which varied < ±50%.</p><p><i>In vitro</i> activity against <i>L</i>. <i>donovani</i> in IC₅₀ (μM) of compounds fulfilling hit criteria.</p

<i>In vitro</i> activity against <i>T</i>. <i>cruzi</i> in IC₅₀ (μM) of compounds fulfilling hit criteria.

<p>^a<i>T</i>. <i>cruzi</i>, strain Tulahuen C4, intracellular amastigotes.</p><p>^bCytotoxicity on L6 cells.</p><p>^cSelectivity index: IC₅₀ Cytotoxicity L6/ IC₅₀<i>T</i>. <i>cruzi</i>.</p><p>IC₅₀ values are means of two independent assays, which varied < ±50%.</p><p><i>In vitro</i> activity against <i>T</i>. <i>cruzi</i> in IC₅₀ (μM) of compounds fulfilling hit criteria.</p

Antiprotozoal Sesquiterpene Lactones and Other Constituents from <i>Tarchonanthus camphoratus</i> and <i>Schkuhria pinnata</i>

In continuation of a search for new antiprotozoal agents from plants of the family Asteraceae, <i>Tarchonanthus camphoratus</i> and <i>Schkuhria pinnata</i> have been investigated. By following the promising in vitro activity of the dichloromethane extracts from their aerial parts, bioassay-guided chromatographic isolation yielded two known sesquiterpene lactones (<b>1</b> and <b>2</b>) from <i>T. camphoratus</i> and 20 known compounds of this type from <i>S. pinnata.</i> From the latter, a new eudesmanolide, (1<i>R</i>*,5<i>S</i>*,6<i>R</i>*,7<i>R</i>*,8<i>R</i>*,10<i>R</i>*)-1-hydroxy-8-[5″-hydroxy-4′-(2″-hydroxyisovaleroyloxy)­tigloyloxy]-3-oxoeudesma-11­(13)-en-6,12-olide (<b>3</b>), and two new germacranolides, 3β-(2″-hydroxyisovaleroyloxy)-8β-(3-furoyloxy)­costunolide (<b>14</b>) and 1(10)-epoxy-3β-hydroxy-8β-[5′-hydroxy-4′-(2″-hydroxyisovaleroyloxy)­tigloyloxy]­costunolide (<b>16</b>), were obtained. Additionally, the flavonoid pectolinarigenin (<b>24</b>) and 3-hydroxy-4,5-dimethoxybenzenepropanol (<b>25</b>) were also isolated from <i>S. pinnata</i>. The compounds were characterized by analysis of 1D and 2D NMR spectroscopic and HR/MS data. In vitro antitrypanosomal activity and cytotoxicity against mammalian cells (L6 cell line) were evaluated for all the compounds. Santhemoidin A (<b>13</b>) and 3β-(2″-hydroxyisovaleroyloxy)-8β-(3-furoyloxy)­costunolide (<b>14</b>) were the most active compounds found in this study, with IC₅₀ values of 0.10 and 0.13 μM against <i>Trypanosoma brucei rhodesiense</i> trypomastigotes and selectivity indices of 20.5 and 29.7, respectively

In vitro activity against T.b. rhodesiense in IC50 (μM) of compounds fulfilling hit criteria.

<p>^a<i>T</i>. <i>b</i>. <i>rhod</i>.:<i>T</i>. <i>b</i>. <i>rhodesiense</i> strain STIB 900, trypomastigotes.</p><p>^bCytotoxicity on L6 cells.</p><p>^cSelectivity index: IC₅₀ Cytotoxicity L6/ IC₅₀<i>T</i>. <i>b</i>. <i>rhodesiense</i>.</p><p>IC₅₀ values are means of two independent assays, which varied < ±50%.</p><p>In vitro activity against T.b. rhodesiense in IC50 (μM) of compounds fulfilling hit criteria.</p

TDR17516 and analogue TDR42098; TDR 22093 and analogue CAS 74944-18-6; and TDR 20364.

<p>TDR17516 and analogue TDR42098; TDR 22093 and analogue CAS 74944-18-6; and TDR 20364.</p