Hydroformylation of Homoallylic Azides: A Rapid Approach toward Alkaloids

Unprecedented hydroformylation of homoallylic azides combined with useful one-pot operations provides an expeditive access to alkaloids

Analysis of the Physicochemical Properties of Anti-Schistosomal Compounds to Identify Next-Generation Leads

To investigate the physicochemical properties of anti-schisto­somal compounds reported between 2008 and 2023, a simple but extensive literature scrutiny was conducted. Keywords were searched in Chemical Abstracts Service (CAS) SciFinder and primary medicinal chemistry and pharmacology literature to locate publications with compounds displaying ex vivo and/or in vivo anti-schisto­somal activity. A total of 57 repurposed U.S. Food and Drug Administration (FDA)-approved drugs, hits and their derivatives were manually extracted, curated and compared to known anti-schisto­somal oral drugs in view of establishing trends of calculated critical molecular properties. From this analysis, it was determined that more than 65% of the compounds display cLogD7.4 > 3 values, whereas oxamniquine, metrifonate and praziquantel (PZQ), previous and currently used oral anti-schisto­somal drugs, possess lower cLogD7.4 values (≤2.5). Furthermore, the lipophilicity associated with PZQ corresponds to a highly permeable and sparingly soluble compound, characteristics that favor drug absorption and compound penetration in the parasite. These physicochemical properties together with PZQ’s anti-schisto­somal activity make PZQ an essential medicine for the treatment of schisto­somiasis and demonstrate the importance of finding the right balance among potency (e.g., EC50 < 5 and 0.5 μM), cell permeability (e.g., Papp > 2 × 106 cm/s) and kinetic aqueous solubility (e.g., >10 μM) to provide high-quality hits and/or leads for the discovery of new oral anti-schisto­somal therapeutics

Analysis of the Physicochemical Properties of Anti-Schistosomal Compounds to Identify Next-Generation Leads

To investigate the physicochemical properties of anti-schisto­somal compounds reported between 2008 and 2023, a simple but extensive literature scrutiny was conducted. Keywords were searched in Chemical Abstracts Service (CAS) SciFinder and primary medicinal chemistry and pharmacology literature to locate publications with compounds displaying ex vivo and/or in vivo anti-schisto­somal activity. A total of 57 repurposed U.S. Food and Drug Administration (FDA)-approved drugs, hits and their derivatives were manually extracted, curated and compared to known anti-schisto­somal oral drugs in view of establishing trends of calculated critical molecular properties. From this analysis, it was determined that more than 65% of the compounds display cLogD7.4 > 3 values, whereas oxamniquine, metrifonate and praziquantel (PZQ), previous and currently used oral anti-schisto­somal drugs, possess lower cLogD7.4 values (≤2.5). Furthermore, the lipophilicity associated with PZQ corresponds to a highly permeable and sparingly soluble compound, characteristics that favor drug absorption and compound penetration in the parasite. These physicochemical properties together with PZQ’s anti-schisto­somal activity make PZQ an essential medicine for the treatment of schisto­somiasis and demonstrate the importance of finding the right balance among potency (e.g., EC50 < 5 and 0.5 μM), cell permeability (e.g., Papp > 2 × 106 cm/s) and kinetic aqueous solubility (e.g., >10 μM) to provide high-quality hits and/or leads for the discovery of new oral anti-schisto­somal therapeutics

A New Method for the Synthesis of Chiral β-Branched α-Amino Acids

A new method for the synthesis of chiral β-branched α-amino acids based on a copper-mediated directed allylic substitution reaction with Grignard reagents is reported. This is the first case in which a δ-stereogenic center is controlling the diastereoselectivity of an o-DPPB-directed allylic substitution. Depending on the alkene geometry of the starting material either diastereomer, anti or syn, is accessible with good levels of acyclic stereocontrol

Short Access to (+)-Lupinine and (+)-Epiquinamide via Double Hydroformylation

Short and efficient access to (+)-lupinine and (+)-epiquinamide by means of an unprecedented double hydroformylation of a bis-homoallylic azide followed by a tandem catalytic hydrogenation/reductive bis-amination is reported

Venn diagram presenting the overlap of structures in the St. Jude, Novartis and GSK datasets.

<p>The data was generated using Pipeline Pilot 8.5, and displayed using R 2.14.1.</p

Selection process for the Malaria Box.

<p>Selection process for the Malaria Box.</p

Principal Component Analysis plots.

<p>Chemical diversity of the GSK, Novartis and St Jude libraries displayed (Panel A); Overlap in chemical diversity of the combined datasets and the commercially available compounds (Panel B); Overlap in chemical diversity of the commercially available compounds where the drug-like and probe-like chemotypes were annotated (Panel C).</p

St Jude's, Novartis and GSK datasets profiled with respect to molecular weight, the number of hydrogen-bond donors, ALogP and N+O (nitrogen count plus oxygen count).

<p>St Jude's, Novartis and GSK datasets profiled with respect to molecular weight, the number of hydrogen-bond donors, ALogP and N+O (nitrogen count plus oxygen count).</p

Correlation (Log scale) between the <i>P. falciparum</i> 3D7 and K1 EC₅₀s for the Malaria Box compounds resulting from the confirmatory screen.

<p>Displayed with Vortex (v2012.11.17233) Dotmatics Limited 2007, 2012.</p