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

<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. 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

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

Methionine-Containing Rhabdopeptide/Xenortide-like Peptides from Heterologous Expression of the Biosynthetic Gene Cluster <i>kj12ABC</i> in <i>Escherichia coli</i>

Seven new methionine-containing rhabdo­peptide/​xenortide-like peptides (1–7) were identified from Escherichia coli expressing the rhabdo­peptide/​xenortide-like peptide biosynthetic gene cluster kj12ABC from Xenorhabdus KJ12.1. Their structures were elucidated by detailed HPLC-HR-MS/MS analysis and confirmed by chemical synthesis. Bioactivity tests of these first rhabdo­peptide/​xenortide-like peptide derivatives (2–7) showing methionine building blocks compared to the usually found derivatives containing exclusively hydrophobic amino acids such as valine, leucine, or phenyl­alanine revealed good activities of 2–7 against protozoan parasites and no cytotoxicity against mammalian L6 cells

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

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

Synthesis and Antimalarial Efficacy of Aza-Fused Rhodacyanines in Vitro and in the <i>P. berghei </i>Mouse Model

Several aza-fused rhodacyanines were synthesized and assessed for their in vitro and in vivo antimalarial activities against Plasmodium falciparum K1 and P. berghei. All synthetic compounds showed strong selective antimalarial in vitro activity. Class II azarhodacyanines, 3, consisting of four heterocyclic units, were found to display good parasitemia suppression and low acute toxicity in vivo. Among them, 3c appeared to be the most effective at a dose of 20−25 mg kg-1 day-1 (ip)

Synthesis and Antimalarial Property of Orally Active Phenoxazinium Salts

Phenoxazinium salts were found to display good antimalarial efficacy in vivo against Plasmodium berghei. Several compounds provided 100% parasitemia clearance at a dose of 20−30 mg kg-1 × 4 days (ip) and good survival effects without obvious acute toxicity. They also showed excellent potency by oral administration. A preliminary pharmacokinetic study revealed that the oral availability of 1a was excellent