A comprehensive benchmark investigation of quantum chemical methods for carbocations.

The application of various density functional approximations (DFAs) and an emphasis on popular methods without any consensus have prevailed in computational studies dedicated to carbocations. More importantly, an extensive and rigorous benchmark investigation on density functionals for the class is still lacking. To close this gap, we present a comprehensive benchmark study of quantum chemical methods on a series of classical and nonclassical carbocations, the CARBO33 dataset. We evaluate a total of 107 DFT methods from all rungs giving particular attention to double hybrid density functionals as the potential of the class has been largely undermined in the context of carbocations. To support our findings, DLPNO-CCSD(T) at the complete basis set (CBS) limit and W1-F12 are used as reference methods. Our results indicate that the composite CBS-QB3 method performs poorly and should not be adopted for target energies. Oftentimes, the tested DFAs of a lower rung perform better than several DFAs in a higher rung of Perdew's "Jacob's ladder". Nonetheless, double hybrids DSD-PBEP86-NL and ωB97X-2-D3(BJ) stand out by showing the overall best performance. Among the hybrids evaluated, about half of them show mean absolute deviation (MAD) below 1.1 kcal mol-1, including the popular hybrids M06-2X and mPW1PW91. In this family, MN15-D3(BJ) performs particularly well (MAD = 0.77 kcal mol-1) displaying reliable results across various tests. Highly popular B3LYP exhibited one of the worst performances (MAD = 4.74 kcal mol-1), and we do not recommend its application to carbocations. We also assess the 24 general-purpose basis sets of single- up to quadruple-ζ quality. The best compromise between accuracy and computational cost is achieved with cc-pVTZ followed by def2-TZVP. Computations on larger structures of general interest, including terpene carbocations, are also presented for selected DFT methods confirming general trends in the results.

Do Double-Hybrid Exchange-Correlation Functionals Provide Accurate Chemical Shifts? A Benchmark Assessment for Proton NMR.

A benchmark density functional theory (DFT) study of 1H NMR chemical shifts for data sets comprising 200 chemical shifts, including complex natural products, has been carried out to assess the performance of DFT methods. Two new benchmark data sets, NMRH33 and NMRH148, have been established. The meta-GGA revTPSS performs remarkably well against the NMRH33 benchmark set (mean absolute deviation (MAD), 0.10 ppm; maximum deviation (max), 0.26 ppm) with the smallest MAD of all evaluated functionals. The best-performing double-hybrid density functional (DHDF), revDSD-BLYP (MAD, 0.16 ppm; max, 0.35 ppm), performs similarly to hybrid-GGA methods (e.g., mPW1PW91/6-311G(d) (MAD, 0.15 ppm; max, 0.36 ppm)), but at a considerably higher computational cost. The results indicate that currently available double-hybrid DFT methods offer no benefit over GGA (including hybrid and meta) functionals in the calculation of 1H NMR chemical shifts.

On the virtues of automated quantitative structure-activity relationship: the new kid on the block.

Quantitative structure-activity relationship (QSAR) has proved to be an invaluable tool in medicinal chemistry. Data availability at unprecedented levels through various databases have collaborated to a resurgence in the interest for QSAR. In this context, rapid generation of quality predictive models is highly desirable for hit identification and lead optimization. We showcase the application of an automated QSAR approach, which randomly selects multiple training/test sets and utilizes machine-learning algorithms to generate predictive models. Results demonstrate that AutoQSAR produces models of improved or similar quality to those generated by practitioners in the field but in just a fraction of the time. Despite the potential of the concept to the benefit of the community, the AutoQSAR opportunity has been largely undervalued.

Development of a pharmacophore for cruzain using oxadiazoles as virtual molecular probes: quantitative structure-activity relationship studies.

Chagas's is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. According to the World Health Organization, 7 million people are infected worldwide leading to 7000 deaths per year. Drugs available, nifurtimox and benzimidazole, are limited due to low efficacy and high toxicity. As a validated target, cruzain represents a major front in drug discovery attempts for Chagas disease. Herein, we describe the development of 2D QSAR ([Formula: see text] = 0.81) and a 3D-QSAR-based pharmacophore ([Formula: see text] = 0.82) from a series of non-covalent cruzain inhibitors represented mostly by oxadiazoles (lead compound, IC50 = 200 nM). Both models allowed us to map key intermolecular interactions in S1', S2 and S3 cruzain sub-sites (including halogen bond and C‒H/π). To probe the predictive capacity of obtained models, inhibitors available in the literature from different classes displaying a range of scaffolds were evaluate achieving mean absolute deviation of 0.33 and 0.51 for 2D and 3D models, respectively. CoMFA revealed an unexplored region where addition of bulky substituents to produce new compounds in the series could be beneficial to improve biological activity.

