Aminoalkyl Derivatives of Guanidine Diaromatic Minor Groove Binders with Antiprotozoal Activity

Considering the strong DNA minor groove binding observed for our previous series of diaromatic symmetric and asymmetric guanidinium and 2-aminoimidazolinium derivatives, we report now the synthesis of new aminoalkyl derivatives of diaromatic guanidines with potential as DNA minor groove binders and antiprotozoal activity. The preparation of these aminoalkyl derivatives (<b>12a</b>–<b>e</b>, <b>13a</b>–<b>e</b>, <b>14a</b>–<b>c</b>,<b>e</b>, <b>15a</b>–<b>e</b>, <b>16a</b>–<b>e</b>) is presented as well as their affinity for DNA which was evaluated by means of DNA thermal denaturation experiments. Finally, the antiprotozoal activity of most of these aminoalkyl minor groove binders was evaluated in vitro against <i>Trypanosoma brucei rhodesiense</i> (8 compounds) and <i>Plasmodium falciparum</i> (18 compounds). The O-linked derivatives <b>13c</b> and <b>14c</b> showed 100 nM activities against <i>P. falciparum,</i> whereas for <i>T. b. rhodesiense</i> all compounds tested showed micromolar activity. Some of the derivatives prepared seem to exert the antimalarial activity by binding to the DNA minor groove whereas other sets of compounds could exert this antimalarial activity by inhibiting the parasite dihydrofolate reductase, for example

Will oral semaglutide be a game-changer in the management of type 2 diabetes in primary care?

GLP-1 receptor agonists (GLP-1RAs) are recommended for patients with type 2 diabetes (T2D), particularly those at high cardiovascular risk. Oral semaglutide is the first oral GLP-1RA. In clinical trials, oral semaglutide 14 mg reduced mean HbA1c by approximately 1.1–1.5% and reduced body weight by up to 5 kg. These changes were significantly greater compared with empagliflozin, sitagliptin and liraglutide (p < 0.05 for estimated treatment differences at 52 weeks in patients on treatment without rescue medication use). The most common side effects were gastrointestinal, mainly mild-to-moderate and transient nausea. Oral semaglutide may change the paradigm of T2D treatment in primary care

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

<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

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

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

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

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

Antiprotozoal Activity-Based Profiling of a Dichloromethane Extract from <i>Anthemis nobilis</i> Flowers

A dichlomethane extract of <i>Anthemis nobilis</i> flower cones showed promising in vitro antiprotozoal activity against <i>Trypanosoma brucei rhodesiense</i> and <i>Leishmania donovani</i>, with IC₅₀ values of 1.43 ± 0.50 and 1.40 ± 0.07 μg/mL, respectively. A comprehensive profiling of the most active fractions afforded 19 sesquiterpene lactones, including 15 germacranolides, two <i>seco</i>-sesquiterpenes, one guaianolide sesquiterpene lactone, and one cadinane acid. Of these, 13 compounds were found to be new natural products. The compounds were characterized by extensive spectroscopic data analysis (1D and 2D NMR, HRMS, circular dichroism) and computational methods, and their in vitro antiprotozoal activity was evaluated. The furanoheliangolide derivative <b>15</b> showed high potency and selectivity in vitro against <i>T. b. rhodesiense</i> bloodstream forms (IC₅₀ 0.08 ± 0.01 μM; SI 63). In silico calculations were consistent with the drug-like properties of <b>15</b>

<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