Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase.

Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.

Syntheses of pseudoceramines A-D and a new synthesis of spermatinamine, bromotyrosine natural products from marine sponges.

Herein we report the total syntheses of pseudoceramine A-D (2-5) and spermatinamine (1) isolated from the marine sponge Pseudoceratina sp. Direct acyl substitution of α-hydroxyiminoesters with amine nucleophiles was developed as a key transformation. The synthetic compounds confirm the reported structures and importantly gives access to non-symmetrical spermine based natural products carrying two different bromotyrosine building blocks. Our new synthesis of spermatinamine is two steps shorter and more efficient than the previously reported sequence.

Synthesis of [4-(2-hydroxyphenyl)thiazol-2-yl]methanones as potential bioisosteres of salicylidene acylhydrazides.

A focused library of [4-(2-hydroxyphenyl)thiazol-2-yl]methanones was prepared in a four-step synthesis with the aim to obtain potent inhibitors of type III secretion in Gram-negative bacteria. The compounds are potential bioisosteres of salicylidene acylhydrazides that are a known class of type III secretion inhibitors.

Chiral N-heterocyclic carbene ligands for asymmetric catalytic oxindole synthesis.

The Pd-catalysed asymmetric intramolecular alpha-arylation of amide enolates containing heteroatom substituents gives chiral 3-alkoxy or 3-aminooxindoles in high yield and with enantioselectivities up to 97% ee when a new chiral N-heterocyclic carbene ligand is used.

Convenient synthesis of 3-alkoxy-3-aryloxindoles by intramolecular arylation of mandelic amides.

Medicinally important 3-alkoxy-3-aryloxindoles are conveniently prepared by the rapid microwave-promoted palladium-catalyzed intramolecular enolate arylation of mandelate-derived anilides.