Advances and Progress in Chagas Disease Drug Discovery.

Chagas disease represents a serious burden for millions of people worldwide. Transmitted by the protozoan parasite Trypanosoma cruzi, this neglected tropical disease causes more than 10,000 deaths each year and is the main cause of heart failure in Latin America, where it is endemic. Although most cases are concentrated in Latin American countries, Chagas disease has been increasingly reported in non-endemic regions, where the low level of public awareness on the subject contributes to the growing prevalence of the disease. The available medicines are characterized by several safety and efficacy drawbacks that prevent millions of people, particularly those with advanced disease, from receiving adequate treatment. This urgent need has stimulated the emergence of diverse initiatives dedicated to the research and development (R&D) of novel therapeutic agents for Chagas disease. Public-private partnerships have been responsible for a significant increase in the investments in R&D programs and major advancements have been achieved over the past ten years. A number of collaborative projects have been leveraged by this organizational model, which privileges sharing of data, expertise, and resources between research institutions and pharmaceutical companies. Among the current strategies employed by these consortia, target-based and phenotypic screenings have achieved the most promising results. This article provides an overview on the current status and recent advances in Chagas disease drug discovery.

Cellulose acetate butyrate/poly(caprolactonetriol) blends: Miscibility, mechanical properties, and in vivo inflammatory response.

This study reports the results of the characterization of cellulose acetate butyrate and polycaprolactone-triol blends in terms of miscibility, swelling capacity, mechanical properties, and inflammatory response in vivo. The cellulose acetate butyrate film was opaque and rigid, with glass transition (T g ) at 134℃ and melting temperature of 156℃. The cellulose acetate butyrate/polycaprolactone-triol films were transparent up to a polycaprolactone-triol content of 60%. T g of the cellulose acetate butyrate films decreased monotonically as polycaprolactone-triol was added to the blend, thus indicating miscibility. FTIR spectroscopy revealed a decrease in intramolecular hydrogen bonding in polycaprolactone-triol, whereas no hydrogen bonding was observed between cellulose acetate butyrate and -OH from polycaprolactone-triol. The increase in polycaprolactone-triol content in the blend decreased the water uptake. An increase in polycaprolactone-triol content decreased the modulus of elasticity and increased the elongation at break. A cellulose acetate butyrate/polycaprolactone-triol 70/30 blend implanted in rats showed only an acute inflammatory response 7 days after surgery. No change in inflammation mediators was observed.

Unravelling the stereoselectivity in 6-exo-trig radical cyclization of alpha,beta-unsaturated ester-tethered sugars. A tale of two stereocenters.

A computational investigation on the origin of the stereoselectivity of 6-exo-trig radical cyclization of alpha,beta-unsaturated ester-tethered sugars has revealed that a boat-like transition state, which keeps the ester in a planar conformation, holds the chiral information. Following this model, the stereocenter to which the ester functionality is connected reports the chirality to the newly formed stereocenter via a 1,4-transfer mechanism.

Indirect approach to C-3 branched 1,2-cis-glycofuranosides: synthesis of aceric acid glycoside analogues.

Aceric acid (3-C-carboxy-5-deoxy-alpha-l-xylofuranose) residues are present in pectic polysaccharide rhamnogalacturonan II (RG II) in the form of synthetically challenging 1,2-cis-glycofuranosides. To access synthetic fragments of RG II incorporating aceric acid, a four-step procedure based on C-2 epimerisation of initially prepared 1,2-trans-glycofuranoside was developed. Readily available derivatives of branched-chain l-lyxofuranose bearing a 3-C-vinyl group as a masked 3-C-carboxyl group were investigated as potential precursors of aceric acid units. In the first step of the procedure, installation of a participating group at C-2 of the furanose ring ensured stereocontrol of the O-glycosylation, which was carried out with the thioglycoside of 2-O-acetyl-3,5-di-O-benzyl-3-C-vinyl-L-lyxofuranose. After the glycosylation step, the 2-O-acetyl group was removed, the free 2-OH group was oxidised and the resulting ketone was finally reduced to form the C-3-vinyl-L-xylofuranoside. The use of L-Selectride in the key reduction reaction was essential to achieve the required stereoselectivity to generate 1,2-cis-furanoside.

Synthesis of triazole-linked pseudo-starch fragments.

Rapid assembly of starch fragment analogues was achieved using 'click chemistry'. Specifically, a pentadecasaccharide and two hexadecasaccharide mimics containing two parallel maltoheptaosyl chains linked via [1,2,3]-triazoles to glucose or maltose core were synthesised using Cu(I)-catalyzed [3+2] dipolar cycloaddition of azidosaccharides and 4,6-di-O-propargylated methyl alpha-d-glucopyranoside and 6,6'- and 4',6'-di-O-propargylated p-methoxyphenyl beta-maltoside.